Cardiovascular disorders associated with cocaine use: myths and truths

Pharmacology & Therapeutics 97 (2003) 181 – 222

Associate editor: G.E. Billman

Cardiovascular disorders associated with cocaine use: myths and truths Mark M. Knuepfer* Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, 1402 S. Grand Boulevard, St. Louis, MO 63104, USA

Abstract Cocaine produces a pattern of cardiovascular responses that are associated with apparent myocardial ischemia, arrhythmias, and other lifethreatening complications in some individuals. Despite recent efforts to better understand the causes of cocaine-induced cardiovascular dysfunction, there remain a number of unanswered questions regarding the specific mechanisms by which cocaine elicits hemodynamic responses. This review will describe the actions of cocaine on the cardiovascular system and the evidence for the mechanisms by which cocaine elicits hemodynamic and pathologic responses in humans and animals. The emphasis will be on experimental data that provide the basis for our understanding of the mechanisms of cardiovascular toxicity associated with cocaine. More importantly, this review will identify several controversies regarding the causes of cocaine-induced cardiovascular toxicity that as yet are still debated. The evidence supporting these findings will be described. Finally, this review will outline the obvious deficits in our current concepts regarding the cardiovascular actions of cocaine in hope of encouraging additional studies on this grave problem in our society. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Myocardial infarction; Coronary vasospasm; Sympathetic nervous system; Cardiomyopathies; Cardiotoxicity; Cardiac function Abbreviations: AMI, acute myocardial infarction; HERG, human ether-a-go-go-related gene; 5-HT, serotonin; IL, interleukin; mGluR, metabotropic glutamate receptor; NMDA, N-methyl-D-aspartate; TNF, tumor necrosis factor.

Contents 1. 2. 3.

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Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . History of cocaine use. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacological actions of cocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Local anesthetic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Monoamine reuptake inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Other actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Cocaine distribution and metabolism . . . . . . . . . . . . . . . . . . . . . . Clinical observations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Cardiac responses to cocaine and hypotheses . . . . . . . . . . . . . . . . . . 4.2. Pathological observations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Central nervous system and cerebrovascular complications . . . . . . . . . . . 4.4. Additional toxic responses to cocaine . . . . . . . . . . . . . . . . . . . . . . Variable responsivity to cocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hemodynamic responses to cocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Arterial pressure and heart rate responses . . . . . . . . . . . . . . . . . . . . 6.2. Myocardial responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Vascular responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Specific questions regarding the actions of cocaine . . . . . . . . . . . . . . . . . . . 7.1. Does cocaine produce its cardiotoxic effects by eliciting coronary vasospasm? . 7.2. By what mechanism does cocaine constrict coronary blood vessels? . . . . . .

* Tel.: 314-577-8542; fax: 314-577-8233. E-mail address: [email protected] (M.M. Knuepfer). 0163-7258/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. doi:10.1016/S0163-7258(02)00329-7

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7.3. 7.4.

Does cocaine produce myocardial infarction? . . . . . . . . . . . . . . . . . . . . Does cocaine produce myocardial ischemia by enhancing platelet aggregation to produce thrombosis? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5. Does cocaine produce myocardial ischemia due to enhanced myocardial workload with inadequate increases in coronary blood supply? . . . . . . . . . . . . . . . . 7.6. Does cocaine produce its cardiotoxic effects by eliciting ventricular arrhythmias? . 7.7. Does cocaine alter myocardial function and blood flow due to increased sympathetic nerve activity?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.8. Does chronic exposure to cocaine enhance the possibility of adverse cardiovascular responses? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.9. Does cocaine produce immediate or delayed cardiotoxicity?. . . . . . . . . . . . . 7.10. What treatments are appropriate for ameliorating acute cardiac toxicity to cocaine? . 7.10.1. a-Adrenoceptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . 7.10.2. b-Adrenoceptor antagonists. . . . . . . . . . . . . . . . . . . . . . . . . 7.10.3. Ca2+ channel antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . 7.10.4. Anticoagulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.10.5. Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.10.6. Bicarbonate and nitrovasodilators . . . . . . . . . . . . . . . . . . . . . 7.10.7. Anticholinergics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.10.8. Cardiovascular complications of treatments for cocaine addiction . . . . . 8. Special considerations for experimental studies . . . . . . . . . . . . . . . . . . . . . . . 9. Remaining challenges and summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Overview The widespread use of cocaine has stimulated some interest in the research community to improve our understanding of the actions of this drug. Cocaine is responsible for considerably more hospital admissions than any other illicit drug [Drug Abuse Warning Network (DAWN) Report, NIDA, 2001: www.samhsa.gov/oas/dawn.htm], emphasizing the importance of understanding the mechanism by which cocaine produces toxicity. The incidence of cocaine toxicity is likely to be substantially underreported, since many cocaine-related deaths are not classified as such (Young & Pollock, 1993). The National Institutes of Health (Bethesda, MD, USA) estimated the cost of illicit drug use for hospital care, criminal behavior, and lost income during 1992 at $97.7 billion (NIDA Notes, 13[4], 1998: www.drugabuse.gov/NIDA_Notes). In 2000, the National Household Surveys on Drug Abuse (Substance Abuse and Mental Health Services Administration, United States Department of Health and Human Services) reported that 25 million people reported using cocaine at some time, and 1.5 million people in the United States use it currently. It is very likely that a considerable proportion of these users may be at risk for cocaine-related cardiovascular diseases because there is evidence that cocaine, in susceptible individuals, could produce alterations in the myocardium and vasculature that may go undetected yet lay the groundwork for cardiac disease, atherosclerosis, or hypertension in later life. While numerous experimental studies and case reports describing the cardiovascular effects of cocaine have been published, our

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understanding of the causes of cocaine-induced cardiovascular toxicity is still highly speculative. In this article, I will briefly review the history of cocaine use and describe its known pharmacologic actions. I will also provide an overview of the reported adverse cardiovascular responses to cocaine and the current hypotheses regarding the causes of undesirable effects in humans. After presenting an overview of the known actions of cocaine on the cardiovascular system, I will present several questions that have been asked regarding the responses to and mechanisms of action of cocaine. I will answer these questions as best as possible using experimental data in humans and in animals. In addressing these issues, I will emphasize specific areas in which additional research is needed to answer many of these questions. Since there are a number of effects of cocaine that might contribute to cardiovascular dysfunction in sensitive individuals, I will provide clinical findings for specific responses, followed by experimental data from human and animal studies that might clarify the mechanisms of action. Finally, I will outline future directions of research that may improve our understanding of cocaine-induced cardiovascular disease. These observations address a prominent cause of cardiovascular disease in our society and offer new hope to minimize the adverse effects.

2. History of cocaine use Cocaine has been used as a pharmacological tool for centuries, if not millennia. Several excellent reviews describing the early history of cocaine use are available

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(Das, 1993; Karch, 1989; Johanson & Fischman, 1989; Petersen, 1977; Rappolt et al., 1979; Van Dyke & Byck, 1982). The earliest use of cocaine is believed to be in South America, where the native population discovered that the leaves of the coca plant (Erythroxolon coca), when chewed, appeared to help overcome weariness and altitude sickness. As in many ancient societies, the use of coca leaves as a mild euphoriant was controlled by religious leaders. For example, the Incas believed that the coca plant was a gift from the Sun god and used coca leaves traditionally in ceremonies. Although the historical record of potential cardiovascular problems associated with chewing coca leaves is incomplete, there appears to be no known reports of adverse effects of any type with oral ingestion of cocaine in this manner. By the mid-nineteenth century, cocaine was isolated by Gaedicke and purified and named by Niemann in Germany. Its use became widespread, as it was added to wine, elixirs, and potions. A soft drink that later became Coca Cola2 was developed using coca leaves as flavoring. Although von Anrep (1880) previously had suggested that cocaine might be useful as a local anesthetic, the first medicinal use of cocaine in Europe is believed to be by Koller in 1884 as a local anesthetic for ocular surgery. Cocaine was widely used for this purpose until it was reported that cocaine produced ischemia and subsequent sloughing of the corneal epithelium (Catterall & Mackie, 2001). With the widespread use of cocaine in many elixirs and drinks, the predisposition to addiction became apparent. This led to the curtailment of its use first by the Pure Food and Drug Act in 1906, requiring labeling of medications with all constituents, then by the Harrison Narcotics Act in 1914, limiting its use to prescription medications. Currently, its only approved pharmacologic use is as a local anesthetic for topical use on mucous membranes of the nasal, oral, or laryngeal cavities. Due to the intoxicating euphoria produced by cocaine, its illicit use has waxed and waned despite the risks. After the rise of amphetamine-related deaths in the 1960s and early 1970s, cocaine use as an apparent substitute psychostimulant rose significantly. Methods of self-administration evolved also. Intravenous use became more popular in the 1970s as those accustomed to intravenous amphetamine administration began to use cocaine. The difference between intranasal and intravenous administration is described by cocaine users as substantial, with intravenous use providing a more rapid rise in plasma concentrations, described as a ‘‘rush’’ by users (Javaid et al., 1978; Fischman, 1984; Johanson & Fischman, 1989; Sherer, 1988). Presumably this is due to a more rapid rise in plasma levels (Javaid et al., 1978; Resnick et al., 1977), and is more likely to produce addiction and cardiovascular toxicity. Siegel (1979) predicted that the rapid development of freebase and crack forms in the late 1970s would enhance the incidence of cardiovascular toxicity. This is likely due to the ability of the freebase to be volatilized for pulmonary absorption, leading to more rapid increases in plasma

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cocaine levels similar to those obtained with intravenous administration (Isenschmid et al., 1992; Jeffcoat et al., 1989). As expected, the use of cocaine became associated with significant toxicity typically due to cardiovascular complications by the 1980s. Currently, the illicit use of cocaine may be waning slightly. From 1999 to 2000, there was a slight decrease in reported recent use of cocaine, whereas use of methamphetamine increased (National Household Surveys on Drug Abuse, Substance Abuse and Mental Health Services Administration, DHHS, 2001: www.sambsa.gov/oas/nhsda/ 2klnhsda/Vol1/toc.htm). Despite this, cocaine-related hospital admissions in 2000 were still considerably greater (174,896 patients) than methamphetamine-related incidences [13,513 patients, Drug Abuse Warning Network (DAWN) Report, NIDA, 2001: www.samhsa.gov/oas/ dawn.htm]. This may result from current trends of using more potent forms of cocaine. The use of intravenous and smoked cocaine bode ill for reducing the incidence of adverse clinical presentations associated with cocaine use. The substantial costs of cocaine use to our health care system and to society cannot be calculated until the extent of sustained alterations to the cardiovascular system caused by cocaine use can be better estimated. Therefore, a clear understanding of the actions of cocaine could be not only of scientific interest, but may provide insight into potential treatments of toxicity and into the causes of cardiac dysfunction in general.

3. Pharmacological actions of cocaine Cocaine has two well-defined pharmacologic actions: it is a local anesthetic and a monoamine reuptake blocker. In addition, there are several other purported actions of cocaine that may be responsible for its unusual euphoric, addictive, and toxic effects. These effects will be discussed briefly, although other reviews have dealt with these properties in greater detail (Johanson & Fischman, 1989; Kuhar et al., 1991; Ritchie & Greene, 1990; Sherer, 1988). In this review, the pharmacologic description of cocaine will emphasize the actions of cocaine that are likely to be responsible for its cardiovascular effects. 3.1. Local anesthetic Cocaine has long been known to be a local anesthetic, and it is believed to be the only naturally occurring agent used for this purpose. Therapeutic local anesthetics depend on the ability of agents to interfere with Na + channel activity, thereby reducing or blocking nerve conduction. Cocaine is known to pass into the Na + channel and to bind on the inside of the membrane to inhibit further conduction of Na + ions through the membrane in electrically active cells, such as myocardial and nerve cells (Crumb & Clarkson, 1990; Hille, 1977; Przywara & Dambach, 1989;

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Weidmann, 1955). Cocaine produces a use-dependent blockade that is rapidly reversible. Numerous analogues with these qualities have been developed as local anesthetics. Unlike other local anesthetics, cocaine also produces euphoria, which led to its widespread abuse (Johanson & Fischman, 1989; Kuhar et al., 1991; Sherer, 1988). It has been argued that other local anesthetics may also produce euphoria, elicit self-administration, and evoke similar cardiovascular responses (Van Dyke et al., 1979; Woolverton & Balster, 1979), although this has not been verified by others (Fischman et al., 1983; Tella & Goldberg, 1998). In any case, it is clear that cocaine is considerably more potent in eliciting specific behavioral responses and addictive behavior. 3.2. Monoamine reuptake inhibitor Cocaine is also capable of interfering with monoamine reuptake systems in catecholaminergic and serotonergic neurons. Early experiments demonstrated that cocaine enhanced the actions of norepinephrine and epinephrine (Fro¨hlich & Loewi, 1910; Furchgott et al., 1963; Trendelenburg, 1959). Cocaine is a competitive antagonist for neuronal uptake of catecholamines via the energy-dependent, uptake I pump (MacMillan, 1959; Muscholl, 1961; Wise, 1984). It is believed that the prominent behavioral effects of cocaine, including the euphoria, are a result specifically of blockade of dopamine reuptake (Kuhar et al., 1991; Ritz et al., 1987; Wise & Bozarth, 1987). Excessive dopamine release in the basal ganglia and cortex is fundamental to several of the effects of cocaine and other substances of abuse (Church et al., 1987; Hurd & Ungerstedt, 1989). These include the behavioral arousal, the increase in motor activity, and the self-administration or reinforcement behavior (Dackis & Gold, 1985; Tella, 1995; Tella & Goldberg, 1998; Wise & Bozarth, 1987). There is not clear evidence that dopamine mediates the hemodynamic responsiveness to cocaine since it has been reported that selective dopamine antagonists that interfere with reinforcement behaviors do not alter the initial cardiovascular responses to cocaine in rat or squirrel monkey (Tella & Goldberg, 1998; Schindler et al., 1991), although D1 agonists produce comparable cardiovascular effects as cocaine (Schindler et al., 2002). There is also evidence that other monoamines may be important since it has been reported that mice with dopamine transporter knockouts maintain cocaine reward behavior (Rocha et al., 1998a; Sora et al., 1998). Therefore, the causes of the behavioral, motor, and cardiovascular responses to cocaine are not completely understood. There are a number of therapeutic and experimental agents that interfere with catecholamine reuptake. These include the tricyclic antidepressants and several experimental compounds. Some of these, such as GBR 12909, appear very selective for dopamine uptake and have little or no abuse potential, as determined by self-administration paradigms, yet reduce cocaine self-administration better

than noradrenergic or serotonergic reuptake inhibitors (Rothman & Glowa, 1995; Tella, 1995). Reuptake inhibitors typically have similar effects on the cardiovascular system as cocaine, although they are less potent than cocaine (Knuepfer & Gan, 1997; Rothman et al., 1989; Schindler et al., 2002; Tella, 1995, 1996). Tella (1996) proposed that the acute pressor and heart rate responses to agents that produce local anesthesia and/or monoamine reuptake blockade may be helpful in predicting the abuse potential of agents and for finding treatments for cocaine addiction. Therefore, the unique combination of local anesthetic and reuptake blockade may define the potential euphoric and adverse cardiovascular responses to similar agents (Tella, 1996; Tella & Goldberg, 1998). Cocaine is believed to produce some of its pharmacologic responses by blocking serotonin (5-HT) reuptake. 5-HT is believed to be important in the euphoric effects of cocaine since fluoxetine administration attenuates the positive reinforcing action of cocaine (Grilly & Pistell, 1996). Recently, Rocha et al. (1998b) reported that 5-HT-1b receptor knockout mice have more prolonged locomotor responses to cocaine. Despite this, a number of 5-HT receptor antagonists do not alter a progressive ratio schedule of cocaine administration (Depoortere et al., 1993; LaCosta & Roberts, 1993). Furthermore, 5-HT reuptake knockout mice will continue to selfadminister cocaine (Sora et al., 1998). The cardiovascular responses may not be dependent on 5-HT since selective 5HT reuptake blockers (fluoxetine, zimeldine) do not mimic the hemodynamic responses of cocaine (Tella, 1996; Tella & Goldberg, 1998). Therefore, 5-HT may contribute to responses to cocaine, but are not likely to be critical for its euphoriant or cardiotoxic effects. Recently, Chiamulera et al. (2001) reported that mice with a metabotropic glutamate receptor (mGluR), mGluR5, knockout do not self-administer cocaine. Furthermore, they found that interference with the mGluR5 receptor reduces self-administration. Therefore, although it is possible that a combination of effects on dopaminergic, noradrenergic, and 5-HTergic neurotransmission plays a role in eliciting euphoria, it is likely that a glutamatergic receptor is critical for manifesting this response. The contribution of a-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid-sensitive glutamatergic receptors in mediating the hemodynamic and cardiotoxic effects are not understood yet. In contrast, there is evidence that N-methyl-D-aspartate (NMDA) receptors play a role in behavioral and autonomic responses to cocaine (Rockhold, 1991, 1998) that will be discussed in Section 7.10. 3.3. Other actions Cocaine has also been suggested to act on cholinergic receptors (Miao et al., 1996b; Shannon et al., 1993; Sharkey et al., 1988). Cocaine acts as a competitive inhibitor of M2 muscarinic cholinergic receptors in the heart and brain (Flynn et al., 1992; Sharkey et al., 1988) and in ferret ventricular myocyte contraction by reducing Ca2 + release

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(Miao et al., 1996b; Huang et al., 1997). These may contribute to the hemodynamic responses and cardiovascular toxicity associated with cocaine. This is unlikely except after exposure to high doses, since significant cholinergic binding requires plasma concentrations 20-fold higher than those necessary to produce euphoria (Schneider, 1991). Several additional hypotheses have been proposed to explain the pathologic alterations of the myocardium. Smith (1973) proposed that cocaine could enhance the responses to catecholamines and thereby exacerbate potential toxicity. More recently, it has been suggested that the cocaineinduced increase in circulating and cardiac catecholamines that could result in increased free radicals, such as O3 and noradrenochrome that could promote the development of cardiomyopathies (Jiang & Downing, 1990; Rump et al., 1995), atherosclerosis, and vasculitis. Wilkins (1992) hypothesized that the actions of catecholamines could be exacerbated by enhanced corticosteroid levels. Cocaine elevates corticosteroids by enhancing adrenocorticotropic hormone release (Calogero et al., 1989; Levy et al., 1991; Moldow & Fischman, 1987; Rivier & Vale, 1987). Corticosteroids are known to enhance organ toxicity elicited by stress or catecholamine administration (Selye, 1958). Therefore, stimulation of the hypothalamic-pituitary axis could contribute to the acute responses and the pathological alterations in the myocardium and vasculature associated with cocaine use. 3.4. Cocaine distribution and metabolism Plasma levels of cocaine have been determined after oral (Barnett et al., 1981; Van Dyke et al., 1978), intranasal (Barnett et al., 1981; Javaid et al., 1978, 1983; Jeffcoat et al., 1989; Lange et al., 1989, 1990; Van Dyke et al., 1976), intravenous (Barnett et al., 1981; Booze et al., 1997; Chow et al., 1985; Isenschmid et al., 1992; Javaid et al., 1978, 1983; Jeffcoat et al., 1989; Nayak et al., 1976), or smoked cocaine (Evans et al., 1996; Foltin & Fischman, 1991; Isenschmid et al., 1992; Jeffcoat et al., 1989; Perez-Reyes et al., 1982; Sofuoglu et al., 2000a, 2000b). Peak plasma levels of cocaine after intranasal administration are typically in the range of 100 –500 mg/L, occurring 20 – 40 min after application. These concentrations are rarely associated with apparent signs of toxicity, but they are capable of eliciting euphoria. While experimental studies in humans on the effects of cocaine typically use low doses to avoid toxicity, intravenous or smoked cocaine naturally results in a more rapid onset of hemodynamic responses due to more rapid increases in plasma levels often exceeding 1 – 2 mg/L (Evans et al., 1996). Moreover, it has been reported that arterial plasma levels may greatly exceed venous levels for 10 –20 min after cocaine administration (Evans et al., 1996), further enhancing exposure of the brain, heart, and other organs to cocaine. It is more difficult to obtain reliable values for peak plasma levels after illicit use of cocaine. In addition, the

