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Ethanol alters hemodynamic responses to cocaine in rats
Drug and Alcohol Dependence 48 (1997) 17 – 24
Ethanol alters hemodynamic responses to cocaine in rats Patrick J. Mueller, Qi Gan, Mark M. Knuepfer * Department of Pharmacological and Physiological Science St. Louis Uni6ersity School of Medicine 1402 South Grand Boule6ard, St. Louis, MO 63104, USA Received 14 February 1997; accepted 27 June 1997
Abstract Cocaine is often used while consuming ethanol despite evidence that this combination may enhance the toxicity of cocaine. In the present study, we examined the cardiovascular effects of ethanol (475 or 950 mg/kg, i.v.) alone and in combination with cocaine (5 mg/kg, i.v.) in conscious rats. Ethanol or cocaine administration produced a consistent pressor response but highly variable cardiac output and systemic vascular resistance responses. The hemodynamic response patterns in individual rats to either drug were similar and related within rats. After ethanol pretreatment, cocaine produced greater decreases in cardiac output. We have proposed that this pattern of responses may reflect a predisposition in individual rats to cocaine-induced cardiomyopathies and hypertension. Furthermore, these data suggest that ethanol administration elicits a similar pattern of hemodynamic responses as previously reported for cocaine or amphetamine administration or acute behavioral stress. © 1997 Elsevier Science Ireland Ltd. Keywords: Cocaine; Ethanol; Arterial pressure; Cardiac output; Systemic vascular resistance; Hemodynamics
1. Introduction Although cocaine use has been linked to adverse cardiovascular effects and sudden death, it is still used by a significant proportion of the population. In addition, combining cocaine with other drugs of abuse is not uncommon (Schuster and Fischman, 1985; Grant and Hartford, 1990). Ethanol, for example, is often ingested while using cocaine (Grant and Hartford, 1990) either by circumstance or perhaps because it may enhance the stimulant properties of cocaine (Masur et al., 1989; Perez-Reyes and Jeffcoat, 1992; Farre´ et al., 1993). However, recent studies suggest that simultaneous use of cocaine and ethanol depresses cardiac function (Henning et al., 1994) and increases the risk of cardiac complications and death, beyond that attributed to either drug alone (Foltin and Fischman, 1988; Farre´ et al., 1993; Higgins et al., 1993; Uszenski et al., 1993). Indeed, ethanol and cocaine is one of the * Corresponding author. Tel.: +1 314 5778542; fax: + 1 314 5778233; e-mail: [email protected]
most common drug combinations found in drug-related emergency room visits (Drug Abuse Warning System, 1987). Previous studies from this laboratory (Branch and Knuepfer, 1993; Knuepfer and Branch, 1993) reported that cocaine elicits consistent decreases in cardiac output in some rats (designated vascular responders) and little change or an increase in cardiac output in other rats (designated mixed responders). Vascular responders are more likely to develop hypertension (Branch and Knuepfer, 1994) and cardiomyopathies (Knuepfer et al., 1993b) after chronic cocaine administration. Therefore, we have proposed that vascular responders may represent a subset of a population at higher risk for cocaine-induced cardiotoxicity. Likewise, it has been suggested that some humans are at greater risk, since substantial variability in individual responsiveness to cocaine-induced coronary vasoconstriction has been reported (Lange et al., 1989, 1990) and the relative dose of cocaine or route of administration appears unrelated to the incidence of electrocardiographic abnormalities (Minor et al., 1991), acute myocardial infarction (Isner
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et al., 1986; Amin et al., 1990) or toxicity (Smart and Anglin, 1987; Minor et al., 1991). The purpose of the present study was to characterize the cardiovascular responses to ethanol administration and compare them to those elicited by cocaine administration. More importantly, the effects of combined treatment with ethanol and cocaine were examined to identify whether ethanol alters the hemodynamic responses to cocaine. Our results suggest that ethanol administration evokes similar response patterns to those noted with cocaine and that the combination appears to exacerbate the cardiodepressant responses to cocaine in conscious rats.
2. Materials and methods
2.1. Animal preparation All procedures were approved by the Saint Louis University Animal Care Committee and are in accordance with the Guide for the Care and Use of Laboratory Animals as adopted by the National Institutes of Health. Male Sprague-Dawley rats (Harlan, Indianapolis, IN) weighing 275–350 g were anesthetized with sodium pentobarbital (45 mg/kg, i.p.). Using aseptic techniques, a pulsed Doppler flow probe (Iowa Doppler Products, Iowa City, IA) was placed around the ascending aorta for estimation of cardiac output as described previously (Branch and Knuepfer, 1993; Knuepfer and Branch, 1993). Rats were treated postoperatively with cefazolin (15 mg/kg, i.m.) and buprenorphine (0.3 mg/kg, s.c.). Following at least one week of recovery (7 – 10 days), rats were anesthetized with methoxyflurane so that femoral venous and arterial cannulae could be implanted for drug administration and determination of arterial blood pressure, respectively. After 2 or 3 days, rats were acclimated for 5 – 6 h in translucent Plexiglas cages 1 day prior to experimentation. On the day of experimentation, rats were placed in their cages for at least 1 h prior to drug administration. Cocaine (5 mg/kg) was administered intravenously over 45 s, while arterial blood pressure, heart rate and ascending aortic blood flow were recorded continuously. Similar to previous studies (Branch and Knuepfer, 1993, 1994; Knuepfer et al., 1993a,b), rats were divided into two groups, according to the maximum change in cardiac output after cocaine administration. Rats exhibiting a maximum decrease in cardiac output greater than eight percent were classified as vascular responders. Animals with an increase in cardiac output or a decrease of less than eight percent were classified as mixed responders. After a minimum of 3 h, 17 rats were pretreated intravenously with ethanol (475 or 950 mg/kg) followed
10 min later by cocaine (5 mg/kg). Similar doses of ethanol (500 and 1000 mg/kg) produce blood ethanol levels of 0.0669 0.007 and 0.1469 0.110% (0.1% is the common legal limit of intoxication in humans) respectively, 10 min after intravenous administration in rats (El-Mas and Abdel-Rahman, 1992). Mean arterial pressure (MAP), heart rate (HR) and cardiac output (CO) were used to calculate changes in systemic vascular resistance (MAP/CO) and stroke volume (CO/HR) as described in previous reports (Branch and Knuepfer, 1993, 1994; Knuepfer and Branch, 1993, 1993). Responses to cocaine and ethanol pretreatment, plus cocaine, were examined at the time of the maximum change in cardiac output. In addition, hemodynamic variables were examined at the peak pressor response and at 1, 3 and 5 min after cocaine administration. After ethanol pretreatment, cocaine-induced changes were compared to pre-ethanol baseline values. Data were also analyzed by comparing cocaine-induced responses to control values obtained 10 min after pretreatment with cocaine (not taking into account shifts in baseline values). These data are described in the results but not depicted in the figures. Baseline values, pretreatment effects, peak pressor responses and maximal changes in cardiac output were analyzed by two way analysis of variance (ANOVA) with a simple main effects test to determine individual group differences (Steel and Torrie, 1960). Sustained responses were analyzed at the three time points by three way ANOVA. All analyses were performed using CRUNCH (CRUNCH software, Oakland, CA). All data are presented as mean9 S.E.M. A P B 0.05 was considered significant. Drugs used included sodium pentobarbital (Fort Dodge Laboratories, Fort Dodge, IA), methoxyflurane (Pitman-Moore, Mundelein, IL), cefazolin (Geneva Pharmaceutical, Broomfield, CO), buprenorphine hydrochloride (Reckitt and Colman Pharmaceuticals, Richmond, VA), cocaine hydrochloride (National Institute on Drug Abuse, Rockville, MD) and ethanol (Aaper Alcohol and Chemical, Shelbyville, KY).