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toxicity is often delayed, so plasma levels may not reflect concentrations at the time of the perception of toxicity when cardiac ischemia may occur. Nonetheless, the evidence from a number of studies of patients presenting with apparent myocardial ischemia after cocaine use suggests that during angina pectoris, the concentration of cocaine in the venous blood is not very high. Plasma levels are typically 0.4– 6 mg/L (Escobedo et al., 1991; Karch et al., 1998; LoraTamayo et al., 1994; Mittleman & Wetli, 1984, 1987; Simpson & Edwards, 1986; Tazelaar et al., 1987; Virmani et al., 1988). Peak plasma concentrations vary considerably between individuals, particularly after nasal insufflation (Javaid et al., 1978; Van Dyke et al., 1976) and intravenous or smoked cocaine (Evans et al., 1996). This likely contributes to varying incidences of cardiovascular toxicity, although there is evidence that the dose-response relationship to toxicity is poor (Lora-Tamayo et al., 1994; Mittleman & Wetli, 1984, 1987; Smart & Anglin, 1987; Wetli & Wright, 1979). The elimination half-life of cocaine in plasma has been determined to be between 40 and 90 min in humans (Ambre et al., 1988; Barnett et al., 1981; Chow et al., 1985; Javaid et al., 1983; Wilkinson et al., 1980). The half-life of cocaine in dogs (72 min) and monkeys (72 – 78 min) are roughly similar (Misra, 1976). In contrast, elimination is considerably faster (12 –18 min) in rats (Booze et al., 1997; Ma et al., 1999; Misra, 1976; Nayak et al., 1976) and mice (Benuck et al., 1987). Therefore, rodents are capable of tolerating greater doses and may require these to mimic adverse effects in humans. Rats may also require more frequent dosing to simulate chronic cocaine use experimentally. There is evidence that repeated treatment may result in enhanced plasma levels of cocaine or may reduce the rate of metabolism (Nayak et al., 1976; Pan et al., 1991; Pettit et al., 1990; Weiss & Gawin, 1988). These changes could account for greater toxicity, and certainly point out the need for repeated or binge dosing in experimental studies. Furthermore, it has been suggested that repeated dosing may result in sequestration of cocaine in brain and fat tissue (Benuck et al., 1987; Boylan et al., 1996; Nayak et al., 1976). This could also lead to enhanced levels with repeated dosing. These considerations must be taken into account in designing appropriate experimental models to study the actions of cocaine. It has been suggested that cocaine metabolites may be involved in producing some of the cardiovascular and behavioral responses to cocaine. While a small amount of cocaine is excreted unchanged in the urine, the majority (75 –90%) of ingested cocaine is hydrolyzed by plasma and liver esterases, and possibly undergoes spontaneous hydrolysis to ecgonine methyl ester and benzoylecgonine (Jatlow, 1988; Nayak et al., 1976). Hepatic microsomes N-demethylate a small amount of cocaine to produce norcocaine (Hawks et al., 1975; Kloss et al., 1983; Misra et al., 1974; Nayak et al., 1976). Benzoylecgonine and ecgonine methyl ester are not very active in producing cardiovascular responses and pre-

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sumably toxicity (Branch & Knuepfer, 1994b; Erzouki et al., 1993; Morishima et al., 1999). In contrast, norcocaine is pharmacologically active, eliciting similar cardiovascular effects (Erzouki et al., 1993; Misra et al., 1975; Morishima et al., 1999), and is at least as toxic as cocaine (Mets & Virag, 1995; Misra et al., 1975). The small amount of norcocaine produced and its roughly equipotent effects suggests that it could contribute to hemodynamic responses, but is not likely to be a major determinant of toxicity. Ethanol is often consumed before and during cocaine self-administration (Grant & Hartford, 1990), yet this combination may enhance toxicity in humans (Farre´ et al., 1993; Foltin & Fischman, 1988; Perez-Reyes & Jeffcoat, 1992; Perez-Reyes et al., 1994). Concomitant cocaine and ethanol administration has been reported to produce more severe cardiodepression (Henning et al., 1994; Mueller et al., 1997; Uszenski et al., 1992) and cardiomyopathies (Maillet et al., 1994) than cocaine alone. It has been suggested that the toxicity may result from the formation of an active metabolite, cocaethylene, that is more toxic than cocaine or ethanol alone (Farre´ et al., 1993; Perez-Reyes & Jeffcoat, 1992). Henning & Wilson (1996) reported that cocaethylene or cocaine depressed cardiac contractility and stroke volume to an equivalent extent, but not as much as cocaine plus ethanol in a-chloralose-anesthetized, ventilated dogs. Therefore, cocaethylene may exacerbate the cardiodepression evoked by cocaine. Cocaethylene is also more potent than cocaine in inhibiting the human ether-a-go-go-related gene (HERG)-encoded K + channel (Ferreira et al., 2001). This would result in inhibition of the delayed rectifier K + current and would enhance acute cocaine-induced arrhythmogenesis (O’Leary, 2001). Using isolated ferret myocytes, Qiu and Morgan (1993) reported that cocaethylene not only reduced the peak increase in intracellular Ca2 + (like cocaine), but also reduced Ca 2 + responsiveness in myofilaments. The enhanced cardiodepression may be responsible for some of the reported cases of delayed toxicity to cocaine (Ascher et al., 1988; Benchimol et al., 1978; Isner et al., 1986; Nademanee et al., 1989; Schachne et al., 1984; Tardiff et al., 1989) since plasma cocaethylene levels rise later due to relatively slow hepatic metabolism and a prolonged half life (Hart et al., 2000; Perez-Reyes & Jeffcoat, 1992). Studies in human subjects suggest that cocaethylene is less potent in producing tachycardia or in eliciting euphoria (Hart et al., 2000; Perez-Reyes & Jeffcoat, 1992). The frequent combined use of cocaine and ethanol complicate interpretation of the causes of toxicity in humans. Cocaine has also been reported to interact with nicotine. Both cocaine and nicotine increase dopamine turnover and c-fos expression in the nucleus accumbens and striatum, with cross-tolerance to cocaine after exposure to nicotine (Izenwasser & Cox, 1992; Pich et al., 1997). It has been reported that nicotine combined with cocaine produces a synergistic effect on dopamine release in the nucleus accumbens of the rat (Gerasimov et al., 2000), yet nicotine

pretreatment (via a transdermal patch) reduces the euphoria reported after cocaine administration without affecting the pressor, heart rate, and skin temperature responses to cocaine in humans (Kouri et al., 2001). In contrast, it has been reported that nicotine and cocaine interact to produce synergistic effects on arterial pressure and cardiac contractility in conscious dogs (Mehta et al., 2001). Since nicotine, like cocaine, is a risk factor for cardiac disease (Benowitz, 1988), the possibility that smoking could enhance the incidence of myocardial dysfunction after cocaine use remains a distinct likelihood. In summary, cocaine acts on a number of different receptor systems from ion channels to selective monoamine uptake systems. Since cocaine crosses the blood-brain barrier, the resulting effects on central neural transmission are quite complex. It is certain that the combination of actions of cocaine on these systems is important not only in explaining its potent euphoriant properties, but also in causing cardiovascular dysfunction. Moreover, the relative sensitivity of individuals to these actions due to underlying cardiovascular abnormalities or receptor responsivity also varies, which further complicates explanations for cocaineinduced toxicity. It is necessary to understand the specific responses noted in humans in order to define the outcome of these various actions of cocaine.

4. Clinical observations 4.1. Cardiac responses to cocaine and hypotheses Numerous reviews have described the occurrence of serious, and sometimes fatal, heart disease in individuals using cocaine (Benowitz, 1993; Benzaquen et al., 2001; Billman, 1995; Cregler & Mark, 1986; Karch & Billingham, 1988; Kloner et al., 1992; Lange & Willard, 1993; Minor et al., 1991; Om et al., 1992; Rezkalla et al., 1990; Rowbotham & Lowenstein, 1990; Pellegrino & Bayer, 1998; Virmani, 1991). The most common symptom is chest pain, occasionally associated with ventricular fibrillation, elevated S-T segment, and/or serum creatine phosphokinase levels, suggesting myocardial ischemia (Isner et al., 1986; Karch & Billingham, 1988; Karch et al., 1995; Kossowsky & Lyon, 1984; Minor et al., 1991; Mittleman & Wetli, 1984, 1987; Pasternack et al., 1985; Simpson & Edwards, 1986; Smith, 1973; Smith et al., 1987; Zimmerman et al., 1991). Cocaine use significantly increases the prevalence of chest pain in the general population (Mittleman et al., 1999; Qureshi et al., 2001), suggesting a causative relationship. Several hypotheses have been suggested to explain the causes of acute angina pectoris and apparent myocardial ischemia (Table 1). These include (1) local occlusive spasm of a major coronary artery or diffuse vasoconstriction with resultant transmural ischemia (Isner et al., 1986; Kossowsky & Lyon, 1984; Pasternack et al., 1985; Smith, 1973); (2) a2adrenergic stimulation of platelet aggregation, leading to

M.M. Knuepfer / Pharmacology & Therapeutics 97 (2003) 181–222 Table 1 Hypothetical mechanisms of acute adverse responses to cocaine Focal coronary vasospasm Enhanced platelet aggregation leading to thrombosis Excessive increase in myocardial workload Inhibition of Na + channels leading to conduction block and arrhythmias Interactions with Ca2 + and/or K + channel activity Generalized coronary vasoconstriction Direct toxic action on coronaries or myocardium Seizures leading to hypertensive crisis and/or cardiovascular collapse

thrombotic occlusion of a coronary artery (Howard et al., 1985; Isner et al., 1986; Kossowsky & Lyon, 1984; Kugelmass et al., 1993; Rod & Zucker, 1986; Simpson & Edwards, 1986); (3) excessive increases in heart rate and arterial pressure, resulting in subendocardial ischemia due to enhanced myocardial oxygen demand (Isner et al., 1986; Mathias, 1986; Pasternack et al., 1985); (4) a local anesthetic action, leading to ventricular fibrillation (Beckman et al., 1991; Fraker et al., 1990; Kabas et al., 1990; Nanji & Filipenko, 1984; Sherief & Carpentier, 1991); (5) coronary vasoconstriction due to excessive Ca2 + release (Billman, 1995; Premkumar, 1999); (6) a direct toxic action on the coronary vasculature and/or heart (Foy et al., 1991; Morcos et al., 1993; Nu´n˜ez et al., 1994a; Rhee et al., 1990; Uszenski et al., 1992); and (7) seizures causing hypertension followed by cardiovascular collapse (Ruttenber et al., 1997; Wetli et al., 1996). None of these hypotheses can explain all cases since symptoms vary widely. Furthermore, few cases have documented coronary vasospasm (Ascher et al., 1988; Vincent et al., 1983; Zimmerman et al., 1987) or thrombotic occlusion of a major coronary artery (Hadjimiltiades et al., 1988; Kossowsky & Lyon, 1984; Minor et al., 1991; Simpson & Edwards, 1986; Smith et al., 1987), despite numerous attempts to verify this using angiography. Signs of occlusive disease or significant risk factors, other than smoking, are rarely present (Frishman et al., 1989; Gitter et al., 1991; Isner et al., 1986; Karch & Billingham, 1988; Kossowsky & Lyon, 1984; Majid et al., 1990; Minor et al., 1991). In addition, it is likely that various combinations of these actions are responsible for precipitating chest pain. The evidence for each of these hypotheses will be discussed with regard to specific hypotheses in Section 7. Several unique actions of cocaine have been suggested as additional potential mechanisms leading to cardiac ischemia and cardiotoxicity. These include a unique combination of behavioral and local anesthetic actions (Tella, 1996); a direct muscarinic action (Huang et al., 1997; Miao et al., 1996b; Shannon et al., 1993; Sharkey et al., 1988; Wang et al., 1995); a cholinesterase deficiency, leading to impaired cocaine metabolism (Hoffman et al., 1992a; Jatlow et al., 1988; Om et al., 1993); and effects on L-type Ca2 + and HERG K + ion channels (Ferreira et al., 2001; Josephson & Sperelakis, 1976; O’Leary, 2001; Thomas et al., 1991; Zhang et al., 2001) or excitation-contraction coupling (Stewart et al., 1991). These mechanisms, possibly contrib-

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uting to toxicity, will be discussed in the light of evidence from experimental studies in Sections 6 and 7. 4.2. Pathological observations Cocaine use is associated with pathological alterations in myocardial structure (Isner et al., 1986; Karch, 1991; Karch & Billingham, 1988; Karch et al., 1995, 1998; Kolodgie et al., 1991; Peng et al., 1989; Simpson & Edwards, 1986; Tazelaar et al., 1987; Virmani et al., 1988; Virmani, 1991). These include contraction bands, a cardinal sign of myocardial dysfunction, signs of focal myocyte necrosis, and inflammatory cell infiltrates (Karch, 1991; Karch & Billingham, 1988; Karch et al., 1995, 1998; Isner et al., 1986; Simpson & Edwards, 1986; Virmani et al., 1988; Virmani, 1991). Since risk factors are often not demonstrable in patients with cocaine-related cardiotoxicity (Frishman et al., 1989; Gradman, 1988; Isner et al., 1986; Lange & Willard, 1993; Minor et al., 1991), the reasons for cardiac dysfunction remain elusive. Ultrastructural alterations included diffusely distributed, focal abnormalities, sarcoplasmic vacuolization, and myofibrillar loss (Peng et al., 1989) similar to those changes observed in sudden cardiac death of non-ischemic origin (Baroldi, 1965; Gitter et al., 1991; Reichenbach & Benditt, 1970). Several effects of repeated cocaine use have been identified (Table 2). These will be discussed below (see also Section 7.8). Diffuse cardiomyocyte abnormalities and myocarditis are consistent findings in cocaine-related death (Duell, 1987; Hogya & Wolfson 1990; Isner & Chokshi, 1991; Karch & Billingham, 1988; Kloner et al., 1992; Peng et al., 1989; Rezkalla et al., 1990; Tazelaar et al., 1987; Virmani et al., 1988; Wiener et al., 1986). These differ from evidence of myocardial or coronary ischemic disease, where confluent regions are characterized by coagulation necrosis or thrombotic occlusion is documented. The diffuse pattern of patchy fibrosis and contraction band necrosis are similar to those described after behavioral stress (Cebelin & Hirsch, 1980; Corley et al., 1977; Raab, 1966; Selye, 1958; Tanaka et al., 1980); excessive sympathoexcitation (Giudicelli et al., 1980; Raab, 1966; Reichenbach & Benditt, 1970); epinephrine, norepinephrine, or isoproterenol administration (Haft, 1974; Moss & Schenk, 1970; Reichenbach & Benditt, 1970; Selye, 1958; Todd et al., 1985a); or adrenal medullary tumors (Rosenbaum et al., 1987; Van Vliet et al., 1966). The characteristic ultrastructural alterations include myofi-

Table 2 Effects of chronic cocaine use Accelerated atherosclerosis Cardiomyocyte apoptosis Sympathoadrenal-induced myocyte damage Chronic arrhythmias Cardiac hypertrophy Dilated cardiomyopathy

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brillar disruption, dilated sarcoplasmic reticulum, fibrosis, mitochondrial alterations, and discrete lesions within cardiomyocytes. These aberrations are often associated with susceptibility to arrhythmogenesis. At the light microscopic level, contraction band necrosis, interstitial edema, and sites of necrosis have been described after cocaine use, behavioral stress, or exposure to catecholamines. Interestingly, these interventions produce highly variable pathologic alterations when comparing experimental subjects, despite identical treatments (Corley et al., 1977; Haft, 1974; Moss & Schenk, 1970; Tanaka et al., 1980; Todd et al., 1985a, 1985b). We can conclude that (1) the structural myocardial changes elicited by cocaine appear to be similar to those evoked by sympathoadrenal hyperactivity and (2) individuals may or may not manifest these pathologic alterations. The mechanisms for catecholamine-induced, diffuse (non-ischemic) cardiomyopathies are likely to result from activation of a1-adrenergic receptors (Downing & Lee, 1983; Lee & Sponenberg, 1985; Reichenbach & Benditt, 1970) and the ensuing enhanced Ca2 + entry or Ca2 + overload (Billman, 1995; Carpentier et al., 1998; Flaim & Zelis, 1981; Fleckenstein et al., 1975; Todd et al., 1986). Alternatively, it has been suggested that cocaine may enhance contractility due to direct facilitation of L-type Ca2 + channel currents in the vasculature and cardiomyocytes (Carpentier et al., 1998; Premkumar, 1999). This contradicts reports suggesting cocaine inhibits Ca2 + channel activity in cardiac myocytes (Huang et al., 1997; Josephson & Sperelakis, 1976; Kimura et al., 1992; Renard et al., 1994; Stewart et al., 1991; Thomas et al., 1991). Qiu and Morgan (1993) demonstrated that cocaine decreased intracellular Ca2 + concentrations directly in isolated myocytes, and suggested that this may oppose the sympathomimetic effects of cocaine on Ca2 + entry. Therefore, cocaine may have opposite direct and indirect effects on Ca2 + channel activity that complicates the elucidation of their contribution to cocaine-induced cardiomyopathies. Other adverse effects of cocaine on myocardial structure have been described. Chronic cocaine use has been associated with the development of cardiac hypertrophy in humans (Brickner et al., 1991; Chakko et al., 1992; Escobedo et al., 1992; Cigarroa et al., 1992; Gitter et al., 1991; Karch et al., 1995, 1998; Om et al., 1993) and animals (Besse et al., 1997; Sutliff et al., 1996). Since cardiac hypertrophy is a known risk factor for sudden cardiac death, it has been suggested that this could contribute to cocaineinduced cardiotoxicity. The presence of hypertrophy without concomitant angiogenesis could also lead to a predisposition to a mismatch between oxygen supply and demand during cardiac stimulation. Several investigators suggested that repeated cocaine administration accelerates the development of atherosclerosis and coronary arteriosclerosis in humans (Bacharach et al., 1992; Dressler et al., 1990; Kolodgie et al., 1991, 1992; Virmani et al., 1988) and animals (Egashira et al., 1991;

Kolodgie et al., 1993). Wang et al. (1995) reported that repeated cocaine and cholesterol administration to pigs reduced vasodilation due to b-adrenoceptor and to some endothelium-dependent vasodilators. On the other hand, considerable evidence suggests that inflammatory processes may mediate or at least initiate atherosclerotic plaque formation and rupture (Blake & Ridker, 2001; Fazio & Linton, 2001; Hansson, 2001; Kaul, 2001). Acute or chronic cocaine administration alters immune and inflammatory function (Pellegrino & Bayer, 1998; Wang et al., 1994; Watzl & Watson, 1990). For example, cocaine treatment enhances interleukin (IL)-6 and tumor necrosis factor (TNF)-a levels (Wang et al., 1994). Both IL-6 and TNF-a have been implicated in atherosclerotic plaque formation (Blake & Ridker, 2001; Fazio & Linton, 2001; Kaul, 2001). In addition, deficits in myocardial antioxidant systems may also be responsible for the alterations in cardiomyocytes, including apoptosis or programmed cell death (Devi & Chan, 1999; Zhang et al., 1999). Therefore, the high incidence of myocarditis and atherosclerosis associated with cocaine use (Karch & Billingham, 1988; Virmani et al., 1988) may be due to excessive cytokines, reactive oxygen species, or enhanced apoptosis. Cocaine use has been reported to be associated with dilated cardiomyopathy in some cases (Chokshi et al., 1989; Hogya & Wolfson, 1990; Sauer, 1991; Wiener et al., 1986; Willens et al., 1994). Dilated cardiomyopathy may contribute to susceptibility to myocardial ischemia and other cardiovascular complications associated with cocaine use in those individuals that are particularly sensitive to cocaine. Unfortunately, these observations are not completely documented since these studies have not excluded the possibility of acute or chronic ischemic disease by arteriography and verified primary cardiac muscle disease by biopsy. Therefore, the extent to which these cardiac responses contribute to cocaine-induced myocardial dysfunction is not clear. 4.3. Central nervous system and cerebrovascular complications Cocaine use has been associated with a number of abnormalities in the cerebral vasculature. The most common complications are hemorrhagic or thromboembolic strokes (Altura & Gupta, 1992; Brust & Richter, 1977; Levine & Welch, 1988; Lichtenfeld et al., 1984; Sauer, 1991; Wang et al., 1990). The hemorrhagic strokes have been suggested to result from a direct inhibitory effect of cocaine on platelet aggregation (Jennings et al., 1993). In addition, cocaine has been implicated in causing cerebral hemorrhage, possibly by rupturing cerebral aneurysms due to acute hypertension (Lowenstein et al., 1987; Howard et al., 1985; Tardiff et al., 1989) or cytokine-induced plaque rupture. Since cocaine use is often not reported (Young & Pollock, 1993), it is likely that these and other complications associated with cocaine self-administration are not known to be risk factors on hospital admission.