3. Results
3.1. Effects of cocaine treatment Baseline values are shown in Table 1. These values were not significantly different before cocaine or ethanol administration in the two groups studied. The hemodynamic effects of cocaine are shown in Fig. 1 (solid line). Cocaine administration resulted in increases in blood pressure, systemic vascular resistance and stroke volume in 17 rats. Typically, tachycardia occurred during the peak pressor response while bradycardia was observed 1, 3 and 5 min after cocaine.
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Likewise, cardiac output responses were increased initially in all rats and then decreased (in some rats) after cocaine. As reported in previous studies (Knuepfer and Branch, 1993; Branch and Knuepfer, 1993, 1994), the maximum change in cardiac output in individual animals varied such that some rats had a decrease in cardiac output (\8%) and a greater increase in systemic vascular resistance (designated vascular responders, n=9), whereas other animals (designated mixed responders, n =8) had little change or an increase in cardiac output. Despite these differences in responsiveness, arterial blood pressure and heart rate responses to cocaine were similar in all rats. 3.2. Effects of ethanol treatment alone Ten rats received both low and high doses of ethanol on separate days. Of the remaining rats, four did not get the high dose and three did not receive the low dose, usually due to failures in the arterial pressure or cardiac output recording. Control doses (cocaine alone) were obtained before each dose of ethanol for statistical comparisons. Table 1 Baseline hemodynamic variables and effects of ethanol pretreatment Ethanol (475 mg/kg) Before COC
Mixed responders AP (mmHg) HR (b/min) CO (kHz shift)
(n= 6) 122 9 5 3859 12 9.4 90.7
Vascular responders (n =7) AP (mmHg) 112 93 HR (b/min) 388 97 CO (kHz 9.7 90.8 shift)
Before EtOH
After EtOH, before COC
1249 2 3869 11 9.39 0.6
1319 4 3829 11 9.49 0.6
1169 4 3909 14 9.79 0.7
1269 6* 352 9 7* 9.09 0.7
Ethanol (950 mg/kg) Before COC
Mixed responders AP (mmHg) HR (b/min) CO (kHz shift)
(n =7) 114 9 4 376 9 13 9.6 90.6
Vascular responders (n = 7) AP (mmHg) 117 9 2 HR (b/min) 369 913 CO (kHz 10.4 90.5 shift)
Before EtOH
After EtOH, before COC
1179 4 3829 16 9.69 0.8
1319 4* 3519 13* 9.49 0.6
1239 1 3859 10 10.49 0.7
1359 4* 3439 8* 9.39 0.6
No differences between values from vascular and mixed responders were noted in these two groups. * Represents significant change from baseline after ethanol pretreatment; AP, arterial pressure.
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Ethanol administration (475 or 950 mg/kg, i.v.) resulted in an increase in mean arterial blood pressure, due in part to an increase in systemic vascular resistance and, to a lesser extent, an increase in cardiac output (Fig. 1). Heart rate had a biphasic response (a tachycardia followed by a bradycardia). Despite the differences in pharmacologic profile, the hemodynamic responses to cocaine (5 mg/kg) and to ethanol (particularly 950 mg/kg) were strikingly similar in magnitude and duration. Rats were separated into vascular and mixed responders according to their cardiac output response as described above. The lower dose of ethanol (475 mg/kg) evoked differential heart rate, cardiac output and systemic vascular resistance responses (Fig. 2). Responses at the time of the peak change in cardiac output (usually occurring within 2 min) were similar to those elicited by 5 mg/kg cocaine, except that vascular responders had a smaller decrease in cardiac output (Fig. 2). The hemodynamic responses to a higher dose of ethanol (950 mg/kg) were also variable, but the responses did not resemble those elicited by cocaine as closely. An ANOVA revealed that there were no differences between responses evoked by both doses of ethanol and by the single dose of cocaine. Ten minutes after ethanol pretreatment, just prior to cocaine administration, arterial blood pressure and systemic vascular resistance were elevated. Heart rate was significantly lower but cardiac output had returned to baseline (Table 1). These data are represented in Figs. 3 and 4 as changes in baseline at the zero time point.
3.3. Effects of ethanol pretreatment on cocaine responses Pretreatment with the lower dose of ethanol (475 mg/kg) caused an enhancement of the cocaine-induced pressor response, bradycardia and increase in systemic vascular resistance in all rats. These responses may represent a shift from baseline values (Fig. 3 and Table 1). The cardiac output responses at the time of the peak pressor response and at 1 min after cocaine administration were reduced significantly, without a change in baseline values (Fig. 3 and Table 1). Stroke volume was not affected (data not shown). Analysis of the changes using post-ethanol treatment control values demonstrated an enhanced decrease in cardiac output and increase in systemic vascular resistance (data not shown). The higher dose of ethanol (950 mg/kg) altered hemodynamic responses to cocaine such that the decreases in cardiac output and heart rate and the increase in systemic vascular resistance were enhanced (Fig. 4). As noted earlier, the change in heart rate and systemic vascular resistance may have been due to differences in baseline values after pretreatment with
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Fig. 1. Cardiovascular effects of cocaine (5 mg/kg, open circles), ethanol (475 mg/kg, solid squares) and ethanol (950 mg/kg, solid circles) at the peak pressor response and at 1, 3 and 5 min following the initiation of drug injection (black bar). Significant effects of ethanol, as determined by two way (peak pressor response) and three way (1, 3 and 5 min) analysis of variance (ANOVA), are denoted with an asterisk. Abbreviations include: MAP, mean arterial blood pressure; HR, heart rate; CO, cardiac output; and SysVR, systemic vascular resistance. All data are expressed as mean9S.E.M.
ethanol (Fig. 4 and Table 1). In contrast, the change in cardiac output could not be attributed to this effect. Vascular responders also had a greater decrease in stroke volume after pretreatment with the higher dose of ethanol (data not shown). When examined using post-ethanol values as control, there was a decrease in the cocaine-induced pressor response and more negative cardiac output and stroke volume responses (data not shown). At the time of the maximal change in cardiac output induced by cocaine, ethanol (475 mg/kg) pretreatment potentiated the increases in blood pressure by enhancing the increase in systemic vascular resistance (data not shown). Ethanol (950 mg/kg) enhanced the decrease in cardiac output and heart rate and the increase in arterial pressure and systemic vascular resistance at the time of the maximal cardiac output change (data not shown). Therefore, cardiac output responses were more negative in both groups after ethanol pretreatment suggesting that the rats may be more prone to cocaine-induced cardiodepression.
4. Discussion The present results suggest that the hemodynamic effects of cocaine are altered in several ways by pretreatment with ethanol. While it is difficult to ascertain whether toxicity is enhanced because the doses utilized were not excessively high, the specific characteristics of
these responses suggest that toxicity would be enhanced, since cardiac function is more severely depressed with combined treatment than with either agent alone. Similarly, Hennings and coworkers (1994) noted that the combination of cocaine and ethanol depressed dP/dt synergistically in chloralose-anesthetized dogs. Maillet et al. (1994) reported that ethanol coadministration enhances myocardial ultrastructural damage in cocaine treated rats. Since the cocaine-induced decrease in cardiac output noted in some rats has been associated with a higher incidence of cardiomyopathies (Knuepfer and Branch, 1993), we speculate that ethanol coadministration would potentiate cocaine-induced cardiomyopathies in rats. Several interactions between cocaine and ethanol have been reported in clinical studies. Ethanol potentiates cocaine-induced increases in heart rate (PerezReyes and Jeffcoat, 1992; Farre´ et al., 1993; Higgins et al., 1993) and blood pressure in humans (Foltin and Fischman, 1988; Perez-Reyes and Jeffcoat, 1992). Hime et al. (1991) cite an epidemiological study that suggests ethanol increases the risk of cocaine-related sudden death in humans by more than twenty fold. These findings indicate that the concurrent use of these agents may have detrimental effects. Our results from rats concur with these conclusions and offer a more detailed description of the hemodynamic consequences of their combined use. Several reports have described differential responsiveness in humans to coronary vasoconstriction (Lange et
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Fig. 2. Cardiovascular effects of cocaine (5 mg/kg) and ethanol (475 and 950 mg/kg) at the time of the maximum change in cardiac output (usually within the two minutes after drug). Large symbols (c ) represent overall differences between vascular responders (solid bars) and mixed responders (open bars) as determined by two way ANOVA. Asterisks represent differences between responses to cocaine and those to ethanol for individual doses of ethanol as determined by a simple main effects test. Abbreviations are defined in Fig. 1.