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Cocaine can produce seizures in individuals, although this is typically associated with very high doses such as those noted in body packers (Jonsson et al., 1983; Miner & Marley, 1995; Suarez et al., 1972). There may be a subset of the population susceptible to idiosyncratic seizures since convulsions have been noted at moderate doses (Winbery et al., 1998). Cocaine has also been shown to produce kindled seizures, suggesting that chronic exposure may enhance sensitivity to seizures (Downs & Eddy, 1932; Miller et al., 2000; Wilson & Holbrook, 1978). In addition, some individuals are vulnerable to cocaine-induced excited delirium (Ruttenber et al., 1997; Wetli & Fishbain, 1985). This syndrome is characterized by hyperthermia; extreme behavioral agitation; and, in some cases, violent behavior. Cocaine-induced excited delirium often results in a delayed cardiovascular collapse and sudden cardiac death. There may be an increase in the incidence of cocaine-induced excited delirium during the past decade (Wetli et al., 1996). Therefore, seizures and excited delirium are responsible for at least some of the toxic effects of cocaine. Cocaine elicits hyperthermia in humans (Campbell, 1988; Roberts et al., 1984; Rowbotham et al., 1987; Winbery et al., 1998) and animals (Catravas & Waters, 1981; Ishizuka et al., 1989, 1990; Rockhold et al., 1991a). Cocaine administration in humans produces a pressor response concomitantly with a decrease in skin temperature (Walsh et al., 1996). This redistribution in blood flow suggests that cocaine interferes with hypothalamic dopamine receptors regulating body temperature (Callaway & Clark, 1994). Excessive dopamine release in the preoptic area would be expected to result in cutaneous vasoconstriction and corresponding increases in core temperature. Catravas and Waters (1981) demonstrated that prevention of cocaine-induced hyperthermia, either with drug treatments or a cold room, prevented death after administering a lethal dose of cocaine to dogs. Similarly, Ishizuka et al. (1989, 1990) reported that cocaine-induced hyperthermia was positively correlated with the incidence of convulsions and death in restrained spontaneously hypertensive rats. The causes of cocaine-induced hyperthermia are not understood yet; the data further implicate a role for the CNS and neural control of the peripheral circulation in evoking toxicity. 4.4. Additional toxic responses to cocaine Several reports have linked cocaine use with a number of other pathological effects, including rhabdomyolysis and renal failure (Anand et al., 1989; Di Paolo et al., 1997; Herzlich et al., 1988; Kanel et al., 1990; Merigian & Roberts, 1987; Nzerue et al., 2000; Pogue & Nurse, 1989; Roth et al., 1988), hepatotoxicity (Kanel et al., 1990; Kloss et al., 1984; Mallat & Dhumeaux, 1991; Perino et al., 1987; Poet et al., 1996; Wang et al., 2001), and pulmonary toxicity (Itkonen et al., 1984; Meisels & Loke, 1993; Walsh & Atwood, 1989; Weiss et al., 1981). It is possible that some of these toxic effects are mediated by cardiovascular actions of cocaine

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secondary to ischemia. On the other hand, these adverse effects may be similar to those responsible for the diffuse cocaine-related cardiomyopathies. The diffuse lesions associated with catecholamine or cocaine administration or the combination may be responsible for the causes of cocaineinduced apoptosis and tissue damage (Keller & Todd, 1994; Zhang et al., 1999). Cocaine use also alters immune function (Baldwin et al., 1998; Delafuente & DeVane, 1991; Di Francesco et al., 1992; Knuepfer et al., 2002; Pellegrino & Bayer, 1998; Ruiz et al., 1994; Watzl & Watson, 1990). In some cases, immune deficits may be particularly notable in human immunodeficiency virus positive patients (Baldwin et al., 1998; Chaisson et al., 1989; Chiasson et al., 1991). We reported that exposure to cocaine and endotoxin enhances toxicity in those rats that have greater TNF-a and IL-1b plasma levels (Knuepfer et al., 2002). Although these adverse consequences of cocaine use will not be described in detail in this review, they may contribute to predisposition to cardiovascular disease or immunoincompetency. Cocaine elicits a number of different responses due to its multiple sites of action. This has certainly contributed to the difficulty in understanding the mechanisms of action of the drug and the numerous adverse responses noted above. Therefore, the causes of cocaine toxicity are likely to be dependent on a variety of actions of cocaine. I propose that another confusing factor may be the individual variability to the apparent cardiotoxic effects of cocaine that has been referred to by many investigators studying human or animal models.

5. Variable responsivity to cocaine Considering the extent of the clinical problem that cocaine use presents and the considerable resources of the National Institute of Drug Abuse and health care organizations devoted to resolving the problem, it is unusual that we seem no closer to understanding or preventing adverse responses to cocaine now than we were three decades ago when the problem became obvious. The single greatest difficulty in understanding the actions of cocaine lies in determining the causes of varying sensitivity to cocaine in individuals since several observations suggest that susceptibility to cocaine-induced cardiotoxicity varies widely in humans (Lora-Tamayo et al., 1994; Karch et al., 1998; Karch & Billingham, 1995; Minor et al., 1991; Mittleman & Wetli, 1984, 1987; Smart & Anglin, 1987; Wetli & Wright, 1979). Clinical reports of cocaine toxicity describe a poor dose-response relationship with respect to the occurrence of myocardial ischemia and related electrocardiographic alterations (Amin et al., 1990; Minor et al., 1991; Lange & Willard, 1993), coronary vasoconstriction (Flores et al., 1990; Lange et al., 1989, 1990; Moliterno et al., 1994), cardiomyopathies (Isner et al., 1986; Karch & Billingham, 1988; Karch et al., 1995, 1998; Kloner et al., 1992;

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Minor et al., 1991; Smart & Anglin, 1987), and to morbidity (Lora-Tamayo et al., 1994; Mittleman & Wetli, 1984, 1987; Smart & Anglin, 1987; Wetli & Wright, 1979). Furthermore, the symptoms preceding lethality vary greatly in individuals (George, 1991a, 1991b; Miner & Marley, 1995; Ruttenber et al., 1997). It is clear from these data that a small fraction of those using cocaine experience toxicity (Miller et al., 1977), yet we are unable to predict which individuals are at risk. Several investigators have suggested that genetic variability in responsivity to cocaine is likely to be responsible for the predisposition to cardiac disease in some individuals (Isner & Chokshi, 1989; Minor et al., 1991; Mittleman & Wetli, 1984; Rezkalla et al., 1990; Virmani et al., 1988). With advances in our ability to identify polymorphisms, variations in a number of different hemodynamic responses have been described, including substantial interindividual variability in coronary vasomotor responses (Heusch et al., 2001). Future studies on the genetic causes of cocaine sensitivity are likely to shed light on other causes of cardiac disease. Despite this evidence, few experimental models have addressed variability in responsiveness that could contribute to our understanding of the causes of variable sensitivity in humans. A wide variety of parameters appear to differ in response to cocaine, as summarized in Table 3. A number of findings suggest that genetic factors contribute significantly to variability in responsiveness to cocaine and other psychoactive agents with regard to the incidence of seizures, hyperthermia, coronary vasoconstriction, hemodynamic responsiveness and central sympathoexcitatory, drugseeking, and locomotor responses. Predisposition to cocaineinduced convulsions varies widely in animals (George, 1991a, 1991b; Ishizuka et al., 1989, 1990; Miner & Marley, 1995; Shi et al., 1999; Wilson & Holbrook, 1978), and has been noted with moderate cocaine exposure in humans (Campbell, 1988; Winbery et al., 1998). Ishizuka et al. (1989, 1990) demonstrated that they could divide restrained spontaneously hypertensive rats into those with a hyperthermic response to intravenous or intraperitoneal cocaine and those that had a hypothermic response. Those rats experiencing cocaine-induced hyperthermia had a greater susceptibility to convulsions and death with a cocaine infusion. These data suggest that individuals vary in their sensitivity to cocaine and that those with a more pronounced hyperthermia are more prone to experience toxicity. There-

Table 3 Variable individual responsiveness to cocaine Increase in systemic vascular resistance Change in heart rate and cardiac output Coronary vasoconstriction Hyperthermia Arrhythmias Behavioral sensitization Locomotor activity Convulsions Lethality

fore, differences in thermoregulatory mechanisms and/or cutaneous vasoconstriction correlate with the predisposition to cocaine toxicity. A better understanding of the genetic factors responsible for differences in responsiveness and toxicity may shed light on the causes of toxicity. Our laboratory has studied varying responses to cocaine in conscious rats (for a review, Knuepfer & Mueller, 1999). In the first report on this phenomenon (Branch & Knuepfer, 1993), we noted differences in hemodynamic responses to cocaine such that some rats had consistent decreases in cardiac output and substantial increases in systemic vascular resistance in response to cocaine (named vascular responders), whereas others had little change or an increase in cardiac output and a smaller increase in systemic vascular resistance (mixed responders). Since pressor responses were equivalent in both groups, the designation as vascular and mixed responders reflected the causes of the pressor responses in individual rats. We reported that vascular responders were more prone to develop cardiomyopathies and hypertension with repeated cocaine administration (Knuepfer et al., 1993a; Branch & Knuepfer, 1994a). We saw similar patterns of responsiveness to other psychoactive agents (Branch & Knuepfer, 1994a; Knuepfer & Gan, 1997; Mueller et al., 1997) and to conditioned or unconditioned behavioral stress (Knuepfer et al., 1993b, 2001, 2002; Muller et al., 2001), leading us to conclude that these response patterns were not due to the specific pharmacologic effects of cocaine per se, but were likely due to the arousal evoked by these various stimuli (Knuepfer & Mueller, 1999). A similar difference in hemodynamic responsiveness to acute stress in humans has been reported (Brod, 1963; Herd, 1991), and it has been reported to correlate with the predisposition to develop hypertension (Light et al., 1992; Turner et al., 1992) and heart disease (Eliot, 1988, 1992). In a similar manner, we demonstrated that repeated stress in outbred Sprague-Dawley rats was capable of producing a sustained elevation in arterial pressure in vascular responders, but not mixed responders (Muller et al., 2001). Therefore, we proposed that the rat may provide a model to better understand the variability in responsiveness that predisposes some humans to heart disease and to hypertension (Knuepfer & Mueller, 1999). We identified another critical difference between vascular and mixed responders. Vascular responders have significantly greater increases in renal sympathetic nerve activity in chloralose-anesthetized or conscious rats compared with mixed responders (Branch & Knuepfer, 1994b; Purcell et al., 2001). Greater sympathetic responsiveness has been reported to be responsible for increased susceptibility to heart disease, ventricular arrhythmias, stroke, and hypertension (Hasking et al., 1986; Julius, 1993; Korpelainen et al., 1999; Leenan, 1999; Manolis et al., 1994; Natelson, 1983; Meredith et al., 1991). Therefore, this may explain a potential cause of predisposition of vascular responders to hypertension and heart disease, as well as revealing a mechanism by which cocaine exerts cardiotoxicity.

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There has been considerable variability noted in the predisposition to cocaine-induced pressor responses (Miao et al., 1996a), arrhythmogenesis (Inoue & Zipes, 1988), coronary vasoconstriction (Lange et al., 1989, 1990; Flores et al., 1990; Moliterno et al., 1994), and lethality (Shi et al., 1999). Miao et al. (1996a) reported that systemic vascular responses in two strains of swine under isoflurane anesthesia were considerably different. Cocaine elicited a decrease in mean arterial pressure and rate pressure product in Yorkshire swine, whereas it produced an increase in mean arterial pressure and rate pressure product in Yucatan miniature swine. Miniature swine had greater increases in coronary vascular resistance and smaller increases in systemic vascular resistance compared with Yorkshire swine (Miao et al., 1996a), suggesting genetic variability in cocaine responsiveness. Tella and co-workers (1990, 1991) reported that the heart rate response to cocaine in squirrel monkeys varied greatly between and within strains. Shi and co-workers (1999) demonstrated that a rat strain that is prone to kindlinginduced seizures is more resistant to cocaine-induced toxicity compared with a rat strain that is resistant to seizures. Likewise, we reported that vascular responders are more susceptible to cocaine-induced toxicity (J. B. Williams, S. M. Keenan, Q. Gan, & M. M. Knuepfer, submitted for publication). We also have evidence that kindling-resistant rats are more likely to be vascular responders than kindlingsensitive rats of this strain (T. B. Stonely & M. M. Knuepfer, unpublished data). Therefore, these data suggest that differences in predisposition to cardiovascular toxicity to cocaine and epileptic seizures may be related. These data also suggest that differences in hemodynamic responses noted in humans might be better understood by studying different genetic strains of animals. Furthermore, improved understanding of the specific genomic variability would improve our understanding of the causes of variability. There are differences between individual rats in cocaineinduced locomotor responses, behavioral sensitization, central dopamine responsivity, and predisposition to self-administration (Benuck et al., 1987; Cailhol & Mormede, 1999; Glick et al., 1994; Haile & Kosten, 2001; Morse et al., 1995; Ruth et al., 1988; Shuster et al., 1977). Greater locomotor responsiveness to cocaine or amphetamine has been shown to be correlated with enhanced dopamine overflow in the basal ganglia and with a predilection towards self-administration of psychostimulants (Deminiere et al., 1989; Hooks et al., 1992; Piazza et al., 1989; Segal & Kuczenski, 1987). Considerable variability in the reinforcing and self-administration of cocaine has been demonstrated in humans, rhesus monkeys, and rats, suggesting that predisposing factors for drug abuse differ in the population (Bozarth et al., 1989; Davidson et al., 1993; Deneau et al., 1969; Morse et al., 1995). Differences in locomotor responsiveness may also reflect varying predisposition to cocaine-induced seizures (Campbell, 1988; George, 1991a, 1991b; Winbery et al., 1998). Self-administration of cocaine in Lewis rats was more dependent on D2 receptors, whereas Fisher 344 rats

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were more dependent on D1 receptors (Haile & Kosten, 2001). These differences suggest that variable responsiveness of central neuronal systems is responsible for differences in drug seeking and in reactivity to drugs. Some of the differences in responsiveness to cocaine may be in the susceptibility to cocaine-induced increases in adrenal catecholamine release. There is substantial interstrain variability in adrenal catecholamine release in response to acute stress (McCarty & Kopin, 1978). Han et al. (1996) reported that cocaine caused a dramatic enhancement of plasma catecholamine levels in some rats with exercise. This increase could contribute to hemodynamic response variability predisposing susceptible individuals to catecholamine-induced vasoconstriction, arrhythmias, or cardiomyopathies. These findings, along with confounding factors such as multi-substance abuse, poor nutrition, smoking, and greater risk-taking behaviors in general (Hudgins et al., 1995), make it virtually impossible to identify causes of toxicity from clinical observations in cocaine users alone. The variability also makes it particularly difficult to determine the mechanism of the toxic effects in an animal model since we are not certain which animal might reflect varying sensitivity to cocaine and what parameters might be variable. It also entails a considerably larger number of subjects that would have to be studied to identify a subset of the population at risk. The inherent variability in responsiveness and susceptibility to toxicity is arguably the single greatest obstacle that has prevented investigators from identifying the mechanisms of action of cocaine on the cardiovascular and nervous systems. In the following section, I will discuss specific studies addressing the causes of cocaine-induced cardiovascular responses. Due to the inherent response variability, I will clarify which responses appear consistent and which may be responsible for varying sensitivity.