al., 1989; Flores et al., 1990), cardiac pathology (Isner et al., 1986; Amin et al., 1990) and lethal effects of cocaine (Smart and Anglin, 1987; Minor et al., 1991). With the limited evidence available (Hime et al., 1991), it appears that humans consuming ethanol and cocaine concomitantly may be at higher risk for adverse cardiac events. Although suggested by our data and that of the substantial number of clinical cases of morbidity associated with combined use of cocaine and ethanol, it is unknown whether humans have differential susceptibilities to cocaine or whether ethanol may enhance this effect in particular individuals. The data suggest that ethanol pretreatment selectively alters the cardiovascular effects of cocaine in a subset of rats classified on the basis of their susceptibility to cocaine. In previous studies, this laboratory has reported that some rats have decreases in cardiac output after cocaine administration (Branch and Knuepfer, 1993). These animals have been termed vascular responders (called responders in previous papers) as the pressor response in these animals is mediated entirely by an increase in systemic vascular resistance. The pressor response in mixed responders (formerly named nonresponders), although identical to that of vascular responders, is typically mediated by a smaller increase in systemic vascular resistance and a small increase in cardiac output. Compared to mixed responders, vascular responders have been shown to be more likely to develop hypertension (Branch and Knuepfer, 1994) and severe cardiomyopathies (Knuepfer et al., 1993b) after chronic cocaine treatment. These observations suggest
that vascular responders represent a subset of the population that is more susceptible to cocaine-induced cardiotoxicity. In the present paper, ethanol pretreatment altered hemodynamic responses in mixed responders such that most rats had significant decreases in cardiac output and greater increases in systemic vascular resistance. Vascular responders had greater decreases in cardiac output despite no significant change in resting aortic flow after pretreatment with the higher (950 mg/kg) dose of ethanol, suggesting enhanced cardiac depression. The rationale for comparing data using the preethanol control values should be clarified, since previous studies from our laboratory (Branch and Knuepfer, 1993, 1994; Knuepfer and Branch, 1993, 1993) compared data to the control value immediately before cocaine administration (ignoring any changes in baseline values due to drug pretreatment). The data were analyzed in this manner in order to incorporate the effects of the ethanol alone, such that changes due to an ethanol-induced shift in the baseline values were clearly evident in the figures. In this manner, changes elicited by ethanol before cocaine administration could be readily noted with regard to their effect on cocaine-induced responses. This analysis assumes that the hemodynamic values at 10 min after ethanol were unchanged for the following 5 min (after cocaine administration) since the control experiment (ethanol alone) was not performed. We believe that this assumption is appropriate in this case for two reasons. Firstly, the hepatic metabolism of ethanol is relatively slow compared to the metabolism
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Fig. 3. Cardiovascular effects of cocaine (COC, 5 mg/kg), compared to ethanol plus cocaine ( +EtOH 475 mg/kg). Significant effects of ethanol, as determined by two way ANOVA, are denoted with an asterisk. Significant differences, as determined by a simple main effects test, between vascular responders (solid bars) and mixed responders (open bars) are described in the text. Abbreviations are defined in Fig. 1.
of cocaine, suggesting that responses after 10 min are not going to be much different at 15 min. Secondly, the major hemodynamic responses to cocaine of interest to us (pressor and cardiac output responses) are maximal in the first 1–2 min after cocaine administration. For these reasons, we analyzed the data as depicted. The results with regard to the cardiac output responses, in particular, were similar whether the pre- or postethanol treatment values were used. The cardiovascular effects of ethanol administration alone are also intriguing. We reported that the characteristic hemodynamic responses to cocaine in individual rats are similar to those elicited by air jet stress (Knuepfer et al., 1993a) and amphetamine administration (Branch and Knuepfer, 1994). In the present paper, we observed that ethanol, like cocaine, produces differential cardiac output and systemic vascular resistance responses that correlate with the response patterns noted with cocaine. In other words, vascular responders (to cocaine) also exhibited decreases in cardiac output and greater increases in systemic vascular resistance with ethanol administration, while arterial blood pressure and heart rate responses were not different. In conjunction with previous papers (Branch and Knuepfer, 1994; Knuepfer et al., 1993a,b), these results suggest that individuals may exhibit differential sensitivities to a large group of agents and provocations which include stimulants (amphetamine, cocaine), depressants (ethanol) and behavioral stressors (acute air jet). We propose that they either directly (air jet) or
indirectly (psychoactive agents) produce behavioral stress. The hemodynamic response pattern to this stress may reflect differential susceptibilities to cardiovascular disease and sudden death. There are several mechanism by which ethanol might alter the cardiovascular effects of cocaine. The effects of ethanol on cocaine-mediated responses could be due to the formation of cocaethylene, a metabolite formed when ethanol and cocaine are administered in humans (Perez-Reyes and Jeffcoat, 1992; Farre´ et al., 1993) and rats (Levine and Tebbett, 1994). Although some of the long term adverse effects of cocaine have been attributed to cocaethylene (Hearn et al., 1991; Farre´ et al., 1993), evidence supporting cocaethylene’s role in the acute cardiovascular effects of ethanol and cocaine combinations is lacking (Perez-Reyes and Jeffcoat, 1992; Uszenski et al., 1993). In clinical studies where cocaethylene levels were measured, a decline in subjective and heart rate responses was observed at a time when cocaethylene levels were only beginning to appear in the blood (Perez-Reyes and Jeffcoat, 1992). In the present paper, ethanol pretreatment had little effect on arterial blood pressure and heart rate responses to cocaine. In addition, only mixed responders were dramatically affected by the ethanol and cocaine combinations. If a metabolite, such as cocaethylene, was involved in these responses, we would have expected more dramatic effects on blood pressure, heart rate and other corresponding variables. Similar responses would result if there were enhanced levels of cocaine after
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Fig. 4. Cardiovascular effects of cocaine (COC, 5 mg/kg) compared to ethanol and cocaine (EtOH, 950 mg/kg). Data were analyzed as described in Fig. 3. Abbreviations are defined in Fig. 1.
ethanol pretreatment. Prior ethanol consumption appears to increase plasma levels of intranasally administered cocaine in humans (Perez-Reyes and Jeffcoat, 1992; Farre´ et al., 1993). However, it has been reported that ethanol pretreatment does not alter blood levels of cocaine in rats (Dean et al., 1992; Levine and Tebbett, 1994) or dogs (Uszenski et al., 1993). Although we did not measure cocaine or cocaethylene levels, we suggest neither inhibition of cocaine metabolism nor formation of cocaethylene are likely to be involved in these early hemodynamic responses. Although ethanol (Hayes and Bove, 1988) and cocaine (Lange et al., 1989, 1990) have been shown to produce coronary vasoconstriction, it does not appear that ethanol potentiates cocaine-induced coronary vasoconstriction, at least in sedated dogs (Uszenski et al., 1993). Therefore, the effect of ethanol on the cardiovascular responses to cocaine as yet do not appear to be mediated by an ischemic mechanism (Uszenski et al., 1993). It has been suggested that ethanol and cocaine have additive effects, since a 2 h infusion of ethanol depressed left ventricular ejection fraction (LVEF) prior to injecting cocaine, which further reduced LVEF (Uszenski et al., 1993). Interestingly, in the present paper, cocaine or ethanol alone increased cardiac output in mixed responders, but when combined, produced decreases in cardiac output. In summary, our results concur with others in that coadministration of ethanol with cocaine appears to enhance cardiac depression. This effect is, at least, additive in vascular responders and possibly synergistic
in mixed responders where responses were reversed. The mechanism by which this occurs is unclear, but may depend on initial susceptibility to cocaine-induced cardiotoxicity. In addition, ethanol alone appears to produce responses similar to and related to hemodynamic responses to cocaine, amphetamine and air jet stress. These data suggest that some individuals may be more sensitive to a variety of agents that evoke behavioral stress perhaps due to the specific autonomic nervous system responses that are evoked by these stimuli.