6. Hemodynamic responses to cocaine 6.1. Arterial pressure and heart rate responses Cocaine produces cardiovascular responses that reflect its sympathomimetic actions (Table 4). Cocaine administration produces an increase in arterial pressure and little change or an increase in heart rate in humans (Cascella et al., 1989; Fischman & Schuster, 1982; Fischman et al., 1976, 1983,

Table 4 Acute effects of cocaine Increase in arterial pressure Increase in heart rate (variable) Coronary vasoconstriction (variable) Increase in myocardial oxygen demand Hyperthermia due to cutaneous vasoconstriction (variable) Increased locomotor activity (variable)

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1985; Foltin et al., 1995; Resnick et al., 1977; Rowbotham et al., 1987; Walsh et al., 1996). The pressor response and tachycardia are attenuated by labetalol or phentolamine, suggesting that they require activation of adrenergic receptors (Boehrer et al., 1993; Lange et al., 1989; Sofuoglu et al., 2000a). The experiments in humans have not determined whether responses are due to the enhancement of the actions of central or peripheral catecholamines, but most investigators imply a peripheral site of action for cocaine. Experiments in humans have not distinguished between a central and peripheral mechanism of action on catecholaminergic nerve terminals. Cocaine-induced pressor responses are also reduced by verapamil, presumably due to the impairment of catecholamine-induced vasoconstriction (Negus et al., 1994). There is also evidence that there is a significant placebo effect that contributes to cocaine-induced arterial pressure and heart rate responses (Cascella et al., 1989). Experimental animal models have examined the mechanisms by which cocaine increases arterial pressure and heart rate. The cardiovascular effects of cocaine have been studied in a number of different species, including monkeys, dogs, pigs, sheep, cats, rabbits, rats, and mice. In conscious animals, a pressor response is noted after cocaine administration and, typically, an increase in heart rate that is more variable between animals or species. While greater control over hemodynamic variables and more extensive instrumentation is possible under anesthesia, it is clear from a number of studies comparing anesthetized and conscious animals that anesthesia alters responsiveness to cocaine (Fraker et al., 1990; Knuepfer & Branch, 1992; Pitts et al., 1987; Schwartz et al., 1989b; Tella et al., 1992a; Wang et al., 1999; Wilkerson, 1988). This includes an attenuation in the pressor response and the tachycardia in response to cocaine (Knuepfer & Branch, 1992; Pitts et al., 1987; Tella et al., 1990; Wang et al., 1999; Wilkerson, 1988). In fact, several investigators reported that higher doses of cocaine elicit a decrease in arterial pressure in anesthetized animals (Beckman et al., 1991; Friedrichs et al., 1990; Hale et al., 1991; Hayes et al., 1991; Hernandez et al., 1996; Pierre et al., 1985; Sutliff et al., 1999). Since this is clearly contrary to responses noted in conscious animals or humans, the presence of anesthesia is at least one likely source of confusion in efforts designed to determine the mechanism of action of cocaine. Another confounding point is the fact that many studies, particularly those in rats, did not report responses to cocaine other than arterial pressure and heart rate. Arterial pressure, in particular, is a complex response representing the combination of cardiac effects and the sum of the vascular responses in numerous organs. As such, alterations in responsiveness are particularly difficult to interpret when addressing the mechanism of action of a drug. Furthermore, the attenuation by drug treatments of the pressor response has often been suggested to reflect the propensity toward preventing cardiac toxicity (Schindler et al., 1992a; Tella et al., 1992a; Wilkerson, 1989). No such relationship has been

clearly demonstrated, particularly considering the modest increases in arterial pressure and relatively short duration of the increase noted in many studies. Therefore, the findings of studies on treatments for cardiotoxicity using these criteria may not be conclusive. As such, the effects of selective drug treatments on arterial pressure will only be discussed in this review with regard to more specific changes in cardiac or vascular responses. In this manner, we will be more likely to discern possible mechanisms of action. 6.2. Myocardial responses Cardiac responses to cocaine have been assessed in a limited number of experiments in humans (Boehrer et al., 1992; Eisenberg et al., 1993; Pitts et al., 1998). Cocaine elicits a brief increase in cardiac contractility, but little change in ejection fraction or ventricular wall motion. These effects have been noted even with ST segment elevation, suggesting that there is little evidence for a mismatch between myocardial oxygen demand and cardiac work or for direct myocardial depressant effects of cocaine (Eisenberg et al., 1993). Experiments using animal models have also been performed. Most of the early experiments were performed under pentobarbital, pentothal, a-chloralose, halothane, or isoflurane anesthesia (Abel et al., 1989; Beckman et al., 1991; Bedotto et al., 1988; Boylan et al., 1996; Friedrichs et al., 1990; Hale et al., 1989a, 1991; Henning, 1993; Kuhn et al., 1990; Liu et al., 1993; Miao et al., 1996a; Nu´n˜ez et al., 1994a, 1994b; Oster et al., 1991; Valentine et al., 1991). As previously mentioned, anesthesia attenuates most cardiovascular responses to cocaine (Fraker et al., 1990; Knuepfer & Branch, 1992; Pitts et al., 1987; Wilkerson, 1988). In anesthetized dogs, cocaine elicits a decrease in contractility and ejection fraction and an increase in left ventricular end diastolic pressure (Abel et al., 1989; Bedotto et al., 1988; Friedrichs et al., 1990; Hale et al., 1989a, 1991; Henning et al., 1994; Henning & Wilson, 1996; Kuhn et al., 1990; Liu et al., 1993; Mehta et al., 1995; Stewart et al., 1963; Uszenski et al., 1992; Wilkerson, 1989). Cocaine causes no change or decrease in cardiac output in anesthetized dogs (Abel et al., 1989; Beckman et al., 1991; Bedotto et al., 1988; Fraker et al., 1990; Liu et al., 1993). Therefore, cocaine appears to have a general depressant effect on myocardial function in anesthetized animals. These results are, for the most part, substantially different than those obtained from conscious humans and animals. In conscious animals, cocaine has been reported to elicit an increase in contractility and left ventricular end diastolic and systolic pressure (Billman & Lappi, 1993; Billman, 1993a, 1993b, 1994; Pagel et al., 1992, 1994; Shannon et al., 1993, 1996; Stambler et al., 1993) and an increase in cardiac output (Pagel et al., 1994; Shannon et al., 1996; Stambler et al., 1993). As mentioned in Section 6.1, there was also a consistent increase in arterial pressure and heart

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rate noted in conscious, but not anesthetized, animals. Interestingly, one of the few responses that does not appear to be altered by anesthesia or autonomic blockade is the depression in myocardial function as determined by a decrease in ejection fraction noted in conscious or anesthetized dogs, leading several investigators to suggest that this may be a direct effect of cocaine on the heart (Fraker et al., 1990; Kenny et al., 1992; Liu et al., 1993; Mehta et al., 1995; Pagel et al., 1992; Roig et al., 2000; Uszenski et al., 1992; Wilkerson, 1988). The likelihood of this being responsible for toxicity is tempered by the fact that this response is short-lived. Since cocaine enhances plasma catecholamines and potentiates the actions of released norepinephrine on adrenergic receptors (Fro¨hlich & Loewi, 1910; Trendelenburg, 1959), the cardiostimulatory effects of cocaine might result from enhanced catecholamine-induced stimulation of the heart. Cocaine enhances the pressor and tachycardic responses due to norepinephrine (Graham et al., 1965; Jain et al., 1990; Johnson & Kahn, 1966; Koerker & Moran, 1971; Levy & Blattberg, 1978; Masuda et al., 1980; Sabra et al., 2000) or epinephrine administration (Ruben & Morris, 1952). Several studies suggest that this is not due to endogenous norepinephrine release since cocaine does not enhance sympathetic nerve stimulation-induced increases in arterial pressure and heart rate (Graham et al., 1965; Koerker & Moran, 1971; Matsuda et al., 1979), although some data do not agree with this conclusion (Jain et al., 1990; Masuda & Levy, 1984). Inoue and Zipes (1988) reported that cocaine enhanced the shortening of atrioventricular conduction and the ventricular effective refractory period elicited by norepinephrine, but not by cardiac nerve stimulation. Even low doses of cocaine produced significant cardiomyopathies in the presence of elevated plasma catecholamine levels in anesthetized dogs (Keller & Todd, 1994). Therefore, we can conclude that cocaine enhances the actions of exogenous catecholamines on the myocardium, which may produce prolonged detrimental effects on myocardial structure and function. Cocaine has been suggested to affect the cardiovascular system by acting directly on cholinergic receptors (Flynn et al., 1992; Huang et al., 1997; Miao et al., 1996b; Shannon et al., 1993; Sharkey et al., 1988). Our laboratory noted that atropine methylbromide reduced the decrease in cardiac output and the increase in systemic vascular resistance elicited by cocaine in rats (Knuepfer & Branch, 1992; Knuepfer & Gan, 1999). We suggested that muscarinic receptors on adrenergic nerve terminals might modulate catecholamine release and, therefore, alter cocaine-induced hemodynamic responses (Lavalle´e et al., 1978). Alternatively, it has been reported that muscarinic receptor activation may elicit coronary vasoconstriction in some species (Knight et al., 1991), potentially inducing myocardial ischemia. Wang et al. (1995) reported that cocaine elicited coronary vasoconstriction in vitro that was blocked by a muscarinic antagonist. In addition, atropine methylbromide

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administration inhibited cocaine-induced coronary vasoconstriction in conscious dogs (Shannon et al., 1993). In contrast, the centrally acting atropine sulfate enhanced pressor responses to cocaine in anesthetized dogs (Wilkerson, 1989). The specific contribution of muscarinic receptors to the hemodynamic responses and possible cardiac toxicity to cocaine is not clear yet. 6.3. Vascular responses Few studies have addressed specific changes in regional vascular tone elicited by cocaine. In anesthetized and conscious animals, cocaine has been reported to elicit an increase in systemic vascular resistance (Bedotto et al., 1988; Boylan et al., 1996; Branch & Knuepfer, 1994a; Graham et al., 1965; Liu et al., 1993; Pagel et al., 1992; Stambler et al., 1993). As noted before, anesthesia appears to blunt this since other investigators reported little or no change in systemic vascular resistance in anesthetized dogs (Hale et al., 1991; Kuhn et al., 1990). Despite their observations, Kuhn et al. (1990) proposed that cocaine-induced systemic vasoconstriction was likely due to adrenal release of epinephrine, not norepinephrine. Our data suggest that the initial pressor response (within the first 5– 30 sec) to intravenous cocaine is a result of an increase in systemic vascular resistance in conscious rats (Knuepfer & Branch, 1992; Branch & Knuepfer, 1992, 1994a). The systemic vascular responses are, in part, dependent on increases in mesenteric and hindquarters vascular resistance (skeletal muscle) in anesthetized or conscious rats (Branch & Knuepfer, 1992; Knuepfer & Branch, 1992). After the initial pressor response, a modest pressor response follows that is mediated by mesenteric, but not skeletal muscle, vasoconstriction (Knuepfer & Branch, 1992). In fact, skeletal muscle vasodilation, mediated by activation of b-adrenergic receptors, results and is even noted when motor activity is prevented by anesthesia (Branch & Knuepfer, 1992; Knuepfer & Branch, 1992). We suggested that the vasodilation may result from a baroreflex-induced hindquarters vasodilator response to the initial pressor effects of cocaine (Branch & Knuepfer, 1992). Vascular responses to cocaine also include a cutaneous vasoconstriction that is responsible for cocaine-induced hyperthermia (Callaway & Clark, 1994; Rowbotham et al., 1987; Walsh et al., 1996). Sutliff et al. (1999) reported that cocaine administration reduced blood flow to a number of organs, including the spleen and kidneys, but not the heart, in anesthetized rabbits. It is not clear whether this is due to enhanced central sympathetic nerve activity, enhanced actions of norepinephrine released at the synaptic cleft, and/or greater sympathoadrenal release of catecholamines. Several studies have reported that cocaine elicits a decrease in cerebral blood flow and an increase in cerebral vascular resistance in humans, suggestive of cocaineinduced cerebral vasospasm and ischemia (Gollub et al.,

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1998; Herning et al., 1999; Kaufman et al., 1998; Pearlson et al., 1993; Wallace et al., 1996). Experimental studies have shown that cocaine can cause vasoconstriction (He et al., 1994; Kurth et al., 1993; Madden et al., 1995) and, in combination with methamphetamine, cerebral vasospasm (Wang et al., 1990), although a transient increase in cerebral blood flow has been reported in anesthetized rats (Knuepfer & Branch, 1992; Muir & Ellis, 1993). Alternatively, this response may result from a reduction in neuronal activity since glucose uptake is reduced (London et al., 1990; Van Dyke & Byck, 1982). The mechanisms for these effects of cocaine are not understood yet, nor are the possible contributory roles in cerebrovascular dysfunction. Cocaine may produce sustained alterations in peripheral blood vessels that affect contractile function. For example, coronary vascular lesions were more prevalent in coronary vessels of cocaine users compared with trauma fatalities (Karch et al., 1995). In addition, there is a greater incidence of atherosclerotic disease in cocaine users that would also reduce contractile function (Bacharach et al., 1992; Dressler et al., 1990; Kolodgie et al., 1991, 1992; Virmani et al., 1988). Cocaine-induced abnormalities in connective tissue and in heat-shock protein expression in the aorta suggest that signs of vascular damage after cocaine administration have been reported in animals after cocaine treatment (Blake et al., 1994; Langner & Bement, 1991). These alterations suggest that repeated cocaine use may interfere with normal vascular function. In conclusion, the majority of hemodynamic responses to cocaine obtained in conscious experimental subjects are consistent with a general sympathoexcitatory response. The contribution of vascular responses dependent on direct effects compared with neuronal actions (indirect) is still controversial. Some of the confusion regarding the responses to cocaine in experimental studies arises from conflicting data obtained in anesthetized and conscious animals or from studies in vitro, particularly, those that employ excessive doses of cocaine. These caveats must be considered when reviewing the literature to ascertain the adverse effects of cocaine. The contribution of the autonomic nervous system will be discussed in the following sections.

7. Specific questions regarding the actions of cocaine 7.1. Does cocaine produce its cardiotoxic effects by eliciting coronary vasospasm? Coronary vasospasm is the most commonly ascribed cause of myocardial dysfunction caused by cocaine (Amin et al., 1990; Ayala & Altieri, 1993; Brody et al., 1990; Cregler & Mark, 1985; Howard et al., 1985; Isner et al., 1986; Kossowsky & Lyon, 1984; Kossowsky et al., 1989; Nademanee et al., 1989; Pasternack et al., 1985; Rollingher et al., 1986; Schachne et al., 1984; Zimmerman et al., 1987),

yet in only a few cases, vasospasm has been documented using coronary angiography (Ascher et al., 1988; Vincent et al., 1983; Zimmerman et al., 1987). In many cases, signs of cardiac ischemia due to ECG alterations, such as ST segment elevation and T wave inversions, are the only evidence presented for vasospasm. Vasospasm is often proposed, despite angiographic evidence of normal coronary blood flow and negative responses to ergonovine or cold pressor challenges in the majority of patients (Cregler & Mark, 1985; Halle et al., 1993; Isner et al., 1986; Kossowsky et al., 1989; Majid et al., 1990; Nademanee et al., 1989). Unequivocal proof of coronary vasospasm can only be obtained angiographically (Maseri & Chierchia, 1982). Therefore, either the cocaine-induced vasospasm resolves rapidly, making it clinically difficult to verify, or the diagnosis of vasospasm after cocaine use is often incorrect. Vasospasm has been demonstrated in patients experiencing repeated angina without cocaine use (Hillis & Braunwald, 1978; Maseri et al., 1978; Oliva & Breckenridge, 1977). It is possible that vasospasm is a common diagnosis used to explain non-thrombotic myocardial ischemia in patients with normal appearing coronary arteries, but electrocardiographic signs of ischemia. Considering the paucity of corroborative angiographic evidence, it is not likely that this is a common cause of chest pain after cocaine use. In order to directly demonstrate that cocaine elicits coronary vasoconstriction in humans, Lange, Hillis, and co-workers have performed several studies treating lightly sedated patients with cocaine while performing coronary angiography (Boehrer et al., 1993; Brogan et al., 1991, 1992; Daniel et al., 1996; Flores et al., 1990; Lange et al., 1989, 1990; Moliterno et al., 1994; Negus et al., 1994). Cocaine produced a 21 –33% increase in coronary vascular resistance with no evidence of focal vasospastic events (Brogan et al., 1991, 1992; Flores et al., 1990; Lange et al., 1989, 1990; Moliterno et al., 1994). The dose of intranasal cocaine used was relatively low (2 mg/kg), and it should also be noted that these patients did not experience chest pain. Despite this, some individuals had very profound increases in coronary vascular resistance of > 50– 60% (Brogan et al., 1991; Flores et al., 1990; Lange et al., 1989, 1990), suggesting that there may be a subset of individuals that are particularly sensitive to the coronary vasoconstrictor effects of cocaine. Even in these patients, there was no evidence for acute coronary vasospasm, suggesting that vasospasm is not a common response to cocaine. Moreover, sites of coronary stenosis had substantially greater vasoconstrictor responses to cocaine, further emphasizing the potential problems with inherent coronary vascular disease (Brogan et al., 1991; Flores et al., 1990; Moliterno et al., 1994) that may be accelerated in cocaine users (Bacharach et al., 1992; Dressler et al., 1990; Karch & Billingham, 1995; Kolodgie et al., 1991, 1992; Virmani et al., 1988). Cocaine administration produced a sustained decrease in coronary blood flow in anesthetized dogs and pigs (Abel et al., 1989; Beckman et al., 1991; Billman & Lappi, 1993;

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Hale et al., 1989a, 1991; Henning et al., 1994; Henning & Wilson, 1996; Miao et al., 1996a; Pierre et al., 1985), although a few investigators have noted small increases (Uszenski et al., 1992; Wilkerson, 1989) or little change (Melon et al., 1994; Zimring et al., 1994). Some of the confusion may result from the fact that there may be a biphasic response since cocaine elicits an initial vasodilation followed by vasoconstriction in pentobarbital-anesthetized dogs (Pierre et al., 1985; Valentine et al., 1991). In addition, the canine myocardium contains considerable anastamoses in coronary vessels, unlike humans or pigs. This may affect responsiveness to cocaine or to locally released vasoactive substances and predisposition to ischemia. The only documented indisputable occurrence of cocaine-induced vasospasm in animals appears to have been described by Egashira et al. (1991). They reported that cocaine produced angiographically documented coronary vasospasm in isoflurane-anesthetized pigs at sites where the endothelial barrier was removed. In contrast, later studies provided no evidence for coronary vasospasm, despite microvascular vasoconstriction in anesthetized pigs without endothelial damage (Miao et al., 1996a; Nu´n˜ez et al., 1994b). Kuhn et al. (1992) reported that endothelial denudation had no effect on cocaine-induced reductions in coronary diameter in sufentanil-anesthetized dogs. Oster et al. (1991) reported that cocaine elicited a brief, but profound, reduction in perfusion of the left ventricle using Thallium-201 imaging and microspheres in anesthetized dogs. These changes were suggested to result from coronary vasospasm, possibly of the microvasculature, although microvascular vasospasm could not be differentiated from microvascular vasoconstriction in this study. These changes in coronary blood flow have been suggested to contribute to the potential adverse effects of cocaine and its temporal relationship to cardiac ischemia in humans. Once again, these findings are suspect since cocaine elicited an increase in coronary blood flow in conscious dogs (Fraker et al., 1990; Kenny et al., 1992; Pagel et al., 1994; Shannon et al., 1993, 1995, 1996, 2000) and baboons (Shannon et al., 2000). Several studies have reported that cocaine elicits an increase in coronary vascular resistance in anesthetized (Beckman et al., 1991; Hale et al., 1989a; Kuhn et al., 1990; Miao et al., 1996a; Nu´n˜ez et al., 1994a, 1994b; Uszenski et al., 1992) or conscious animals (Fraker et al., 1990; Pagel et al., 1994; Shannon et al., 1993, 1995, 2000). Using pulsed Doppler flowmetry, our laboratory reported that cocaine elicited a small increase in coronary blood flow and coronary vascular resistance in conscious rats (Mueller & Knuepfer, 1994). We subsequently retracted this finding after discovering an error in the method of recording coronary blood flow (Knuepfer & Mueller, 1999). Nonetheless, these findings are consistent with those of other investigators. There may be important species differences that should also be taken into consideration since it has been shown that