Acknowledgements This work was supported by USPHS Grants DA 05180 and NS 07254. The authors would like to thank Dr Terry M. Egan for constructive criticism of this manuscript. Portions of this work were presented in abstract form (Gan, Q. and M.M. Knuepfer and Branch, 1993, FASEB J. 7, A473 and Gan, Q. and M.M. Knuepfer, 1994, NIDA Monograph 141, 317).
References Amin, M., Gabelman, G., Karpel, J., Buttrick, P., 1990. Acute myocardial infarction and chest pain syndromes after cocaine use. Am. J. Cardiol. 66, 1434 – 1437. Branch, C.A., Knuepfer, M.M., 1993. Dichotomous cardiac and systemic vascular responses to cocaine in conscious rats. Life Sci. 52, 85 – 93.
P.J. Mueller et al. / Drug and Alcohol Dependence 48 (1997) 17–24
24
Branch, C.A., Knuepfer, M.M., 1994. Causes of differential cardiovascular sensitivity to cocaine I: Studies in conscious rats. J. Pharmacol. Exp. Ther. 269, 674–683. Dean, R.A., Harper, E.T., Dumaual, N., Stoeckel, D.A., Bosron, W.F., 1992. Effects of ethanol on cocaine metabolism: Formation of cocaethylene and norcocaethylene. Toxicol. Appl. Pharmacol. 117, 1 – 8. Drug Abuse Warning System (DAWN), 1987. National Institute on Drug Abuse, Washington DC, NIDA Statistical Series, no. 7, DHHS publication no. (ADM) 88. El-Mas, M.M., Abdel-Rahman, A.A., 1992. Role of aortic baroreceptors in ethanol-induced impairment of baroreflex control of heart rate in conscious rats. J. Pharmacol. Exp. Ther. 262, 157– 165. Farre´, M., De la Torre, R., Llorente, M., Lamas, X., Ugena, B., Segura, J., Cami, J., 1993. Alcohol and cocaine interactions in humans. J. Pharmacol. Exp. Ther. 266, 1364–1373. Flores, E.D., Lange, R.A., Cigarroa, R.G., Hillis, L.D., 1990. Effect of cocaine on coronary artery dimensions in atherosclerotic coronary artery disease: Enhanced vasoconstriction at sites of significant stenoses. J. Am. Coll. Cardiol. 16, 74–79. Foltin, R.W., Fischman, M.W., 1988. Ethanol and cocaine interactions in humans: Cardiovascular consequences. Pharmacol. Biochem. Behav. 31, 877–883. Grant, B.F., Hartford, T.C., 1990. Concurrent and simultaneous use of alcohol with cocaine: results of national survey. Drug Alcohol Depend. 25, 97 – 104. Hayes, S.N., Bove, A.A., 1988. Ethanol causes epicardial coronary artery vasoconstriction in the intact dog. Circulation 78, 165 – 170. Hearn, W.L., Rose, S., Wagner, J., Ciarleglio, A., Mash, D.C., 1991. Cocaethylene is more potent that cocaine in mediating lethality. Pharmacol. Biochem. Behav. 39, 531–533. Henning, R.J., Wilson, L.D., Glauser, J.M., 1994. Cocaine plus ethanol is more cardiotoxic than cocaine or ethanol alone. Crit. Care Med. 22, 1896 –1906. Higgins, S.T., Rush, C.R., Bickel, W.K., Hughes, J.R., Lynn, M., Capeless, M.A., 1993. Acute behavioral and cardiac effects of cocaine and alcohol combinations in humans. Psychopharmacology 111, 285 – 294. Hime, G.W., Hearn, W.L., Rose, S., Cofino, J., 1991. Analysis of cocaine and cocaethylene in blood and tissues by GC-NPD and GC-ion trap mass spectrometry. J. Anal. Toxicol. 15, 241 – 245. Isner, J.M., Estes, N.A., Thompson, P.D., Costanzo-Nordin, M.R., Subramanian, R., Miller, G., Katsas, G., Sturner, W.Q., 1986. Acute cardiac events temporally related to cocaine abuse. New Engl. J. Med. 315, 1438–1443.
.
Knuepfer, M.M., Branch, C.A., 1993. Calcium channel antagonists reduce the cocaine-induced decrease in cardiac output in a subset of rats. J. Cardiovasc. Pharmacol. 21, 390 – 396. Knuepfer, M.M., Branch, C.A., Mueller, P.J., Gan, Q., 1993a. Stress and cocaine elicit similar cardiac output responses in individual rats. Am. J. Physiol. 265, H779 – H782. Knuepfer, M.M., Branch, C.A., Gan, Q., Fischer, V.W., 1993b. Cocaine-induced myocardial ultrastructural alterations and cardiac output responses in rats. Exp. Mol. Pathol. 59, 155–168. Lange, R.A., Cigarroa, R.G., Flores, E.D., McBride, W., Kim, A.S., Wells, P.J., Bedotto, J.B., Danziger, R.S., Hillis, L.D., 1990. Potentiation of cocaine-induced coronary vasoconstriction by beta-adrenergic blockade. Ann. Intern. Med. 112, 897 – 903. Lange, R.A., Cigarroa, R.G., Yancy, C.W., Willard, J.E., Popma, J.J., Sillis, J.N., McBride, W., Kim, A.S., Hillis, L.D., 1989. Cocaine-induced coronary-artery vasoconstriction. New Engl. J. Med. 321, 1557 – 1562. Levine, B.S., Tebbett, I.R., 1994. Cocaine pharmacokinetics in ethanol-pretreated rats. Drug Metab. Dispos. 22, 498 – 500. Maillet, M., Chiarasini, D., Heller, M., Latour, C., Nahas, G., 1994. Interactions of alcohol and cocaine administration on myocardial ultrastructure. FASEB J. 8, A312. Masur, J., Souza-Formigoni, J.L.O., Pires, J.L.N., 1989. Increased stimulatory effect by the combined administration of cocaine and alcohol in mice. Alcohol 6, 181 – 182. Minor, R.L. Jr., Scott, B.D., Brown, D.D., Winniford, M.D., 1991. Cocaine-induced myocardial infarction in patients with normal coronary arteries. Ann. Int. Med. 115, 797 – 806. Perez-Reyes, M., Jeffcoat, A.R., 1992. Ethanol/cocaine interaction: Cocaine and cocaethylene plasma concentrations and their relationship to subjective and cardiovascular effects. Life Sci. 51, 553 – 563. Schuster, C.R., Fischman, M.W., 1985. Characteristics of humans volunteering for a cocaine research project. In: Kozel, J.J., Adams, E.H. (Eds.), Cocaine Use in America: Epidemiologic and Clinical Perspectives. US Government Printing Office Washingtion, DC, NIDA Res. Monog. 61, pp. 158 – 170. Smart, R.G., Anglin, L., 1987. Do we know the lethal dose of cocaine?. J. Forensic Sci. 32, 303 – 312. Steel, R.G.D., Torrie, J.H., 1960. Principles and Procedures of Statistics, McGraw-Hill, New York, pp. 196 – 197. Uszenski, R.T., Gillis, R.A., Schaer, G.L., Analouei, A.R., Kuhn, F.E., 1993. Additive myocardial depressant effects of cocaine and ethanol. Am. Heart J. 124, 1276 – 1283.