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the cardiovascular responses in conscious dogs and baboons may differ. Shannon et al. (2000) reported that the increase in coronary blood flow to cocaine was greater in dogs, whereas the increase in coronary vascular resistance was greater in baboons, after cocaine administration. More importantly, the dog appeared to compensate for the acute increase in oxygen demand by releasing erythrocytes from the spleen to increase plasma hemoglobin content, providing them with a significantly greater oxygen delivery, whereas baboons responded by increasing myocardial oxygen extraction (Shannon et al., 2000). These observations suggest that species differences in coronary responses may be critical for determining the contribution of coronary vasoconstriction to the incidence of chest pain in humans using cocaine. These are further obfuscated by the possible interindividual variability in animals that may reflect differences in coronary responses reported in humans (Heusch et al., 2001; Flores et al., 1990; Lange et al., 1989, 1990). In summary, it is clear that cocaine elicits an increase in coronary vascular resistance in conscious humans and animals. In this regard, the animal model for studying the mechanisms responsible for coronary vasoconstriction must be chosen carefully. The putative mechanisms will be discussed in the following section. In any case, there is little doubt that studies in conscious rather than anesthetized animals are necessary to study this effect. It is not clear whether the coronary vasoconstriction provokes a significant and sustained ischemia that could lead to angina or structural alterations in the myocardium (Benzaquen et al., 2001). It is likely that cocaine does not typically evoke coronary vasospasm, although it is, and is likely to remain for some time, possible that this is due to the difficulty in clearly differentiating vasospasm from vasoconstriction. 7.2. By what mechanism does cocaine constrict coronary blood vessels? It is clear from observations and experiments in humans that cocaine can elicit coronary vasoconstriction, at least in some individuals. The causes of cocaine-induced coronary vasoconstriction have been investigated both in humans and in animals. While substantial evidence has been accumulated, there is considerable debate regarding the mechanism responsible for coronary vasoconstriction. I will discuss the evidence suggesting that the vasoconstriction is dependent on adrenergic, cholinergic, Ca2 + channel-mediated, or some other direct effect of cocaine on the vasculature. The clinical studies of Lange, Hillis, and co-workers have provided considerable evidence describing the cause of cocaine-induced coronary vasoconstriction (Boehrer et al., 1993; Brogan et al., 1991, 1992; Daniel et al., 1996; Flores et al., 1990; Lange et al., 1989, 1990; Moliterno et al., 1994; Negus et al., 1994). These experiments were performed in cocaine-naı¨ve patients undergoing cardiac catheterization for evaluation of chest pain. As described in Section 7.1, administration of cocaine evoked an average decrease in

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coronary vessel diameter of 13 –21% in normal coronary vessels and an average increase in coronary vascular resistance of 21– 33%. Intracoronary phentolamine prevented the increase in coronary vascular resistance and reduced the pressor response elicited by cocaine (Lange et al., 1989). Labetalol administration reduced the pressor response, but not the coronary vasoconstriction, to cocaine (Boehrer et al., 1993). Intracoronary propranolol administration did not alter the pressor response, but enhanced the decrease in coronary blood flow and the increase in coronary vascular resistance (Lange et al., 1990). Therefore, b-adrenergic receptors appear to be important for ameliorating the coronary effects of cocaine, whereas a-adrenoceptor activation is, at least in part, responsible for the coronary vasoconstriction. This was particularly disturbing since the use of propranolol for treating cocaine-induced chest pain and apparent myocardial ischemia was promoted earlier (Gay, 1982; Rappolt et al., 1977, 1979; Resnick & Resnick, 1984; Gradman, 1988), despite some conflicting evidence suggesting it exacerbated the clinical course of cocaine-related cardiac abnormalities (Ramoska & Sacchetti, 1985; Orr & Jones, 1968; Walsh & Atwood, 1989). Propranolol potentiates coronary artery vasoconstriction in response to a cold pressor test in patients with variant angina, further suggesting that b-adrenoceptor blockade may be inappropriate (Kern et al., 1983). Therefore, if coronary vasoconstriction contributes to the syndrome of cocaine-induced chest pain, b-blockers are contraindicated as a treatment for cardiac toxicity. The effects of adrenoceptor antagonists on responses in animals have been examined by many investigators. Propranolol administration has been reported to enhance the cocaine-induced decrease in coronary blood flow and increase in coronary vascular resistance in anesthetized and conscious dogs (Henning, 1993; Shannon et al., 1993, 1995). In contrast, a-adrenoceptor antagonists have been reported to reduce cocaine-induced coronary vasoconstriction in anesthetized animals (Egashira et al., 1991; Kuhn et al., 1990). Likewise, the combined a- and b-adrenoceptor antagonist labetalol reduced the cocaine-induced increase in coronary blood flow in conscious dogs (Kenny et al., 1992). Ganglionic blockade is also capable of preventing the cocaine-induced coronary vasoconstriction in anesthetized dogs (Liu et al., 1993). Finally, intracoronary cocaine did not produce significant coronary vasoconstriction in humans, dogs, or pigs (Daniel et al., 1996; Shannon et al., 1995; Zimring et al., 1994). These data suggest that aadrenergic receptors in the coronary vasculature are activated by cocaine-induced central sympathetic excitation to produce coronary vasoconstriction. The contribution of the nervous system will be discussed in greater detail in Section 7.7. Ca2 + channel activation is critical for coronary vasoconstriction (Nayler, 1988; Pepine & Lambert, 1988; Taira, 1989). Ca2 + channel antagonists are often used to treat chest pain associated with cocaine use (Ayala & Altieri,

1993; Haines & Sexter, 1987; Nanji & Filipenko, 1984; Schachne et al., 1984; Zimmerman et al., 1987). Ca2 + channel antagonists have also been shown to ameliorate the coronary vasoconstriction in response to cocaine in dogs (Hale et al., 1991). This effect may be due to an impairment of Ca2 + movement necessary for a vasoconstriction or could result from the proposed anticholinergic effects of cocaine on Ca2 + utilization (Huang et al., 1997; Miao et al., 1996b; Sharkey et al., 1988). Atropine attenuated the increase in coronary blood flow in conscious dogs (Shannon et al., 1993), but did not alter coronary responses to cocaine in anesthetized dogs (Wilkerson, 1989). Therefore, the competitive antimuscarinic effects of cocaine may contribute to coronary vascular responsiveness, although it would appear that these responses would reduce Ca2 + influx and coronary vasoconstriction. Responses from intact animals are complex due to the effects of neural reflexes and circulating hormones. A number of studies on the coronary effects of cocaine have been performed in isolated hearts or coronary vessels to determine whether a direct, non-neural coronary vasoconstriction contributes to cardiac ischemia. Cocaine produces a decrease in coronary blood flow or coronary diameter in isolated, perfused dog, rabbit, or rat hearts, although this was typically observed only at relatively high (> 20 mg/L) doses (Avakian et al., 1990; Branch & Knuepfer, 1994b; Rhee et al., 1990; Vitullo et al., 1989). Since plasma levels in all but a few attempted overdose or body packer victims are typically < 10 mg/L and average 0.4 –6 mg/L (Escobedo et al., 1991; Karch et al., 1998; Lora-Tamayo et al., 1994; Mittleman & Wetli, 1984, 1987; Simpson & Edwards, 1986; Tazelaar et al., 1987; Virmani et al., 1988), it is likely that some of these data are irrelevant regarding the mechanism of action in humans. Therefore, there is little evidence from in vitro studies that cocaine produces coronary vasoconstriction by a direct effect in the vast majority of toxic reactions. There is some confusion regarding the participation of catecholamines in the coronary responses to cocaine. Several investigators have suggested that the coronary effects of cocaine are mediated by catecholamines (Carpentier et al., 1998; Shannon et al., 2001; Smith, 1973). Cocaine has been reported to constrict bovine or canine coronary rings even in the presence of a- or b-adrenoceptor blockade (Foy et al., 1991; Jones & Tackett, 1990; Kalsner, 1993). In contrast, others were unable to record an increase in coronary vessel tone in vitro (Egashira et al., 1991; Vargas et al., 1991). Perreault et al. (1993) reported that isolated human epicardial coronary vessels were relaxed by cocaine due to decreases in peak intracellular Ca2 + levels (independent of the sympathetic nervous system). This could result from interference with Ca2 + movement and spikes in intracellular Ca2 + , as suggested by others using cardiac myocytes (Josephson & Sperelakis, 1976; Qiu & Morgan, 1993; Renard et al., 1994; Stewart et al., 1991) or indirectly by a local anesthetic action. Cocaine may also impede nitric

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oxide release by inhibiting the Ca2 + -ATPase pump, thereby limiting the capacity of blood vessels to dilate (Togna et al., 2001). Again, some of the confusion in many of these studies arises from the relatively high cocaine concentrations and sustained exposure described in some of these studies, the lack of sympathetic tone and, possibly, to varying degrees of endothelial damage in isolated vessels. Nonetheless, they do not provide clear evidence for a direct vasoconstrictor effect of cocaine on coronary vessels. The evidence suggests that cocaine increases coronary vascular resistance, but that this increase is modest. The increase in resistance may be blunted by cholinergic, local anesthetic, or Ca2 + channel effects of cocaine. The specific mechanisms responsible are most likely to be observed in conscious animals. Considerable evidence suggests that coronary vasoconstriction results from activation of adrenergic neurons, further supporting the sympathomimetic actions of cocaine. These actions will be addressed in Section 7.7. 7.3. Does cocaine produce myocardial infarction? Many clinical reports suggest that myocardial ischemia occurs frequently after cocaine use. While the incidence of cocaine-related myocardial abnormalities, particularly in the ECG, is not in question, it still is debated whether these are due specifically to acute myocardial ischemia or acute myocardial infarction (AMI) (Benzaquen et al., 2001; Eisenberg et al., 1993; Gitter et al., 1991; Weber et al., 2000). Various authors have ascribed cocaine-related cardiac problems to a relative incidence of AMI of  6% in patients presenting with angina (Hollander et al., 1994; Weber et al., 2000; Zimmerman et al., 1987). The incidence of verifiable AMI associated with cocaine use has been reported as 22 of 71 patients (Amin et al., 1990), 3 of 48 patients (Zimmerman et al., 1987), and 8 of 42 patients (Tokarski et al., 1990). More recent reviews are considerably more conservative in their estimates of the incidence of myocardial infarction. For example, Kontos et al. (1999) reported AMI in 6 of 218 patients, Weber et al. (2000) identified 15 of 250, Hollander et al. (1994) described 14 of 246, and Qureshi et al. (2001) reported 6 of 532 selfdeclared frequent users of cocaine. In fact, 1 review found no evidence for AMI in 101 patients presenting with chest pain after cocaine use (Gitter et al., 1991). These data suggest that the interpretation of these results is not definitive when based solely on electrocardiographic data or chest pain symptoms (Gitter et al., 1991; Hollander et al., 1994; Weber et al., 2000). Therefore, the final diagnosis of AMI often may not be justified. Much of the confusion likely results from incomplete diagnosis in earlier reports and the development of more stringent criteria for diagnosis of AMI. Myocardial ischemia or cardiomyopathy cannot be diagnosed only by alterations in the ECG (Bestetti et al., 1987; Hollander et al., 1994), although this appears to be prevalent in the cocaine litera-

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ture. In addition, the multiple actions of cocaine and the varying sensitivity in individuals to these different actions complicate interpretations (Isner and Chokshi, 1989; Minor et al., 1991; Rezkalla et al., 1990; Virmani et al., 1988). Clearly, if there was a single or very limited cause of toxicity in an identified subset of the population, it would be considerably easier to determine the mechanism of cardiac toxicity. In any case, the risk of AMI is clearly greater in cocaine users than age-matched controls (Hollander et al., 1994; Mittleman et al., 1999). This is likely to be related to the sympathomimetic effects of cocaine since anger can also provoke (AMI) (Mittleman et al., 1995). The verification of AMI is difficult since most of the abnormalities resolve and are often indistinguishable from myocardial ischemia. While it is apparent that the incidence of myocardial infarction is elevated in cocaine users, the appropriate control studies in age-matched individuals with other similar risk factors is difficult, if not impossible, to perform. Furthermore, the myocardial alterations induced by AMI < 24 hr after the insult are not easily diagnosed. This makes the differential diagnosis of AMI difficult to verify if there is no previous damage. Despite this, it could contribute to the incidence of ventricular fibrillation and sudden cardiac death. 7.4. Does cocaine produce myocardial ischemia by enhancing platelet aggregation to produce thrombosis? Thrombotic occlusion of coronary or cerebral arteries has also been suggested to be responsible for cocaine-related toxicity. The occurrence of thrombotic occlusion leading to myocardial infarction in otherwise normal coronaries in the absence of cocaine is documented (Fernandez et al., 1983). Enhanced sympathetic activity due to reuptake blockade of catecholamines and to excessive circulating catechols has been suggested to increase platelet aggregation by a2-adrenoceptor stimulation leading to thrombotic occlusion. This has been verified in some individuals, but not, by any means, in all cases (Frishman et al., 1989; Hadjimiltiades et al., 1988; Howard et al., 1985; Isner et al., 1986; Kossowsky & Lyon, 1984; Minor et al., 1991; Rod & Zucker, 1987; Simpson & Edwards, 1986; Smith et al., 1987; Vincent et al., 1983; Virmani et al., 1988). Cocaine has been reported to enhance platelet aggregation in vitro (Rezkalla et al., 1992; Togna et al., 1985), although other investigators do not concur (Jennings et al., 1993). Togna et al. (1985) suggested that cocaine may promote thrombosis due to increased platelet responsiveness to arachidonic acid and enhanced thromboxane synthesis, not from a direct adrenergic response. In some patients, the combination of coronary vasospasm and thrombosis may enhance the possibility of thrombotic occlusion and infarction (Vincent et al., 1983; Zimmerman et al., 1987). Therefore, both vasospasm and thrombosis may contribute to elicit myocardial ischemia and infarction. Few experiments have directly addressed the potential change in platelet aggregation. Kugelmass et al. (1995)

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demonstrated that cocaine, but not norepinephrine, elicited a delayed increase in platelet P-selectin expression that could contribute to enhanced thrombosis. Branch and Knuepfer (1994a) reported that heparin pretreatment did not reduce the hemodynamic responses to cocaine in rats, particularly in those rats predisposed to cardiovascular disease (vascular responders). Therefore, we concluded that this model of cocaine toxicity does not appear to be dependent on coronary thrombosis leading to myocardial ischemia and cardiodepression. Furthermore, we did not note myocardial infarctions in more than 100 rats after repeated cocaine treatment (Knuepfer et al., 1991, 1993a; P. J. Mueller & M. M. Knuepfer, unpublished data). It should be noted that rats are not likely to be a good model for cocaine-induced myocardial infarction, since most strains appear more resistant to AMI and myocardial ischemia compared with humans. While it is difficult to estimate from case studies, coronary thrombosis appears to account for 20 – 30% of incidences of chest pain associated with cocaine use. The mechanism of the increase in thrombogenesis after cocaine use is not clear. It is clear that thrombosis contributes to cocaine-induced myocardial dysfunction in some patients, since thrombolytic therapy has been demonstrated angiographically to open coronary vessels (Frishman et al., 1989; Hadjimiltiades et al., 1988; Isner & Chokshi, 1991; Rod and Zucker, 1987; Smith et al., 1987). Considering the previously mentioned critical role of cytokines and immune components in the process of plaque formation and rupture (Blake & Ridker, 2001; Fazio & Linton, 2001; Hansson, 2001; Kaul, 2001) and the effects of cocaine on modulating inflammatory and immune responsiveness (Pellegrino & Bayer, 1998; Wang et al., 1994; Watzl & Watson, 1990), it is possible that pharmacological manipulation of immune responsiveness may be beneficial. This area of research, with regard to cocaine, has not been studied, yet may provide a new approach for treatment or amelioration of cocaine-related toxicity.

doses is not dramatic (Boehrer et al., 1992; Eisenberg et al., 1993; Fischman et al., 1976, 1985), but may be greater with intravenous or smoked cocaine (Foltin & Fischman, 1991; Paly et al., 1982; Perez-Reyes et al., 1982; Sofuoglu et al., 2000b) or intracoronary cocaine (Pitts et al., 1998). This is more likely to contribute in patients with fixed coronary disease, yet again, this is uncommon in younger individuals using cocaine. The increase in myocardial oxygen demand may also become life threatening in the face of simultaneous ischemia due to coronary thrombosis or vasospasm (Gradman, 1988). Studies in experimental animals have not supported the hypothesis that cocaine produces a mismatch between oxygen demand and oxygen supply in the heart (Fraker et al., 1990; Shannon et al., 1995). Shannon et al. (1995) reported that there was only a brief mismatch in myocardial oxygen demand and supply in conscious dogs, which was quickly overcome by enhanced hemoglobin levels, allowing greater oxygen transport. The exercise and coronary ischemia model used by Billman and co-workers (Billman & Hoskins, 1988; Billman, 1995) demonstrated that rather extreme myocardial oxygen demand is necessary to ensure that inadequate blood supply will produce ischemia and ventricular fibrillation. The extent of the increase in rate pressure product possible in patients with and without coronary artery disease is considerably greater than that produced by cocaine (Bruce, 1971). Zimring et al. (1994) estimated the mismatch in myocardial oxygen supply and demand, concluding that the brief effects of cocaine would not be capable of producing a clinically significant ischemia that could account for the decrease in left ventricular function in the anesthetized pig. Therefore, there is not conclusive data suggesting a prominent role for myocardial oxygen demand in precipitating chest pain, although it cannot be ruled out as a contributing factor.

7.5. Does cocaine produce myocardial ischemia due to enhanced myocardial workload with inadequate increases in coronary blood supply?

As discussed in Section 7.3, much of the evidence for myocardial ischemia in cocaine users results from abnormalities in the ECG. Furthermore, cocaine has both acute and long-term effects on the ECG that may enhance arrhythmogenesis, leading to sudden cardiac death. Acutely, cocaine produces a number of electrophysiological abnormalities in humans (Amin et al., 1990; Benchimol et al., 1978; Castro & Nacht, 2000; Chakko et al., 1994; Kloner et al., 1992; Kossowsky & Lyon, 1984; Lange & Willard, 1993; Minor et al., 1991; Nademanee et al., 1989; Perera et al., 1997; Young & Glauber, 1947). Due to its ability to interfere with the Na + channel, cocaine intoxication is often associated with prolonged PR, QRS, QT, and QTc intervals. In some, but not all, cases, these are described as indicative of acute myocardial ischemia with ST segment elevation and other S-T alterations, ventricular tachycardia or fibrillation, and various degrees of conduction abnormalities, including

Cocaine elicits an increase in arterial pressure and heart rate, and, therefore, myocardial work load (Fischman et al., 1976, 1985). The increase in myocardial oxygen demand resulting from increases in heart rate without appropriate coronary vasodilation might lead to ischemia (Gradman, 1988; Isner et al., 1986; Mathias, 1986; Pasternack et al., 1985). There is little evidence supporting this mechanism, considering the relative youth of many victims of cardiovascular toxicity and the fact that other physiological responses, such as exercise or behavioral stress, increase myocardial oxygen demand to a greater extent than noted after cocaine. The actual extent of heart rate stimulation or cardiac depression using therapeutic or relevant intranasal

7.6. Does cocaine produce its cardiotoxic effects by eliciting ventricular arrhythmias?

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reduced AV nodal conduction and bundle branch block. The occurrence of these and other abnormalities in the ECG is highly variable in humans, and has been described as an idiosyncratic response to cocaine (Young & Glauber, 1947). Alternatively, some cocaine addicts may develop cardiac hypertrophy, thereby enhancing their predisposition to ventricular arrhythmias and sudden cardiac death (Karch et al., 1995, 1998). Cocaine has several effects on the ECG of experimental animals. The acute responses to cocaine include an increase in the PR, QRS, QT, and QTc intervals; an increase in the atrial and ventricular effective refractory periods; and/or an increase in atrial and ventricular extrasystoles and tachycardic bouts (Beckman et al., 1991; Boylan et al., 1996; Clarkson et al., 1993; Hale et al., 1989b; Kabas et al., 1990; Schwartz et al., 1989a, 1989b; Temesy-Armos et al., 1992; Tracy et al., 1991). Cocaine has been demonstrated to slow atrial and AV conduction at higher doses (Kabas et al., 1990; Kanani et al., 1998; Schwartz et al., 1989b; TemesyArmos et al., 1992; Tracy et al., 1991; Watt & Pruitt, 1964). The net result is a decrease in conduction due to a reduction in Phase 0 depolarization. In fact, Watt and Pruitt (1964) reported that bundle branch block is demonstrable with cocaine administration to the canine heart. These observations are consistent with the known Na + channel blocking activity of cocaine (Crumb & Clarkson, 1990; Przywara & Dambach, 1989; Weidmann, 1955), and are responsible for its classification as a Class I antiarrhythmic (Daniel et al., 1995; Lange & Willard, 1993; Schwartz et al., 1988; Tracy et al., 1991). Despite these observations, studies report that ventricular fibrillation or other serious arrhythmias are not prevalent in otherwise normal animals treated with cocaine (Schwartz et al., 1989a; Temesy-Armos et al., 1992). Therefore, while some alterations in the ECG suggest that cocaine enhances the potential for sudden cardiac death in humans, significant changes leading to conduction block and ventricular fibrillation are typically observed at high, but not low, doses (Clarkson et al., 1993; Pagel et al., 1992; Schwartz et al., 1988, 1989a, 1989b). The actions of cocaine on cardiac electrophysiology are likely responsible for producing ventricular fibrillation and seizures, at least in patients exposed to high doses (e.g., body packers) or those with underlying cardiac disease (Jonsson et al., 1983; Mittleman & Wetli, 1984). It is also likely to contribute to the occurrence of early after-depolarizations and torsades de pointes in susceptible patients (Kimura et al., 1992; Schrem et al., 1990). It is not certain that these conduction alterations are responsible for the majority of cardiac aberrations associated with cocaine use. This is further corroborated by the lack of ventricular arrhythmias or chest pain associated with direct intracoronary administration of cocaine in humans (Daniel et al., 1996). Cocaine produces a Brugada-like ECG pattern in otherwise asymptomatic patients (Littmann et al., 2000; OrtegaCarnicer et al., 2001). The Brugada syndrome is character-

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ized by a prominent J wave that obscures the T wave (Brugada & Brugada, 1992; Brugada & Roberts, 2001). Defects in the cardiac Na + channel, SCN5A, have been correlated with a predisposition to sudden cardiac death and electrocardiographic abnormalities resembling the Brugada syndrome (Grant, 2001; Rook et al., 1999). Therefore, the Brugada pattern may result from specific channel defects and may predispose individuals to lethal arrhythmias. In patients predisposed to long QT syndrome or Brugada syndrome, channelopathies in the myocardium may also enhance arrhythmogenesis in response to cocaine (Gussak et al., 1999; Perera et al., 1997). This may be exacerbated by hyperthermia (Dumaine et al., 1999), a known side effect of cocaine in some individuals. While this is particularly appealing as a cause of unexplained sudden cardiac death, the Brugada syndrome is rare except in natives of Southeast Asia (Brugada & Brugada, 1992; Brugada & Roberts, 2001; Nademanee et al., 1997). Therefore, individuals predisposed to the Brugada syndrome may explain a negligible number of cocaine-related deaths. In contrast, cocaine may produce similar ion channel abnormalities as seen in patients with the Brugada syndrome, suggesting a role for specific channels in mediating cocaine-induced arrhythmias. There is also evidence that cocaine interferes with the inward rectifier K + channel in the myocardium (O’Leary, 2001). At clinically relevant doses, cocaine inhibits the HERG channel, but not the KvLQT1 + mink K + channel (Ferreira et al., 2001; Zhang et al., 2001). Inhibition of the inward rectifier current could contribute to a predisposition to arrhythmias and to conduction abnormalities. Several investigators have examined the effects of exercise and acute coronary ischemia on the predisposition to ventricular fibrillation using a conscious canine model described by Schwartz and Stone (1982). A predisposition to ventricular arrhythmias after coronary ischemia has also been noted in anesthetized dogs (Inoue & Zipes, 1988). Billman (1993a, 1993b, 1994) demonstrated that the administration of cocaine to dogs before exercise and coronary occlusion elicited ventricular fibrillation in most dogs. Using this model, he reported that either L-type Ca2 + channel antagonists or the Ca2 + chelator BAPTA-AM was capable of reducing or preventing ventricular fibrillation (Billman & Hoskins, 1988; Billman, 1993a, 1993b). This model is based on the premise that an imbalance of sympathetic and parasympathetic tone predisposes animals to lethal ventricular fibrillation (Randall et al., 1976; Schwartz & Stone, 1982). This will be discussed further in the following section. These studies provide further evidence that cocaine enhances the likelihood of lethal ventricular arrhythmias, particularly with pre-existing coronary disease, and that Ca2 + may play a permissive role. Cocaine has also been reported to enhance the predisposition to ventricular arrhythmias and fibrillation with programmed electrical stimulation (Gantenberg & Hageman, 1992; Hageman & Simor, 1993). These data suggest that cocaine may enhance arrhythmogenesis under condi-

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tions of excessive sympathoadrenal activity. Temesy-Armos et al. (1992) suggested that the conflicting actions of local anesthetic- and cocaine-induced sympathomimetic effects are particularly important in the ventricle in preventing the cocaine-induced increase in the effective refractory period noted in atrial tissue. These alterations could contribute to cocaine-induced toxicity, although their very short duration would suggest that this would only explain immediate toxicity to cocaine in humans. The mechanisms by which cocaine alters the ECG and predisposes individuals to ventricular arrhythmias have been examined using several selective agents that alter cocaineinduced arrhythmogenesis. There is evidence that the autonomic nervous system participates in the arrhythmogenic effects of cocaine, since the likelihood of ventricular fibrillation with programmed electrical stimulation was reduced with propranolol or atropine (Gantenberg & Hageman, 1992). Prazosin or propranolol administration reduced ventricular fibrillation resulting from cocaine, exercise, and coronary ischemia (Billman, 1994). In contrast, Tracy et al. (1991) reported that combined a- and b-adrenoceptor blockade resulted in enhanced cocaine-induced ECG alterations indicative of a conduction blockade. Likewise, atenolol and atropine enhanced cocaine-induced conduction abnormalities in dogs (Clarkson et al., 1993). Propranolol, phentolamine, and atropine treatment did not alter the enhanced predisposition to arrhythmias elicited by cocaine during programmed electrical stimulation, suggesting that there are other, non-autonomic mechanisms by which cocaine enhances arrhythmogenesis (Gantenberg & Hageman, 1992). Orr and Jones (1968) reported that cocaineinduced arrhythmias observed during laryngoscopy could be prevented by propranolol treatment, but that other adverse cardiovascular responses may be enhanced. Other mechanisms of cocaine-induced arrhythmogenesis have been proposed. The common treatment for Type Ia antiarrhythmic overdose, NaHCO3, was effective in preventing the QRS prolongation and other conduction abnormalities associated with cocaine administration (Beckman et al., 1991; Ortega-Carnicer et al., 2001; Schindler et al., 1995a). Schindler et al. (1995a) proposed that this was due to increased Na + availability, which partially counteracts the competitive antagonism of Na + by cocaine. Inhibition of nitric oxide synthesis has been also suggested to enhance cocaine-induced arrhythmogenesis (Heavner et al., 1995). Chronic treatment with the D1 antagonist SCH 39166 had effects consistent with a reduction in arrhythmogenesis (Kanani et al., 1998). Finally, the NMDA receptor antagonist dizocilpine reduces the predisposition to ventricular arrhythmias induced by programmed electrical stimulation, reportedly due to actions in the brain stem that attenuate cocaine-induced sympathoinhibition (Hageman & Simor, 1993) primarily in anesthetized animals. The wide variety of agents interfering with a number of receptor systems further exemplifies the complexity of the arrhythmogenic effects of cocaine.

Sustained alterations in cardiac electrophysiology have also been reported in chronic cocaine users (Chakko et al., 1992, 1994; Nademanee et al., 1989; Tanenbaum & Miller, 1992). These included increased QRS voltage, ST elevations and other signs of ischemia or infarction, bundle branch block, and signs of ventricular and septal hypertrophy. Although evidence for these ECG changes was not noted in the majority of patients, the prevalence of these abnormalities in cocaine-using individuals was significantly greater than in control populations. Therefore, chronic cocaine use is likely to enhance the predisposition to sudden cardiac death, possibly due to structural and electrophysiological abnormalities. Few studies have addressed the effects of chronic cocaine administration on cardiac electrophysiology in experimental animals. Smith et al. (1993) reported that repeated cocaine administration exacerbated the extent of ECG broadening, conduction blockade, and occurrence of extrasystoles, despite a tachyphylaxis to the cardiostimulatory effects in conscious rats. Sutliff et al. (1999) reported that rabbits were also more sensitive to cocaine-induced arrhythmias after repeated cocaine administration. While these data suggest that chronic treatment schedules that mimic patterns of use in humans may predispose individuals to ECG abnormalities, there is still very little known about the causes of arrhythmias after repeated exposure in animal models. Such studies would better explain the contribution of arrhythmias to the toxicity associated with repeated cocaine use. 7.7. Does cocaine alter myocardial function and blood flow due to increased sympathetic nerve activity? It has been suggested that cocaine enhances sympathetic activity contributing to cardiac ischemia by constricting coronary vessels under conditions of increased myocardial workload (Mathias, 1986; Pasternack et al., 1985). This hypothesis is supported by evidence of cocaine-induced coronary vasoconstriction in humans (Boehrer et al., 1993; Brogan et al., 1992; Flores et al., 1990; Lange et al., 1989, 1990; Moliterno et al., 1994; Negus et al., 1994) and increases in circulating catecholamines (Nademanee et al., 1989) and in skin sympathetic nerve activity (Vongpatanasin et al., 1999). Lange et al. (1989, 1990) demonstrated that intracoronary phentolamine reduced the increase in coronary vascular resistance to intravenous cocaine, whereas intracoronary propranolol exacerbated the increase in resistance in humans. Moreover, intracoronary cocaine did not cause significant changes in coronary caliper in conscious humans (Daniel et al., 1996) or dogs (Shannon et al., 1995) or in anesthetized pigs (Zimring et al., 1994). These data provide strong support for the role of the CNS in mediating cocaine-induced coronary vasoconstriction. Cocaine has long been believed to be a centrally and peripherally acting sympathomimetic (Ritchie & Greene, 1990). Cocaine administration has been shown to elevate

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plasma catecholamines in humans (Karch, 1987; Nademanee et al., 1989) and animals (Chen et al., 1995; Chiueh & Kopin, 1978; Gunne & Jonsson, 1964; Han et al., 1996; Hayes et al., 1991; Kabas et al., 1990; Kiritsy-Roy et al., 1990; Schwartz et al., 1988; Shannon et al., 1996; Trouve´ et al., 1991) due to enhanced adrenal release, reduced reuptake at peripheral nerve terminals, and/or an increase in central sympathetic drive. Several investigators have suggested that CNS-mediated sympathoexcitation is important in mediating many of the cardiovascular effects of cocaine (Branch & Knuepfer, 1994b; Chiueh & Kopin, 1978; Kiritsy-Roy et al., 1990; Knuepfer & Branch, 1992; MacGregor, 1939; Poon & van den Buuse, 1998; Sabra et al., 2000; Shannon et al., 1995, 2001; Tella et al., 1990, 1992a, 1993; Wilkerson, 1988). Cocaine administration elicits mydriasis (Fro¨hlich & Loewi, 1910; MacGregor, 1939), and, besides the increase in plasma catecholamines, evokes an increase in plasma corticosteroids (Levy et al., 1991; Moldow & Fischman, 1987; Rivier & Vale, 1987) similar to adrenal responses to behavioral stress. Ganglionic blockade reduces arterial pressure and heart rate responses to cocaine (Branch & Knuepfer, 1994a; Kiritsy-Roy et al., 1990; Knuepfer & Branch, 1992; Poon & van den Buuse, 1998; Szabo et al., 1995; Tella et al., 1990; 1992a, 1993; Wilkerson, 1988). We reported that this is due, in part, to an attenuation of the initial increase in mesenteric and hindquarters vascular resistances (Knuepfer & Branch, 1992). In contrast, the delayed hindquarters vasodilation and mesenteric vasoconstriction are attenuated by adrenal demedullation (Knuepfer & Branch, 1992). Others have argued that central sympathoexcitation does not contribute to hemodynamic responses (Gillis et al., 1995; Hernandez et al., 1996). Cocaine injected into the vertebral or carotid arteries of pentobarbital-anesthetized cats did not elicit pressor responses or increase stellate or greater splanchnic nerve discharge (Gillis et al., 1995; Raczkowski et al., 1991). Intracerebroventricular administration of cocaine does not typically elicit a pressor response unless high doses are administered (Jones & Tackett, 1990; Kiritsy-Roy et al., 1990; Knuepfer et al., 1993c; Van de Kar et al., 1992). Administration of cocaine methiodide, a tertiary form of cocaine that does not readily cross the blood-brain barrier, elicited an increase in arterial pressure and heart rate in anesthetized dogs (Gillis et al., 1991), suggesting a peripheral site of action. Likewise, cocaine hydrochloride or cocaine methiodide produced a decrease in arterial pressure and heart rate in anesthetized cats (Hernandez et al., 1996). In contrast, Schindler et al. (1992b) reported that cocaine methiodide administration had little effect on arterial pressure or heart rate in squirrel monkeys, supporting a central site of action. Finally, several investigators reported that cocaine elicits a profound decrease in renal sympathetic nerve activity in pentobarbital-anesthetized or decerebrate cats (Raczkowski et al., 1991; Gillis et al., 1995; Hernandez et al., 1996), pentobarbital-anesthetized dogs (Gantenberg & Hageman, 1991), pentobarbital-

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or chloralose-anesthetized or conscious rats (Abrahams et al., 1996a, 1996b; Knuepfer & Branch, 1992; Branch & Knuepfer, 1994b), and pithed or conscious rabbits (Szabo et al., 1995). These data shed doubt on the contribution of the central sympathomimetic effect of cocaine on hemodynamic responses and toxicity. In order to unambiguously test the hypothesis that cocaine produces central sympathoexcitation in conscious animals, our laboratory and others have directly recorded sympathetic nerve activity in rats. Indeed, cocaine administration elicited a brief initial sympathoexcitation in conscious rats and in some anesthetized rats (Abrahams et al., 1996a; Branch & Knuepfer, 1994b; Knuepfer & Branch, 1992; Purcell et al., 2001). As noted in anesthetized animals, there was a prolonged sympathoinhibition following the short-lived increase in nerve activity. While the brief increase may appear insignificant, it is comparable to the brief increase in renal sympathetic nerve activity noted after conditioned stress (Randall et al., 1994). Since Randall and co-workers (1994) did not administer a drug to evoke the response, the pressor response was clearly due to sympathoexcitation. Therefore, brief sympathoexcitatory responses followed by adrenal catecholamine release may result in a sustained pressor response that overrides the subsequent baroreceptor-mediated decrease in sympathetic activity. Recently, it was reported that cocaine elicited a sustained increase in activity of sympathetic peroneal nerves to the skin in humans (Vongpatanasin et al., 1999). Another report suggested that cocaine evoked a decrease in sympathetic activity to skeletal muscle in humans (Jacobsen et al., 1997). While this may seem contradictory, Jacobsen et al. (1997) reported that the decrease in activity to the skeletal muscle was due to baroreflex activity rather than a direct effect, since ameliorating the pressor response to cocaine using nitroglycerin resulted in an almost 3-fold increase in sympathetic activity after cocaine administration. This provides direct support for the hypothesis that cocaine elicits sympathoexcitation. Since many of the adverse effects of cocaine, including pressor responses, cardiac ischemia, and arrhythmias, have been ascribed to the possible contribution of centrally mediated sympathoexcitation, it is important to provide data from animal studies to elucidate these adverse consequences of cocaine use and to provide potential new pharmacologic interventions to prevent toxicity. Therefore, we can conclude that the decrease in sympathetic activity noted in anesthetized and decerebrate animals may be an artifact without clinical relevance or may reflect baroreflex actions mediated by the CNS. Considering the dramatic changes in hemodynamic response patterns to cocaine caused by anesthesia (Fraker et al., 1990; Knuepfer & Branch, 1992; Pitts et al., 1987; Schwartz et al., 1989b; Tella et al., 1992a; Wang et al., 1999; Wilkerson, 1988), this is not surprising. It is very likely that some of the actions of cocaine result from the arousing effects of the psychostimulant, thereby requiring a conscious state. It seems likely