Ethanol alters hemodynamic responses to cocaine in rats Patrick J. Mueller, Qi Gan, Mark M. Knuepfer * Department of Pharmacological and Physiological Science St. Louis Uni6ersity School of Medicine 1402 South Grand Boule6ard, St. Louis, MO 63104, USA Received 14 February 1997; accepted 27 June 1997
Abstract Cocaine is often used while consuming ethanol despite evidence that this combination may enhance the toxicity of cocaine. In the present study, we examined the cardiovascular effects of ethanol (475 or 950 mg/kg, i.v.) alone and in combination with cocaine (5 mg/kg, i.v.) in conscious rats. Ethanol or cocaine administration produced a consistent pressor response but highly variable cardiac output and systemic vascular resistance responses. The hemodynamic response patterns in individual rats to either drug were similar and related within rats. After ethanol pretreatment, cocaine produced greater decreases in cardiac output. We have proposed that this pattern of responses may reflect a predisposition in individual rats to cocaine-induced cardiomyopathies and hypertension. Furthermore, these data suggest that ethanol administration elicits a similar pattern of hemodynamic responses as previously reported for cocaine or amphetamine administration or acute behavioral stress. © 1997 Elsevier Science Ireland Ltd. Keywords: Cocaine; Ethanol; Arterial pressure; Cardiac output; Systemic vascular resistance; Hemodynamics
1. Introduction Although cocaine use has been linked to adverse cardiovascular effects and sudden death, it is still used by a significant proportion of the population. In addition, combining cocaine with other drugs of abuse is not uncommon (Schuster and Fischman, 1985; Grant and Hartford, 1990). Ethanol, for example, is often ingested while using cocaine (Grant and Hartford, 1990) either by circumstance or perhaps because it may enhance the stimulant properties of cocaine (Masur et al., 1989; Perez-Reyes and Jeffcoat, 1992; Farre´ et al., 1993). However, recent studies suggest that simultaneous use of cocaine and ethanol depresses cardiac function (Henning et al., 1994) and increases the risk of cardiac complications and death, beyond that attributed to either drug alone (Foltin and Fischman, 1988; Farre´ et al., 1993; Higgins et al., 1993; Uszenski et al., 1993). Indeed, ethanol and cocaine is one of the * Corresponding author. Tel.: +1 314 5778542; fax: + 1 314 5778233; e-mail: [email protected]
most common drug combinations found in drug-related emergency room visits (Drug Abuse Warning System, 1987). Previous studies from this laboratory (Branch and Knuepfer, 1993; Knuepfer and Branch, 1993) reported that cocaine elicits consistent decreases in cardiac output in some rats (designated vascular responders) and little change or an increase in cardiac output in other rats (designated mixed responders). Vascular responders are more likely to develop hypertension (Branch and Knuepfer, 1994) and cardiomyopathies (Knuepfer et al., 1993b) after chronic cocaine administration. Therefore, we have proposed that vascular responders may represent a subset of a population at higher risk for cocaine-induced cardiotoxicity. Likewise, it has been suggested that some humans are at greater risk, since substantial variability in individual responsiveness to cocaine-induced coronary vasoconstriction has been reported (Lange et al., 1989, 1990) and the relative dose of cocaine or route of administration appears unrelated to the incidence of electrocardiographic abnormalities (Minor et al., 1991), acute myocardial infarction (Isner
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et al., 1986; Amin et al., 1990) or toxicity (Smart and Anglin, 1987; Minor et al., 1991). The purpose of the present study was to characterize the cardiovascular responses to ethanol administration and compare them to those elicited by cocaine administration. More importantly, the effects of combined treatment with ethanol and cocaine were examined to identify whether ethanol alters the hemodynamic responses to cocaine. Our results suggest that ethanol administration evokes similar response patterns to those noted with cocaine and that the combination appears to exacerbate the cardiodepressant responses to cocaine in conscious rats.
2. Materials and methods
2.1. Animal preparation All procedures were approved by the Saint Louis University Animal Care Committee and are in accordance with the Guide for the Care and Use of Laboratory Animals as adopted by the National Institutes of Health. Male Sprague-Dawley rats (Harlan, Indianapolis, IN) weighing 275–350 g were anesthetized with sodium pentobarbital (45 mg/kg, i.p.). Using aseptic techniques, a pulsed Doppler flow probe (Iowa Doppler Products, Iowa City, IA) was placed around the ascending aorta for estimation of cardiac output as described previously (Branch and Knuepfer, 1993; Knuepfer and Branch, 1993). Rats were treated postoperatively with cefazolin (15 mg/kg, i.m.) and buprenorphine (0.3 mg/kg, s.c.). Following at least one week of recovery (7 – 10 days), rats were anesthetized with methoxyflurane so that femoral venous and arterial cannulae could be implanted for drug administration and determination of arterial blood pressure, respectively. After 2 or 3 days, rats were acclimated for 5 – 6 h in translucent Plexiglas cages 1 day prior to experimentation. On the day of experimentation, rats were placed in their cages for at least 1 h prior to drug administration. Cocaine (5 mg/kg) was administered intravenously over 45 s, while arterial blood pressure, heart rate and ascending aortic blood flow were recorded continuously. Similar to previous studies (Branch and Knuepfer, 1993, 1994; Knuepfer et al., 1993a,b), rats were divided into two groups, according to the maximum change in cardiac output after cocaine administration. Rats exhibiting a maximum decrease in cardiac output greater than eight percent were classified as vascular responders. Animals with an increase in cardiac output or a decrease of less than eight percent were classified as mixed responders. After a minimum of 3 h, 17 rats were pretreated intravenously with ethanol (475 or 950 mg/kg) followed
10 min later by cocaine (5 mg/kg). Similar doses of ethanol (500 and 1000 mg/kg) produce blood ethanol levels of 0.0669 0.007 and 0.1469 0.110% (0.1% is the common legal limit of intoxication in humans) respectively, 10 min after intravenous administration in rats (El-Mas and Abdel-Rahman, 1992). Mean arterial pressure (MAP), heart rate (HR) and cardiac output (CO) were used to calculate changes in systemic vascular resistance (MAP/CO) and stroke volume (CO/HR) as described in previous reports (Branch and Knuepfer, 1993, 1994; Knuepfer and Branch, 1993, 1993). Responses to cocaine and ethanol pretreatment, plus cocaine, were examined at the time of the maximum change in cardiac output. In addition, hemodynamic variables were examined at the peak pressor response and at 1, 3 and 5 min after cocaine administration. After ethanol pretreatment, cocaine-induced changes were compared to pre-ethanol baseline values. Data were also analyzed by comparing cocaine-induced responses to control values obtained 10 min after pretreatment with cocaine (not taking into account shifts in baseline values). These data are described in the results but not depicted in the figures. Baseline values, pretreatment effects, peak pressor responses and maximal changes in cardiac output were analyzed by two way analysis of variance (ANOVA) with a simple main effects test to determine individual group differences (Steel and Torrie, 1960). Sustained responses were analyzed at the three time points by three way ANOVA. All analyses were performed using CRUNCH (CRUNCH software, Oakland, CA). All data are presented as mean9 S.E.M. A P B 0.05 was considered significant. Drugs used included sodium pentobarbital (Fort Dodge Laboratories, Fort Dodge, IA), methoxyflurane (Pitman-Moore, Mundelein, IL), cefazolin (Geneva Pharmaceutical, Broomfield, CO), buprenorphine hydrochloride (Reckitt and Colman Pharmaceuticals, Richmond, VA), cocaine hydrochloride (National Institute on Drug Abuse, Rockville, MD) and ethanol (Aaper Alcohol and Chemical, Shelbyville, KY).