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that anesthesia or decerebration reduces the centrally mediated sympathoexcitation and the behavioral arousal to cocaine. This is likely to explain why the hemodynamic responses are blunted or abrogated by anesthesia (Fraker et al., 1990; Knuepfer & Branch, 1992; Knuepfer et al., 1994; Wilkerson, 1988). There is additional evidence that cocaine mediates cardiovascular responses by central actions on the autonomic nervous system. Daniel et al. (1996) reported that cocaine administration into the coronary arteries of humans did not elicit coronary vasoconstriction, even at 30 –40 times the systemic concentrations of cocaine that evoke coronary vasoconstriction. In fact, Shannon et al. (2001) suggested that cardiac nerves mitigate hemodynamic responses to cocaine since ventricular denervation enhanced the systemic pressor and heart rate responses to cocaine in conscious dogs. Therefore, the evidence of Shannon et al. (2001) and Jacobsen et al. (1997) suggests that sympathetic reflexes play an important role in buffering the actions of cocaine. Chronic cocaine use may also alter cardiac sympathetic responsiveness. Melon et al. (1994) reported that cocaine depleted cardiac norepinephrine stores since anesthetized dogs had reduced retention of C-11 hydroxyephedrine, as determined by positron emission tomography. Similarly, chronic cocaine users appear to have depleted myocardial stores of norepinephrine (Melon et al., 1997). These changes were interpreted to be a result of excessive sympathetic stimulation. Therefore, in light of the data in humans, we can conclude that central sympathoexcitation plays a significant role in mediating the hemodynamic responses to cocaine, as well as a potential role in mediating the predisposition to cardiovascular toxicity. There is also indication that withdrawal of vagal tone contributes to the hemodynamic and possibly the toxic effects of cocaine (Billman & Lappi, 1993; Newlin, 1995). The contribution of changes in vagal tone could also explain some of the effects of muscarinic antagonists on hemodynamic responses to cocaine (Shannon et al., 1993; Knuepfer & Gan, 1999; Witkin et al., 1989). The effects of cocaine on vagal tone or the antimuscarinic receptor activity may contribute to a predisposition to ventricular fibrillation, since it has been suggested that an imbalance in sympathetic and parasympathetic tone to the heart could lead to ventricular fibrillation (Randall et al., 1976; Schwartz & Stone, 1982), as described in Section 7.1. Billman & Lappi (1993) suggested that cocaine may increase sympathetic tone while decreasing parasympathetic tone, resulting in conduction abnormalities and a greater predisposition to ventricular fibrillation. This may explain the occurrence of ventricular arrhythmias without signs of cardiac ischemia in some individuals using cocaine (Benchimol et al., 1978; Kossowsky et al., 1989; Nanji & Filipenko, 1984; Om et al., 1992; Schachne et al., 1984). These data implicate the sympathetic and, possibly, the parasympathetic nervous system in the cardiovascular and toxic responses to cocaine. The evidence in humans clearly

indicates that cocaine evokes a sympathoexcitation modulated by baroreflexes (Jacobsen et al., 1997; Vongpatanasin et al., 1999). Much of the confusion regarding the sympathoinhibitory effects of cocaine are likely to be due to the suppression of sympathetic and baroreflex responsivity noted in anesthetized preparations. This supports the contention that the anesthetic state affects experimental results in cocaine studies. Furthermore, the sympathoinhibition noted under certain conditions is not likely to mediate the adverse cardiovascular responses to cocaine, unless it can be demonstrated that individuals susceptible to cocaineinduced cardiovascular dysfunction have impaired baroreflex modulation of centrally induced sympathoexcitation. These studies have not been reported. 7.8. Does chronic exposure to cocaine enhance the possibility of adverse cardiovascular responses? Most experimental paradigms examining the cardiovascular effects of cocaine in humans or animals describe the effects of acute cocaine administration. Despite this, there is likely to be important differences on the heart and vasculature that occur with acute binges of cocaine use and with chronic exposure to cocaine for months or years. Several studies have demonstrated acute tachyphylaxis or tolerance to the arterial pressure and heart rate responses to a single dose of cocaine (Chow et al., 1985) or repeated administration over a short period (5- to 120-min intervals) in humans (Ambre et al., 1988; Fischman et al., 1985; Foltin et al., 1995; Javaid et al., 1978; Ward et al., 1997) and animals (Pitts et al., 1987; Lichtman et al., 1995; Pagel et al., 1994; Shannon et al., 1996; Smith et al., 1993; Teeters et al., 1963; Tella et al., 1999). With longer inter-dosing intervals (hoursdays) or continuous infusions, tolerance to the acute hemodynamic responses may not be evident (Branch & Knuepfer, 1994a; Kumor et al., 1988; Smith et al., 1993; Ward et al., 1997), although some reports suggest a diminution in responsiveness over days to weeks in animals (Ambrosio et al., 1996; Matsuzaki et al., 1976; Tella et al., 1999). Mendelson et al. (1998) reported that occasional cocaine users had greater increases in heart rate and arterial pressure after cocaine use compared with cocaine-dependent men, suggesting that prolonged tolerance can be noted in humans, also. Differences in the psychological responsiveness to repeated cocaine use and the motivation to self-administer the drug is also likely to contribute to reductions in cardiovascular responses, suggesting tolerance. Although there is clear evidence for acute tolerance to the effects of cocaine, the chronic effects on the heart and function of other organs has not been studied in detail. For example, there are numerous structural abnormalities in the heart associated with chronic cocaine use in humans (Brickner et al., 1991; Chakko et al., 1992; Escobedo et al., 1992; Cigarroa et al., 1992; Gitter et al., 1991; Karch et al., 1995, 1998; Om et al., 1993; Peng et al., 1989; Virmani et al., 1988) and animals (Besse et al., 1997; Knuepfer et al.,

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1993a; Langner & Bement, 1991; Maillet et al., 1991; Sutliff et al., 1996). Despite the greater likelihood for sudden cardiac death that these alterations may produce, it is not clear whether long-term deficits in cardiac function are manifest, as noted after catecholamine-induced myocarditis (Todd et al., 1985b). Furthermore, the possibility that these changes are reversible has not been explored, although Chokshi et al. (1989) reported this in one patient with left ventricular dysfunction. Since the cardiac abnormalities produced by catecholamines or stress are, to some extent, reversible (Csapo et al., 1972; Ferrans et al., 1970; Rosenbaum et al., 1987; Selye, 1958; Tanaka et al., 1980; Todd et al., 1985a), it is likely that many functional and anatomical consequences of previous cocaine use may also be reduced with abstinence. In contrast, the accelerated atherosclerotic disease and peripheral vasculitis associated with cocaine use is likely to have prolonged effects and to predispose individuals to premature cardiac disease (Bacharach et al., 1992; Dressler et al., 1990; Karch & Billingham, 1995; Kolodgie et al., 1991, 1992; Virmani et al., 1988). At present, we know little about the sustained effects of cocaine use on cardiovascular function, yet this is important in managing patients after chronic cocaine use.

chest pain (Hawks et al., 1975; Jatlow, 1988). It is possible that norcocaine could exacerbate responses to cocaine, although this remains to be determined. Delayed toxicity may also be explained by partitioning of cocaine into discrete tissues. It has been suggested that cocaine may be sequestered in the brain, heart, and other organs and tissues (Benuck et al., 1987; Boylan et al., 1996; Nayak et al., 1976). Evans et al. (1996) reported that there is a more than 10-fold greater concentration of cocaine in arterial compared with venous blood after intravenous or smoked cocaine in humans. Furthermore, the peak concentration in arterial blood and the subsequent decline occurs more rapidly than in venous blood (Evans et al., 1996). This unusual difference between arterial and venous cocaine levels suggests that there may be a pool of cocaine that is maintained in tissues outside of the vascular system. This may explain the delayed response, but little else is known at this point. Therefore, the role of metabolites or sequestration of cocaine and its metabolites in the occurrence of delayed cardiotoxicity is still largely unexplained.

7.9. Does cocaine produce immediate or delayed cardiotoxicity?

Several agents have been proposed for the treatment of chest pain and other side effects of cocaine (for reviews, see Hollander, 1995; Mendelson & Mello, 1996; Pitts et al., 1997; Williams et al., 1996). I will review several agents and consider their mechanisms of action. I will also describe new potential treatments that are being developed for use in ameliorating the cardiovascular complications of cocaine.

A number of reports have described the toxic effects of cocaine on cardiovascular function as a delayed response. For example, many patients do not appear to have symptoms of chest pain for hours after cocaine use (Ascher et al., 1988; Benchimol et al., 1978; Isner et al., 1986; Schachne et al., 1984). Sudden cardiac death can also occur several hours after cocaine use (Nademanee et al., 1989; Tardiff et al., 1989), yet plasma levels of cocaine are reduced considerably and cardiovascular parameters appear to have returned to normal at this time. Few investigators have attempted to address this anomaly. Brogan et al. (1992) reported that there was a recurrent coronary vasoconstriction that occurred 90 min after intranasal cocaine administration in humans when benzoylecgonine and ecgonine methyl ester levels were peaking. They suggested that cocaine metabolites may be responsible for the delayed response. Administration of the primary metabolites benzoylecgonine and ecgonine methyl ester to animals elicits smaller cardiovascular responses and less toxicity than for cocaine or norcocaine (Branch & Knuepfer, 1994b; Erzouki et al., 1993; Mets & Virag, 1995; Morishima et al., 1999). In contrast, cocaine is converted to norcocaine by hepatic metabolism, resulting in a delayed increase in plasma levels. Schindler and co-workers (1995a) demonstrated that norcocaine could elicit hemodynamic responses that were indistinguishable from those produced by cocaine. Since norcocaine is not a prevalent metabolite (10 – 15%) and plasma levels are delayed somewhat, it is not clear that norcocaine could be responsible for the later occurrence of

7.10. What treatments are appropriate for ameliorating acute cardiac toxicity to cocaine?

7.10.1. -Adrenoceptor antagonists a-Adrenergic receptors are critical for many of the hemodynamic responses to cocaine. Phentolamine reversed the increase in arterial pressure and heart rate and the decrease in coronary vessel diameter produced by cocaine administration in humans (Lange et al., 1989). Administration of a-adrenoceptor or a1-adrenoceptor selective antagonists blunts the arterial pressure, heart rate, and the systemic and coronary vasoconstrictor responses to cocaine in animals (Billman, 1994; Branch & Knuepfer, 1992, 1994a; Egashira et al., 1991; Kuhn et al., 1990; Sabra et al., 2000; Schindler et al., 1992a; Tella et al., 1990, 1992a). These findings verify that the primary mechanism for cocaine-induced vasoconstriction is by enhancing the actions of norepinephrine on a1-adrenoceptors at the vascular smooth muscle junction. The role of a2-adrenoceptors in mediating hemodynamic responses to cocaine has also been investigated. Yohimbine pretreatment has been reported to enhance the pressor response in anesthetized dogs (Wilkerson, 1989) and in conscious rats (Tella et al., 1992a). We reported that yohimbine did not alter pressor responses to cocaine, but that the highly selective a2-adrenoceptor antagonist idazoxan did not enhance the pressor response and attenuated

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the initial increase in hindquarters vascular resistance (Branch & Knuepfer, 1992). These effects may also be centrally mediated since intracerebroventricular administration of yohimbine attenuated the pressor response and the increase in systemic vascular resistance to cocaine (Dong et al., 2001). Intracerebroventricular yohimbine also prevented the cocaine-induced suppression of the heart rate index of baroreflex sensitivity (Knuepfer et al., 1993c). These data suggest that central a2-adrenergic or imidazoline receptors may be important in the neural reflex responses to cocaine. Unfortunately, the peripheral side effects of a2-adrenoceptor antagonists may preclude its use as a treatment for cocaine intoxication. 7.10.2. -Adrenoceptor antagonists Several adrenoceptor antagonists have been proposed as treatment for cocaine intoxication. As discussed in Section 7.2, propranolol was promoted for the treatment of chest pain (Gay, 1982; Gradman, 1988; Rappolt et al., 1977, 1979; Resnick & Resnick, 1984), but may exacerbate some adverse responses (Ramoska & Sacchetti, 1985; Walsh & Atwood, 1989). For example, propranolol enhanced cocaine-induced coronary vasoconstriction in conscious humans (Lange et al., 1990) and dogs (Henning, 1993; Shannon et al., 1993, 1995) and in porcine coronary vessels (Vargas et al., 1991). While the extent of coronary vasoconstriction elicited by cocaine is not likely to be severe enough to produce ischemia in most individuals, enhancing this response might make this response clinically relevant. It has been reported that the pressor response to cocaine after propranolol pretreatment is enhanced (Kiritsy-Roy et al., 1990; Schindler et al., 1992a), unaffected (Kuhn et al., 1990; Shannon et al., 1993), or reduced (Catravas & Waters, 1981; Kenny et al., 1992). This confusion may lie not only in the complex nature of the pressor response itself, but in the particular time that measurements were made. We reported that propranolol pretreatment reduced the cocaine-induced initial pressor response (within the first 30 sec), but enhanced the delayed pressor response by augmenting the increase in systemic vascular resistance, although this is blunted somewhat by a more profound decrease in cardiac output (Branch & Knuepfer, 1992, 1994a). Our evidence, and that of others, suggests that the initial pressor response is likely due to central sympathoexcitation since ganglionic blockade attenuates the early response (Branch and Knuepfer, 1994a; Kiritsy-Roy et al., 1990; Knuepfer & Branch, 1992; Poon & van den Buuse, 1998; Sabra et al., 2000; Szabo et al., 1995; Tella et al., 1992a, 1993; Wilkerson, 1988). In contrast, the heart rate responses to cocaine are attenuated by propranolol (Billman, 1994; Branch & Knuepfer, 1994a; Catravas & Waters, 1981; Knuepfer et al., 1998; Schindler et al., 1992a; Stambler et al., 1993; Tella et al., 1990, 1992a). It has been reported that propranolol alters toxicity to lethal doses of cocaine. Some investigators report that toxicity is reduced (Derlet & Albertson, 1990), while others

report that it is enhanced (Guinn et al., 1980; Tella et al., 1992b) or unchanged (Catravas & Waters, 1981; Trouve´ & Nahas, 1990). We discovered that propranolol enhanced toxicity to a lethal infusion of cocaine in vascular responders (Williams et al., submitted), the subset of rats more susceptible to cocaine-induced cardiovascular disease (Knuepfer & Mueller, 1999). Data from these studies might not reflect the common mechanism of toxicity in humans since adverse cardiovascular complications often occur after relatively low doses of cocaine. Therefore, studies employing lethal doses may only be relevant for understanding responses to massive doses, as noted in body packers. The effects of propranolol have often been suggested to be due to antagonism of b-adrenergic receptors in the myocardium. Propranolol readily crosses the blood-brain barrier, interfering with the sympathoexcitation and hyperthermia associated with acute stress (Koepke & DiBona, 1985; Nakamori et al., 1993). Recent evidence from our laboratory suggests that responses to cocaine may be altered due to interference with b-adrenoceptors in the CNS since intracerebroventricular pretreatment with very low doses of propranolol enhances the arterial pressure, systemic vascular resistance, and cardiodepressive responses to cocaine similar to the effects noted after intravenous propranolol (Dong et al., 2001). Therefore, it is likely that propranolol acts to enhance central sympathoexcitatory responses to cocaine, thereby altering the hemodynamic responses to cocaine. The role of b1- and b2-adrenoceptors in mediating hemodynamic responses to cocaine is not completely understood. Schindler et al. (1992a) reported pretreatment with the b1adrenoceptor antagonist atenolol, like propranolol, enhanced the pressor response to cocaine, whereas the b2-adrenoceptor antagonist ICI 118,551 had no effect in conscious squirrel monkeys. We reported that metoprolol altered hemodynamic responses to cocaine in a similar manner as propranolol (Knuepfer et al., 1998). Metoprolol and atenolol, to a lesser extent, also cross the blood-brain barrier, making interpretation of the site of action problematic. The brief, initial pressor response to cocaine was associated with an increase in vascular resistance in the hindquarters and mesenteric vascular beds (Branch & Knuepfer, 1992; Knuepfer et al., 1991). Immediately after this peak pressor response, there was a more modest pressor response characterized by hindquarters vasodilation. We proposed that the delayed vasodilation in the skeletal muscle was likely a baroreflex response that attenuated the pressor response (Knuepfer et al., 1991; Knuepfer & Branch, 1992). We also reported that propranolol, but not metoprolol, could prevent the delayed hindquarters vasodilation (Branch & Knuepfer, 1992; Knuepfer et al., 1991). Recently, we noted that ICI 118,551 pretreatment prevents the delayed hindquarters vasodilation to cocaine (M. M. Knuepfer & Q. Gan, unpublished results). These data implicate b2-adrenoceptors in the skeletal muscle as important in ameliorating the pressor responses to cocaine. Since adrenal demedullation also prevented the hindquarters vasodilatory response to

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cocaine (Knuepfer & Branch, 1992) and cocaine elevates plasma catecholamines (Chiueh & Kopin, 1978; Gunne & Jonsson, 1964; Kabas et al., 1990; Kiritsy-Roy et al., 1990; Schwartz et al., 1988; Shannon et al., 1996), it is likely that the skeletal muscle vasodilation is mediated by circulating epinephrine. It has been argued that antagonizing the b-adrenergic receptors without opposing the a-adrenoceptors could contribute to the toxicity of cocaine (Boehrer et al., 1993; Ramoska & Sacchetti, 1985; Walsh & Atwood, 1989). Therefore, some have proposed the use of labetalol, a combined a- and b-adrenergic receptor antagonist (Dusenberry et al., 1987; Gay & Loper, 1988). In humans, labetalol reduced the pressor responses to cocaine, but not the coronary vasoconstriction, possibly due to the fact that b-adrenergic effects predominate at the dose of labetalol used (Boehrer et al., 1993). In conscious dogs, labetalol pretreatment results in a reduction in the pressor and systemic vasoconstriction elicited by cocaine and abrogation of the cardiostimulatory effects (Kenny et al., 1992). Schindler et al. (1992a) reported that labetalol did not affect the pressor response, but that it reduced the heart rate response in conscious squirrel monkeys. Studies with toxic doses of cocaine in rats are less conclusive since labetalol has been reported by Derlet and Albertson (1990), but not by others (Smith et al., 1991; Trouve´ & Nahas, 1990) to reduce toxicity. Therefore, there is insufficient experimental and clinical data at this time to determine whether labetalol may be beneficial in treating cocaine toxicity. 7.10.3. Ca2+ channel antagonists Ca2 + channel antagonists have been suggested to be effective in treating cocaine-related cardiac dysfunction (Billman, 1995; Bunn & Giannini, 1992; Chakko & Myerburg, 1995; Gradman, 1988; Hollander, 1995; Minor et al., 1991; Williams et al., 1996). Verapamil has been shown to reduce the pressor and coronary vasoconstrictor responses to cocaine when given after cocaine administration in humans (Negus et al., 1994). Several Ca2 + channel antagonists, including diltiazem, nimodipine, nitrendipine, nifedipine, nicardipine, and verapamil, have been shown to be effective in reducing hemodynamic responsiveness and toxicity in animals (Abel & Wilson, 1992; Billman & Hoskins, 1988; Billman, 1993a; Hale et al., 1991; Knuepfer & Branch, 1993; Knuepfer et al., 1998; Schindler et al., 1995b; Tella et al., 1992b; Trouve´ & Nahas, 1990). Hale et al. (1991) reported that 5 mg/kg nifedipine was effective in preventing the cocaine-induced decrease in coronary blood flow and increase in left ventricular end diastolic pressure when given before, but not after, cocaine in anesthetized dogs. Ca2 + channel antagonists are also effective in ameliorating the toxicity of excessive sympathetic stimulation or catecholamine administration (Fleckenstein et al., 1975; Nayler, 1988; Opie et al., 1985). It has been demonstrated that cocaine enhances sympathetic activity, leading to many of