3. Results
3.1. Effects of cocaine treatment Baseline values are shown in Table 1. These values were not significantly different before cocaine or ethanol administration in the two groups studied. The hemodynamic effects of cocaine are shown in Fig. 1 (solid line). Cocaine administration resulted in increases in blood pressure, systemic vascular resistance and stroke volume in 17 rats. Typically, tachycardia occurred during the peak pressor response while bradycardia was observed 1, 3 and 5 min after cocaine.
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Likewise, cardiac output responses were increased initially in all rats and then decreased (in some rats) after cocaine. As reported in previous studies (Knuepfer and Branch, 1993; Branch and Knuepfer, 1993, 1994), the maximum change in cardiac output in individual animals varied such that some rats had a decrease in cardiac output (\8%) and a greater increase in systemic vascular resistance (designated vascular responders, n=9), whereas other animals (designated mixed responders, n =8) had little change or an increase in cardiac output. Despite these differences in responsiveness, arterial blood pressure and heart rate responses to cocaine were similar in all rats. 3.2. Effects of ethanol treatment alone Ten rats received both low and high doses of ethanol on separate days. Of the remaining rats, four did not get the high dose and three did not receive the low dose, usually due to failures in the arterial pressure or cardiac output recording. Control doses (cocaine alone) were obtained before each dose of ethanol for statistical comparisons. Table 1 Baseline hemodynamic variables and effects of ethanol pretreatment Ethanol (475 mg/kg) Before COC
Mixed responders AP (mmHg) HR (b/min) CO (kHz shift)
(n= 6) 122 9 5 3859 12 9.4 90.7
Vascular responders (n =7) AP (mmHg) 112 93 HR (b/min) 388 97 CO (kHz 9.7 90.8 shift)
Before EtOH
After EtOH, before COC
1249 2 3869 11 9.39 0.6
1319 4 3829 11 9.49 0.6
1169 4 3909 14 9.79 0.7
1269 6* 352 9 7* 9.09 0.7
Ethanol (950 mg/kg) Before COC
Mixed responders AP (mmHg) HR (b/min) CO (kHz shift)
(n =7) 114 9 4 376 9 13 9.6 90.6
Vascular responders (n = 7) AP (mmHg) 117 9 2 HR (b/min) 369 913 CO (kHz 10.4 90.5 shift)
Before EtOH
After EtOH, before COC
1179 4 3829 16 9.69 0.8
1319 4* 3519 13* 9.49 0.6
1239 1 3859 10 10.49 0.7
1359 4* 3439 8* 9.39 0.6
No differences between values from vascular and mixed responders were noted in these two groups. * Represents significant change from baseline after ethanol pretreatment; AP, arterial pressure.
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Ethanol administration (475 or 950 mg/kg, i.v.) resulted in an increase in mean arterial blood pressure, due in part to an increase in systemic vascular resistance and, to a lesser extent, an increase in cardiac output (Fig. 1). Heart rate had a biphasic response (a tachycardia followed by a bradycardia). Despite the differences in pharmacologic profile, the hemodynamic responses to cocaine (5 mg/kg) and to ethanol (particularly 950 mg/kg) were strikingly similar in magnitude and duration. Rats were separated into vascular and mixed responders according to their cardiac output response as described above. The lower dose of ethanol (475 mg/kg) evoked differential heart rate, cardiac output and systemic vascular resistance responses (Fig. 2). Responses at the time of the peak change in cardiac output (usually occurring within 2 min) were similar to those elicited by 5 mg/kg cocaine, except that vascular responders had a smaller decrease in cardiac output (Fig. 2). The hemodynamic responses to a higher dose of ethanol (950 mg/kg) were also variable, but the responses did not resemble those elicited by cocaine as closely. An ANOVA revealed that there were no differences between responses evoked by both doses of ethanol and by the single dose of cocaine. Ten minutes after ethanol pretreatment, just prior to cocaine administration, arterial blood pressure and systemic vascular resistance were elevated. Heart rate was significantly lower but cardiac output had returned to baseline (Table 1). These data are represented in Figs. 3 and 4 as changes in baseline at the zero time point.
3.3. Effects of ethanol pretreatment on cocaine responses Pretreatment with the lower dose of ethanol (475 mg/kg) caused an enhancement of the cocaine-induced pressor response, bradycardia and increase in systemic vascular resistance in all rats. These responses may represent a shift from baseline values (Fig. 3 and Table 1). The cardiac output responses at the time of the peak pressor response and at 1 min after cocaine administration were reduced significantly, without a change in baseline values (Fig. 3 and Table 1). Stroke volume was not affected (data not shown). Analysis of the changes using post-ethanol treatment control values demonstrated an enhanced decrease in cardiac output and increase in systemic vascular resistance (data not shown). The higher dose of ethanol (950 mg/kg) altered hemodynamic responses to cocaine such that the decreases in cardiac output and heart rate and the increase in systemic vascular resistance were enhanced (Fig. 4). As noted earlier, the change in heart rate and systemic vascular resistance may have been due to differences in baseline values after pretreatment with
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Fig. 1. Cardiovascular effects of cocaine (5 mg/kg, open circles), ethanol (475 mg/kg, solid squares) and ethanol (950 mg/kg, solid circles) at the peak pressor response and at 1, 3 and 5 min following the initiation of drug injection (black bar). Significant effects of ethanol, as determined by two way (peak pressor response) and three way (1, 3 and 5 min) analysis of variance (ANOVA), are denoted with an asterisk. Abbreviations include: MAP, mean arterial blood pressure; HR, heart rate; CO, cardiac output; and SysVR, systemic vascular resistance. All data are expressed as mean9S.E.M.
ethanol (Fig. 4 and Table 1). In contrast, the change in cardiac output could not be attributed to this effect. Vascular responders also had a greater decrease in stroke volume after pretreatment with the higher dose of ethanol (data not shown). When examined using post-ethanol values as control, there was a decrease in the cocaine-induced pressor response and more negative cardiac output and stroke volume responses (data not shown). At the time of the maximal change in cardiac output induced by cocaine, ethanol (475 mg/kg) pretreatment potentiated the increases in blood pressure by enhancing the increase in systemic vascular resistance (data not shown). Ethanol (950 mg/kg) enhanced the decrease in cardiac output and heart rate and the increase in arterial pressure and systemic vascular resistance at the time of the maximal cardiac output change (data not shown). Therefore, cardiac output responses were more negative in both groups after ethanol pretreatment suggesting that the rats may be more prone to cocaine-induced cardiodepression.
4. Discussion The present results suggest that the hemodynamic effects of cocaine are altered in several ways by pretreatment with ethanol. While it is difficult to ascertain whether toxicity is enhanced because the doses utilized were not excessively high, the specific characteristics of
these responses suggest that toxicity would be enhanced, since cardiac function is more severely depressed with combined treatment than with either agent alone. Similarly, Hennings and coworkers (1994) noted that the combination of cocaine and ethanol depressed dP/dt synergistically in chloralose-anesthetized dogs. Maillet et al. (1994) reported that ethanol coadministration enhances myocardial ultrastructural damage in cocaine treated rats. Since the cocaine-induced decrease in cardiac output noted in some rats has been associated with a higher incidence of cardiomyopathies (Knuepfer and Branch, 1993), we speculate that ethanol coadministration would potentiate cocaine-induced cardiomyopathies in rats. Several interactions between cocaine and ethanol have been reported in clinical studies. Ethanol potentiates cocaine-induced increases in heart rate (PerezReyes and Jeffcoat, 1992; Farre´ et al., 1993; Higgins et al., 1993) and blood pressure in humans (Foltin and Fischman, 1988; Perez-Reyes and Jeffcoat, 1992). Hime et al. (1991) cite an epidemiological study that suggests ethanol increases the risk of cocaine-related sudden death in humans by more than twenty fold. These findings indicate that the concurrent use of these agents may have detrimental effects. Our results from rats concur with these conclusions and offer a more detailed description of the hemodynamic consequences of their combined use. Several reports have described differential responsiveness in humans to coronary vasoconstriction (Lange et
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Fig. 2. Cardiovascular effects of cocaine (5 mg/kg) and ethanol (475 and 950 mg/kg) at the time of the maximum change in cardiac output (usually within the two minutes after drug). Large symbols (c ) represent overall differences between vascular responders (solid bars) and mixed responders (open bars) as determined by two way ANOVA. Asterisks represent differences between responses to cocaine and those to ethanol for individual doses of ethanol as determined by a simple main effects test. Abbreviations are defined in Fig. 1.
al., 1989; Flores et al., 1990), cardiac pathology (Isner et al., 1986; Amin et al., 1990) and lethal effects of cocaine (Smart and Anglin, 1987; Minor et al., 1991). With the limited evidence available (Hime et al., 1991), it appears that humans consuming ethanol and cocaine concomitantly may be at higher risk for adverse cardiac events. Although suggested by our data and that of the substantial number of clinical cases of morbidity associated with combined use of cocaine and ethanol, it is unknown whether humans have differential susceptibilities to cocaine or whether ethanol may enhance this effect in particular individuals. The data suggest that ethanol pretreatment selectively alters the cardiovascular effects of cocaine in a subset of rats classified on the basis of their susceptibility to cocaine. In previous studies, this laboratory has reported that some rats have decreases in cardiac output after cocaine administration (Branch and Knuepfer, 1993). These animals have been termed vascular responders (called responders in previous papers) as the pressor response in these animals is mediated entirely by an increase in systemic vascular resistance. The pressor response in mixed responders (formerly named nonresponders), although identical to that of vascular responders, is typically mediated by a smaller increase in systemic vascular resistance and a small increase in cardiac output. Compared to mixed responders, vascular responders have been shown to be more likely to develop hypertension (Branch and Knuepfer, 1994) and severe cardiomyopathies (Knuepfer et al., 1993b) after chronic cocaine treatment. These observations suggest
that vascular responders represent a subset of the population that is more susceptible to cocaine-induced cardiotoxicity. In the present paper, ethanol pretreatment altered hemodynamic responses in mixed responders such that most rats had significant decreases in cardiac output and greater increases in systemic vascular resistance. Vascular responders had greater decreases in cardiac output despite no significant change in resting aortic flow after pretreatment with the higher (950 mg/kg) dose of ethanol, suggesting enhanced cardiac depression. The rationale for comparing data using the preethanol control values should be clarified, since previous studies from our laboratory (Branch and Knuepfer, 1993, 1994; Knuepfer and Branch, 1993, 1993) compared data to the control value immediately before cocaine administration (ignoring any changes in baseline values due to drug pretreatment). The data were analyzed in this manner in order to incorporate the effects of the ethanol alone, such that changes due to an ethanol-induced shift in the baseline values were clearly evident in the figures. In this manner, changes elicited by ethanol before cocaine administration could be readily noted with regard to their effect on cocaine-induced responses. This analysis assumes that the hemodynamic values at 10 min after ethanol were unchanged for the following 5 min (after cocaine administration) since the control experiment (ethanol alone) was not performed. We believe that this assumption is appropriate in this case for two reasons. Firstly, the hepatic metabolism of ethanol is relatively slow compared to the metabolism
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Fig. 3. Cardiovascular effects of cocaine (COC, 5 mg/kg), compared to ethanol plus cocaine ( +EtOH 475 mg/kg). Significant effects of ethanol, as determined by two way ANOVA, are denoted with an asterisk. Significant differences, as determined by a simple main effects test, between vascular responders (solid bars) and mixed responders (open bars) are described in the text. Abbreviations are defined in Fig. 1.
of cocaine, suggesting that responses after 10 min are not going to be much different at 15 min. Secondly, the major hemodynamic responses to cocaine of interest to us (pressor and cardiac output responses) are maximal in the first 1–2 min after cocaine administration. For these reasons, we analyzed the data as depicted. The results with regard to the cardiac output responses, in particular, were similar whether the pre- or postethanol treatment values were used. The cardiovascular effects of ethanol administration alone are also intriguing. We reported that the characteristic hemodynamic responses to cocaine in individual rats are similar to those elicited by air jet stress (Knuepfer et al., 1993a) and amphetamine administration (Branch and Knuepfer, 1994). In the present paper, we observed that ethanol, like cocaine, produces differential cardiac output and systemic vascular resistance responses that correlate with the response patterns noted with cocaine. In other words, vascular responders (to cocaine) also exhibited decreases in cardiac output and greater increases in systemic vascular resistance with ethanol administration, while arterial blood pressure and heart rate responses were not different. In conjunction with previous papers (Branch and Knuepfer, 1994; Knuepfer et al., 1993a,b), these results suggest that individuals may exhibit differential sensitivities to a large group of agents and provocations which include stimulants (amphetamine, cocaine), depressants (ethanol) and behavioral stressors (acute air jet). We propose that they either directly (air jet) or
indirectly (psychoactive agents) produce behavioral stress. The hemodynamic response pattern to this stress may reflect differential susceptibilities to cardiovascular disease and sudden death. There are several mechanism by which ethanol might alter the cardiovascular effects of cocaine. The effects of ethanol on cocaine-mediated responses could be due to the formation of cocaethylene, a metabolite formed when ethanol and cocaine are administered in humans (Perez-Reyes and Jeffcoat, 1992; Farre´ et al., 1993) and rats (Levine and Tebbett, 1994). Although some of the long term adverse effects of cocaine have been attributed to cocaethylene (Hearn et al., 1991; Farre´ et al., 1993), evidence supporting cocaethylene’s role in the acute cardiovascular effects of ethanol and cocaine combinations is lacking (Perez-Reyes and Jeffcoat, 1992; Uszenski et al., 1993). In clinical studies where cocaethylene levels were measured, a decline in subjective and heart rate responses was observed at a time when cocaethylene levels were only beginning to appear in the blood (Perez-Reyes and Jeffcoat, 1992). In the present paper, ethanol pretreatment had little effect on arterial blood pressure and heart rate responses to cocaine. In addition, only mixed responders were dramatically affected by the ethanol and cocaine combinations. If a metabolite, such as cocaethylene, was involved in these responses, we would have expected more dramatic effects on blood pressure, heart rate and other corresponding variables. Similar responses would result if there were enhanced levels of cocaine after
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Fig. 4. Cardiovascular effects of cocaine (COC, 5 mg/kg) compared to ethanol and cocaine (EtOH, 950 mg/kg). Data were analyzed as described in Fig. 3. Abbreviations are defined in Fig. 1.
ethanol pretreatment. Prior ethanol consumption appears to increase plasma levels of intranasally administered cocaine in humans (Perez-Reyes and Jeffcoat, 1992; Farre´ et al., 1993). However, it has been reported that ethanol pretreatment does not alter blood levels of cocaine in rats (Dean et al., 1992; Levine and Tebbett, 1994) or dogs (Uszenski et al., 1993). Although we did not measure cocaine or cocaethylene levels, we suggest neither inhibition of cocaine metabolism nor formation of cocaethylene are likely to be involved in these early hemodynamic responses. Although ethanol (Hayes and Bove, 1988) and cocaine (Lange et al., 1989, 1990) have been shown to produce coronary vasoconstriction, it does not appear that ethanol potentiates cocaine-induced coronary vasoconstriction, at least in sedated dogs (Uszenski et al., 1993). Therefore, the effect of ethanol on the cardiovascular responses to cocaine as yet do not appear to be mediated by an ischemic mechanism (Uszenski et al., 1993). It has been suggested that ethanol and cocaine have additive effects, since a 2 h infusion of ethanol depressed left ventricular ejection fraction (LVEF) prior to injecting cocaine, which further reduced LVEF (Uszenski et al., 1993). Interestingly, in the present paper, cocaine or ethanol alone increased cardiac output in mixed responders, but when combined, produced decreases in cardiac output. In summary, our results concur with others in that coadministration of ethanol with cocaine appears to enhance cardiac depression. This effect is, at least, additive in vascular responders and possibly synergistic
in mixed responders where responses were reversed. The mechanism by which this occurs is unclear, but may depend on initial susceptibility to cocaine-induced cardiotoxicity. In addition, ethanol alone appears to produce responses similar to and related to hemodynamic responses to cocaine, amphetamine and air jet stress. These data suggest that some individuals may be more sensitive to a variety of agents that evoke behavioral stress perhaps due to the specific autonomic nervous system responses that are evoked by these stimuli.