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its adverse effects on cardiac function (Daniel et al., 1996; Shannon et al., 1993; Stambler et al., 1993) and possibly to cardiomyopathies resulting from Ca2 + overload (Billman, 1995; Fleckenstein et al., 1975; Opie et al., 1985). These data support the use of Ca2 + channel antagonists for treating cocaine toxicity. In contrast to these reported beneficial effects, Derlet and Albertson (1989) reported that diltiazem, nifedipine, or verapamil could enhance toxicity to a lethal dose of cocaine in rats. These data are not likely to have significant clinical importance for two reasons. First, the doses of Ca2 + channel antagonists used were usually considerably greater than those used clinically. High doses of these agents will lead to cardiac depression, even in the absence of cocaine. In combination with cocaine, the response may be synergistic. Second, these studies use a model of toxicity that employs a dose of cocaine in excess of the LD50. As discussed in a previous review (Knuepfer & Mueller, 1999), this may not reflect the toxic responses noted in the majority of humans. In summary, experimental data suggest that the use of Ca2 + channel antagonists may prevent the acute cardiac depression and the pathologic effects of cocaine on the heart, but point out that they may only be effective when administered before cocaine ingestion. This may limit their usefulness as treatments for cocaine toxicity. 7.10.4. Anticoagulants As described in Section 7.4, there is evidence that thrombolytic therapy alleviates cocaine-induced angina when thrombotic occlusion is verified by angiography (Frishman et al., 1989; Hadjimiltiades et al., 1988; Isner & Chokshi, 1991; Rod & Zucker, 1987; Smith et al., 1987). Therefore, in this subset of patients, thrombolytic therapy is appropriate. It is only important to verify the presence of a coronary thrombus before therapy to avoid the risk of hemorrhage. 7.10.5. Anticonvulsants For immediate treatment of seizures elicited by excessive doses of cocaine, diazepam is effective clinically (Jonsson et al., 1983; Rappolt et al., 1979; Resnick & Resnick, 1984; Spivey & Euerle, 1990). Several studies examining the toxic effects of lethal doses or infusions of cocaine in animals suggest that diazepam would be useful in reducing convulsions and death (Catravas & Waters, 1981; Derlet & Albertson, 1990; Guinn et al., 1980), while others have not reported a protective effect (Smith et al., 1991; Trouve´ & Nahas, 1990). It is clear that diazepam or other antiepileptic drugs (Gasior et al., 1999) are effective in reducing toxicity in patients experiencing seizures. It has also been suggested that diazepam may be effective in treating the cardiovascular dysfunction observed in patients after more moderate doses associated with the majority of cases of toxicity (Baumann et al., 2000; Inyang et al., 1999). The mechanisms by which benzodiazepines reduce cardiovascular toxicity are not clear, but some have suggested that they

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suppress the hyperadrenergic response that many associate with cocaine toxicity (Spivey & Euerle, 1990). The NMDA receptor antagonist dizocilpine (MK-801) has also been used to treat cocaine toxicity experimentally. Dizocilpine decreases cocaine-induced convulsions and lethality in rats and mice (Derlet & Albertson, 1990; Derlet et al., 1990; Hageman & Simor, 1993; Karler & Calder, 1992; Rockhold et al., 1991b, 1992), but does not alter the hemodynamic responses to cocaine (Knuepfer & Gan, 1997; Rockhold et al., 1994). Rockhold (1991, 1998) proposed that NMDA receptor activation is critical for the manifestation of behavioral and autonomic responses to psychostimulants or cerebral hypoxia. Therefore, the use of NMDA receptor antagonists such as dizocilpine to reduce convulsions in treating high-dose cocaine intoxication may prove to be effective. 7.10.6. Bicarbonate and nitrovasodilators There is also evidence for a direct cardiac depressant effect of cocaine that is independent of the sympathetic nervous system and coronary ischemia (Abel et al., 1989; Fraker et al., 1990; Hale et al., 1989a; Pagel et al., 1992; Zimring et al., 1994). As yet, there are not specific treatments for this direct effect, although some treatments have been found to be effective. NaHCO3 has been used to treat acidosis and Na + channel blockade (Beckman et al., 1991; Jonsson et al., 1983; Ortega-Carnicer et al., 2001; Schindler et al., 1995a). Nitrovasodilators, such as nitroprusside or nitroglycerin, have also been administered to reduce the workload of the heart and to promote recovery of cardiac function (Ascher et al., 1988; Ayala & Altieri, 1993; Brogan et al., 1991; Haines & Sexter, 1987; Rollingher et al., 1986; Zimmerman et al., 1987). Cocaine has been reported to reduce nitric oxide release from the vascular endothelium of rabbit aortic rings by inhibiting Ca2 + movement through the Ca2 + -ATPase pump (Togna et al., 2001). Chronic treatment with the nitric oxide synthase inhibitors NG-nitro-L-arginine methyl ester or NG-nitro-Larginine reduced the incidence of convulsions and lethal effects of repeated cocaine administration in conscious mice (Itzhak, 1994). This effect was hypothesized to be a result of nitric oxide preventing up-regulation of cortical NMDA receptors that diminished the sensitization of the mice to chronic cocaine exposure. NG-nitro-L-arginine methyl ester pretreatment enhanced the hemodynamic responses to cocaine, particularly the decrease in cardiac output and increase in systemic vascular resistance in conscious rats (Knuepfer et al., 1998) and anesthetized pigs (Roig et al., 2000). These experiments are problematic because of the significant effects of nitric oxide synthase inhibition on hemodynamic parameters resulting in hypertension. Nitric oxide administration was not reported to reverse the pressor, heart rate, or arrhythmogeneic responses to cocaine with or without inhibition of endogenous nitric oxide synthase in anesthetized rats (Heavner et al., 1995). Therefore, impairment of vasodilator and pos-

sibly myocardial function is likely to exacerbate cocaineinduced toxicity. 7.10.7. Anticholinergics The findings that cocaine is a competitive antagonist at cholinergic muscarinic receptors and a sympathomimetic contribute to the hypothesis that an autonomic imbalance may promote arrhythmias. Anticholinergics such as atropine reduce the heart rate response to cocaine in conscious dogs, rats, and squirrel monkeys (Kiritsy-Roy et al., 1990; Knuepfer & Branch, 1992; Knuepfer & Gan, 1999; Shannon et al., 1993; Tella et al., 1990), but did not affect the heart rate in anesthetized dogs (Wilkerson, 1989). Since the effects of atropine mimic the antimuscarinic effect of cocaine (Miao et al., 1996b; Sharkey et al., 1988), it is not clear that anticholinergics have a therapeutic advantage in cocaine toxicity. Yet, the Ca2 + overload elicited by sympathoexcitation may be ameliorated by cholinergic effects on reducing Ca2 + availability and by local anesthetic effects reducing excitability (Miao et al., 1996b). The combination of atropine and ganglionic or adrenergic blockade may be beneficial in reducing toxicity, since several cardiovascular responses to cocaine are suppressed by autonomic blockade (Pagel et al., 1992; Stambler et al., 1993). This has not been tested clinically, probably due to the prolonged action and severity of side effects with autonomic blockade in humans. Some individuals have reduced pseudocholinesterase activity and, therefore, may be at greater risk for cocaine toxicity since the primary route of inactivation of cocaine is through this enzyme in the plasma and liver (Jatlow, 1988; Nayak et al., 1976). Typically, individuals with succinylcholine sensitivity would be at greater risk for cocaine-induced adverse responses since cocaine would have a longer halflife. This has been suggested to be a mechanism for at least some cocaine-sensitive humans (Hoffman et al., 1992a; Jatlow, 1988; Om et al., 1993) and animals (Cahill-Morasco et al., 1998; Hoffman et al., 1992b), but it does not appear to account for the vast majority of toxic responses to cocaine. Studies in animals are controversial since inhibition of plasma cholinesterases has been reported to enhance toxicity in conscious mice (Hoffman et al., 1996), not to affect toxicity in anesthetized pigs (Kambam et al., 1993), and to reduce toxicity in anesthetized rats (Kambam et al., 1992). In conclusion, there is no definitive evidence that cholinesterase inhibitors are beneficial, but it does appear that reduced cholinesterase activity is likely to predispose some individuals to cocaine toxicity. Because cocaine is metabolized primarily by plasma pseudocholinesterases, enhancing cholinesterase activity may be beneficial in treating cocaine-induced cardiovascular toxicity. Human butyrylcholinesterase has been isolated and shown to enhance the rate of metabolism of cocaine and to reduce toxicity in rats (Lynch et al., 1997; Mattes et al., 1997). Butyrylcholinesterase has also been shown to reduce the half-life of cocaine in squirrel monkey or human plasma

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and to lower cocaine levels in anesthetized squirrel monkeys (Carmona et al., 2000). In a similar manner, the use of antibodies that bind cocaine intermediates has been proposed as a mechanism to reduce plasma cocaine levels (Landry et al., 1993). These could be used to treat addiction or the cardiovascular complications associated with cocaine use. While their clinical usefulness is likely to be limited due to their short half-life, these treatments may be useful in determining whether cocaine or its metabolites are responsible for delayed adverse cardiovascular responses occurring several hours after ingestion of cocaine. 7.10.8. Cardiovascular complications of treatments for cocaine addiction A wide variety of agents have been investigated as possible treatment for cocaine addiction (Halikas et al., 1993; Mendelson & Mello, 1996; Witkin, 1994). Some of these may have usefulness as treatment for cocaine-induced cardiovascular toxicity. Others may exacerbate the effects of cocaine by having additive or synergistic effects. Antidepressants that act as reuptake blockers (e.g., desipramine, chlorpromazine) have been suggested as potential treatments for addiction and for cardiovascular toxicity (Halikas et al., 1993; Knuepfer & Gan, 1997; Schindler et al., 2002; Tella et al., 1993). Although administration of desipramine has been reported to attenuate the tachycardia associated with cocaine use without altering cocaine levels (Kosten et al., 1992), others have suggested that desipramine pretreatment may enhance toxicity by enhancing plasma cocaine concentrations (Fischman et al., 1990; Misra et al., 1986; Tella & Goldberg, 1993). New reuptake blockers that are highly specific for the dopamine reuptake system have also been developed. GBR 12909 is one of these that has been promoted as a potential treatment for cocaine addiction since it reduces self-stimulation and place preference for cocaine (Rothman et al., 1989; Rothman & Glowa, 1995). GBR 12909 was particularly promising since it did not appear to exacerbate the hemodynamic responses to cocaine (Knuepfer & Gan, 1997; Tella, 1995, 1996). Subsequently, experimental and clinical trials suggested that GBR 12909 may prolong the QTc interval, and thereby contribute to the potential arrhythmogenic effects of cocaine. Several other related compounds are being tested for their usefulness in treating cocaine addiction that may be effective for reducing the incidence of cardiovascular toxicity. Partial dopamine agonists such as bromocriptine are also widely used for the treatment of cocaine addiction and may ameliorate the hemodynamic responses in humans (Kumor et al., 1989; Preston et al., 1992) and rats (Knuepfer & Gan, 1997). The mixed opiate agonist/antagonist buprenorphine has also been reported to be effective for treating cocaine addiction (Mello et al., 1989). Buprenorphine pretreatment did not alter hemodynamic responses to cocaine in humans (Teoh et al., 1993) or rats (Knuepfer & Gan, 1997), but did

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reduce toxicity to lethal injections in mice (Shukla et al., 1991; Witkin et al., 1991). Related compounds may also be found to be useful. There is evidence that vasoconstrictor responses may be enhanced by cocaine. Wilbert-Lampen et al. (1998) reported that endothelin accumulation was enhanced by treatment of porcine aortic endothelial cells with cocaine and that plasma and urine levels of endothelin in cocaine-intoxicated patients were elevated. They hypothesized that endothelin release may contribute to the coronary vasoconstriction and coronary ischemia associated with cocaine toxicity by a sreceptor mechanism. Therefore, s-receptor antagonists, such as haloperidol or ditolylguanidine, might be useful in treating toxicity (Wilbert-Lampen et al., 1998). Similarly, it has been proposed that k-agonists, such as enadoline and butorphanol, may reduce the reinforcing effects of cocaine through central actions on reducing dopamine availability (Mello & Negus, 2000). The central effects of these opioid agonists and antagonists may preclude their use in long-term treatment of addiction, but may also be effective for treating cardiovascular complications associated with cocaine. The extent of cocaine addiction in the United States and the relationship of cocaine use with life-threatening cardiovascular complications emphasizes the need for solutions. Novel drug treatments are being considered to curb the use of cocaine, as briefly mentioned here and summarized by others (Halikas et al., 1993; Mendelson & Mello, 1996; Witkin, 1994). As these treatments are being developed, it is important to not only characterize the effects of these drugs on the cardiovascular system, but also to determine their potential synergies with cocaine. In addition, any indication of abnormalities in individual test subjects should be investigated to determine whether idiosyncratic responses might be expected in some individuals.

8. Special considerations for experimental studies This review has attempted to identify not only our advances in understanding the effects of cocaine, but, more importantly, a number of areas in which further study is necessary to verify the causes of toxicity and appropriate treatments. It is apparent from the data obtained to date that some of the confusion regarding the pharmacologic and cardiotoxic effects of cocaine result from limitations of specific experimental protocols. These have been referred to throughout this review, but it is important to recognize these issues specifically in order to design appropriate experiments to clarify the causes of cocaine-induced cardiovascular disorders. Several issues should be considered when interpreting experimental data on the cardiovascular effects of cocaine or cocaine-induced cardiotoxicity. First, anesthesia or decerebration alters most hemodynamic responsiveness to cocaine, probably due to a prominent role of the diencephalon and telencephalon in mediating these responses. Second, in vitro

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Table 5 Factors predisposing individuals to cocaine toxicity Myocarditis Hypercoagulability Premature atherosclerosis Excessive alcohol consumption Smoking Hyperadrenergic syndrome Previous bout of excited delirium Deficit in plasma cholinesterase activity Risky behavior for sepsis (e.g., intravenous drug use or unprotected sex) Previous aneurysm or stroke

studies on the effects of cocaine should be limited to clinically relevant doses ( < 10 mg/L). Without functional innervation, these responses are often different than those observed in vivo. Third, species and strain differences are likely to contribute to variability in hemodynamic responses. Therefore, the responses in humans must be compared whenever possible. Fourth, studies examining the effects of lethal doses of cocaine may be addressing issues of massive overdoses, not the apparent idiosyncratic toxicity that is typically associated with cocaine use. Fifth, clinical data often cannot be directly reflected in animal experiments due to polydrug use by many cocaine addicts, the varying contaminants and diluents found in ‘‘street’’ cocaine, the risky behavior associated with drug abusers (Hudgins et al., 1995), and the poor health and nutrition often noted in drug users. Finally, variable hemodynamic responsiveness to cocaine in experimental studies might be important in identifying the causes of apparent greater sensitivity of some individuals to toxicity. In fact, the description of extreme responses in individual subjects might be particularly informative. This is rarely approached in a systematic manner. At this point, a number of possible factors may predispose individuals to toxicity (Table 5). The question remains as to whether the subset of the population at high risk for cocaine-induced chest pain can be identified and treated appropriately. It is quite likely that predisposition to cocaine-induced cardiac dysfunction and/or toxicity reflects a greater risk or susceptibility to cardiovascular disease in general. The need for additional studies on responsivity in different genetic strains may be instrumental in identifying the causes of greater sensitivity to cardiovascular disorders with or without cocaine use. These causes are likely to vary between individuals, making it particularly difficult to ascertain.

9. Remaining challenges and summary In conclusion, research efforts designed to improve our understanding of the cardiovascular effects of cocaine are, on one hand, promising and, at the same time, daunting. The efforts of many investigators have clarified a number of mechanisms by which cocaine acts on the body, and a

number of anomalies that have yet to be understood. Some of the salient findings are summarized here: (1) Despite the considerable research efforts in the past two decades, the causes of cardiovascular responses to cocaine are still not understood nor are the causes of myocardial toxicity in otherwise asymptomatic humans. Some of the confusion lies in the fact that the causes are likely to be multifactorial, such that the causes of cardiovascular toxicity vary in individuals. At this point, we have more questions than answers for this important problem in our society. Thrombotic occlusion has been verified in some (10 20% of patients). Vasospasm of major coronary vessels is rarely documented, but microvascular vasospasm or vasoconstriction may be enhanced by cocaine-induced arteriosclerosis. Otherwise, the incidence of chest pain associated with cocaine use is poorly understood because myocardial ischemia cannot be verified by acute ECG abnormalities alone, but only by elevated myocardial enzymes and/or angiographic evidence of coronary occlusion. (2) While myocardial infarction is rarely documented, cocaine use does increase the chance of experiencing AMI (Hollander et al., 1994; Mittleman et al., 1999). Although cocaine-related chest pain may often not be associated with true myocardial ischemia, palliative treatments, such as nitrovasodilators, thrombolytics, Ca2 + channel antagonists, and NaHCO3, will ameliorate symptoms in many patients. Thrombolytics, in particular, should only be used if the presence of an acute thrombus is determined to exist in the coronary circulation. (3) Susceptibility to cocaine-induced cardiac arrhythmias, ischemia, and sudden cardiac death varies widely in the population, complicating the identification of the causes in humans or in animal models. The availability of new tools to identify genetic causes of susceptibility to cocaineor stress-induced cardiovascular disease offers new hope to address this variability. (4) Toxicity to cocaine often occurs hours after peak blood levels are obtained. This delayed toxicity suggests a role for cocaine metabolites (Brogan et al., 1992; Nademanee et al., 1989), but little evidence is available to support this. This delay is often ignored in studies in animals, since acute effects are typically recorded. Currently, this is one of the most intractable problems in our understanding of the causes of adverse responses to cocaine in humans. (5) The sympathetic nervous system appears to be integral in determining adverse responsiveness to cocaine. Activation of the CNS sympathetic drive appears to be more important than peripheral effects on catecholamine nerve terminals (Shannon et al., 1995, 2000). Some of the controversy in this field of research is likely to hinge on evidence obtained in anesthetized or decerebrate animals, where sympathetic responsiveness and the behavioral arousal associated with psychostimulants that affects the autonomic response is blunted or abrogated. (6) The systemic vasoconstriction elicited by cocaine is mediated by adrenergic receptors, although the coronary

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vasoconstriction may be an exception (Boehrer et al., 1993; Daniel et al., 1995). Furthermore, coronary vasospasm and coronary vasoconstriction are difficult to differentiate, so the potential causes of apparent myocardial ischemia are unclear. Most studies cannot rule out vasoconstriction rather than vasospasm without conclusive angiographic evidence of vasospasm. Whether this short-lived coronary response contributes to the incidence of chest pain and to myocardial ischemia in most patients is doubtful. (7) The causes of diffuse cardiomyopathies associated with cocaine use are likely due to excess catecholamines rather than a direct toxic effect, since direct toxicity has typically been simulated using high concentrations of cocaine in vitro. The extent and reversibility of these lesions is not known. While the contribution of catecholamineinduced lesions to chronic heart disease is unclear, the myocardial fibrosis (Karch & Billingham, 1988, 1995; Virmani et al., 1988), the enhanced coronary microvascular responsiveness (Miao et al., 1996a) and accelerated atherosclerosis (Bacharach et al., 1992; Dressler et al., 1990; Kolodgie et al., 1991, 1992; Virmani et al., 1988) are more likely to contribute to myocardial dysfunction in the long term. These may be particularly important in understanding premature onset of disease in these patients possibly years after cocaine use with the premature development of myocardial disease processes. It will be difficult to assess whether cocaine use, particularly in younger individuals, accelerates the development of chronic myocardial disease, yet this may be critical to predict the long-term prognosis to prevent subsequent heart disease. In the future, there is a need for further clarification of the detrimental effects of cocaine on the cardiovascular system. Moreover, it will be important to identify whether these effects are unique to cocaine or may be generalized to other psychostimulants or to responses to behavioral stress. While there are certain constraints on the appropriate experimental procedures to obtain these data, there is a tremendous need to minimize the cost of this potent euphoric on our society and our health care system. An improved understanding of the mechanisms by which cocaine exerts its cardiotoxicity will allow better ameliorative and preventative treatment for cocaine toxicity.

Acknowledgements The editorial assistance of Drs. Steven Karch and Vernon Fischer and of Tracy Bloodgood, Ruth Rauls, and Erin Winkeler is gratefully acknowledged. This work was supported by USPHS grants DA 05180 and DA 13256.

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