Acknowledgements This work was supported by USPHS Grants DA 05180 and NS 07254. The authors would like to thank Dr Terry M. Egan for constructive criticism of this manuscript. Portions of this work were presented in abstract form (Gan, Q. and M.M. Knuepfer and Branch, 1993, FASEB J. 7, A473 and Gan, Q. and M.M. Knuepfer, 1994, NIDA Monograph 141, 317).
References Amin, M., Gabelman, G., Karpel, J., Buttrick, P., 1990. Acute myocardial infarction and chest pain syndromes after cocaine use. Am. J. Cardiol. 66, 1434 – 1437. Branch, C.A., Knuepfer, M.M., 1993. Dichotomous cardiac and systemic vascular responses to cocaine in conscious rats. Life Sci. 52, 85 – 93.
P.J. Mueller et al. / Drug and Alcohol Dependence 48 (1997) 17–24
24
Branch, C.A., Knuepfer, M.M., 1994. Causes of differential cardiovascular sensitivity to cocaine I: Studies in conscious rats. J. Pharmacol. Exp. Ther. 269, 674–683. Dean, R.A., Harper, E.T., Dumaual, N., Stoeckel, D.A., Bosron, W.F., 1992. Effects of ethanol on cocaine metabolism: Formation of cocaethylene and norcocaethylene. Toxicol. Appl. Pharmacol. 117, 1 – 8. Drug Abuse Warning System (DAWN), 1987. National Institute on Drug Abuse, Washington DC, NIDA Statistical Series, no. 7, DHHS publication no. (ADM) 88. El-Mas, M.M., Abdel-Rahman, A.A., 1992. Role of aortic baroreceptors in ethanol-induced impairment of baroreflex control of heart rate in conscious rats. J. Pharmacol. Exp. Ther. 262, 157– 165. Farre´, M., De la Torre, R., Llorente, M., Lamas, X., Ugena, B., Segura, J., Cami, J., 1993. Alcohol and cocaine interactions in humans. J. Pharmacol. Exp. Ther. 266, 1364–1373. Flores, E.D., Lange, R.A., Cigarroa, R.G., Hillis, L.D., 1990. Effect of cocaine on coronary artery dimensions in atherosclerotic coronary artery disease: Enhanced vasoconstriction at sites of significant stenoses. J. Am. Coll. Cardiol. 16, 74–79. Foltin, R.W., Fischman, M.W., 1988. Ethanol and cocaine interactions in humans: Cardiovascular consequences. Pharmacol. Biochem. Behav. 31, 877–883. Grant, B.F., Hartford, T.C., 1990. Concurrent and simultaneous use of alcohol with cocaine: results of national survey. Drug Alcohol Depend. 25, 97 – 104. Hayes, S.N., Bove, A.A., 1988. Ethanol causes epicardial coronary artery vasoconstriction in the intact dog. Circulation 78, 165 – 170. Hearn, W.L., Rose, S., Wagner, J., Ciarleglio, A., Mash, D.C., 1991. Cocaethylene is more potent that cocaine in mediating lethality. Pharmacol. Biochem. Behav. 39, 531–533. Henning, R.J., Wilson, L.D., Glauser, J.M., 1994. Cocaine plus ethanol is more cardiotoxic than cocaine or ethanol alone. Crit. Care Med. 22, 1896 –1906. Higgins, S.T., Rush, C.R., Bickel, W.K., Hughes, J.R., Lynn, M., Capeless, M.A., 1993. Acute behavioral and cardiac effects of cocaine and alcohol combinations in humans. Psychopharmacology 111, 285 – 294. Hime, G.W., Hearn, W.L., Rose, S., Cofino, J., 1991. Analysis of cocaine and cocaethylene in blood and tissues by GC-NPD and GC-ion trap mass spectrometry. J. Anal. Toxicol. 15, 241 – 245. Isner, J.M., Estes, N.A., Thompson, P.D., Costanzo-Nordin, M.R., Subramanian, R., Miller, G., Katsas, G., Sturner, W.Q., 1986. Acute cardiac events temporally related to cocaine abuse. New Engl. J. Med. 315, 1438–1443.
.
Knuepfer, M.M., Branch, C.A., 1993. Calcium channel antagonists reduce the cocaine-induced decrease in cardiac output in a subset of rats. J. Cardiovasc. Pharmacol. 21, 390 – 396. Knuepfer, M.M., Branch, C.A., Mueller, P.J., Gan, Q., 1993a. Stress and cocaine elicit similar cardiac output responses in individual rats. Am. J. Physiol. 265, H779 – H782. Knuepfer, M.M., Branch, C.A., Gan, Q., Fischer, V.W., 1993b. Cocaine-induced myocardial ultrastructural alterations and cardiac output responses in rats. Exp. Mol. Pathol. 59, 155–168. Lange, R.A., Cigarroa, R.G., Flores, E.D., McBride, W., Kim, A.S., Wells, P.J., Bedotto, J.B., Danziger, R.S., Hillis, L.D., 1990. Potentiation of cocaine-induced coronary vasoconstriction by beta-adrenergic blockade. Ann. Intern. Med. 112, 897 – 903. Lange, R.A., Cigarroa, R.G., Yancy, C.W., Willard, J.E., Popma, J.J., Sillis, J.N., McBride, W., Kim, A.S., Hillis, L.D., 1989. Cocaine-induced coronary-artery vasoconstriction. New Engl. J. Med. 321, 1557 – 1562. Levine, B.S., Tebbett, I.R., 1994. Cocaine pharmacokinetics in ethanol-pretreated rats. Drug Metab. Dispos. 22, 498 – 500. Maillet, M., Chiarasini, D., Heller, M., Latour, C., Nahas, G., 1994. Interactions of alcohol and cocaine administration on myocardial ultrastructure. FASEB J. 8, A312. Masur, J., Souza-Formigoni, J.L.O., Pires, J.L.N., 1989. Increased stimulatory effect by the combined administration of cocaine and alcohol in mice. Alcohol 6, 181 – 182. Minor, R.L. Jr., Scott, B.D., Brown, D.D., Winniford, M.D., 1991. Cocaine-induced myocardial infarction in patients with normal coronary arteries. Ann. Int. Med. 115, 797 – 806. Perez-Reyes, M., Jeffcoat, A.R., 1992. Ethanol/cocaine interaction: Cocaine and cocaethylene plasma concentrations and their relationship to subjective and cardiovascular effects. Life Sci. 51, 553 – 563. Schuster, C.R., Fischman, M.W., 1985. Characteristics of humans volunteering for a cocaine research project. In: Kozel, J.J., Adams, E.H. (Eds.), Cocaine Use in America: Epidemiologic and Clinical Perspectives. US Government Printing Office Washingtion, DC, NIDA Res. Monog. 61, pp. 158 – 170. Smart, R.G., Anglin, L., 1987. Do we know the lethal dose of cocaine?. J. Forensic Sci. 32, 303 – 312. Steel, R.G.D., Torrie, J.H., 1960. Principles and Procedures of Statistics, McGraw-Hill, New York, pp. 196 – 197. Uszenski, R.T., Gillis, R.A., Schaer, G.L., Analouei, A.R., Kuhn, F.E., 1993. Additive myocardial depressant effects of cocaine and ethanol. Am. Heart J. 124, 1276 – 1283.