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Dichotomous cardiac and systemic vascular responses to cocaine in conscious rats
Life Sciences, Vol. Printed in the USA
52, pp. 85-93
Pergamon Press
DICHOTOMOUS CARDIAC AND SYSTEMIC VASCULAR RESPONSES TO COCAINE IN CONSCIOUS RATS Carrie A. Branch and Mark M. Knuepfer 1 Departments of Pathology, and of 1pharmacological and Physiological Science St. Louis University School of Medicine (Received in final form October 29, 1992)
Summary This study examined the effects of cocaine on cardiac output in conscious freelymoving rats. Although pressor responses were similar at all doses, 14 of 32 rats had consistent declines in cardiac output (> 15%) and greater increases in systemic vascular resistance after administration of cocaine (5 mg/Kg, i.v.). Procaine (10 mg/Kg i.v.) did not mimic this effect in either subgroup. We propose that a subpopulation of rats exists with an enhanced susceptibility to cocaine-induced cardiac and systemic vascular alterations at higher doses.
Cocaine abuse has been associated with a wide variety of cardiac and hemodynamic alterations including myocardial ischemia and infarction, arrhythmias and sudden death, cardiomyopathy, accelerated atherosclerosis and hypertension (1,2). Given that 3-6 million Americans use cocaine regularly (3), it appears that certain individuals are especially at risk for severe cocaine-induced cardiovascular abnormalities. Although factors such as tolerance, sensitization, metabolism, multidrug use, premature coronary atherosclerosis, smoking, and variation in cellular receptors have been suggested to underlie this susceptibility (2,4,5,6,7), the mechanism(s) is/are unknown. While laboratory studies show that cocaine produces a pressor response and impairs cardiac function in most (8,9,10,11,12,18), but not all reports (14,15), an animal model which exhibits variability in susceptibility to cocaine-induced cardiac and hemodynamic effects is not yet available. Recently, we reported that cocaine occasionally induces an acute decrease in cardiac output in conscious, freely-moving rats using pulsed Doppler flowmetry (16). This response was observed in some rats at a dose of 5 mg/Kg, i.v., and in a few rats at 1 mg/Kg. In the present study, we sought to determine whether cocaine's effects on cardiac output are consistent within individual rats; i.e. does repeated cocaine administration (5 mg/Kg, i.v.) produce a decrease in cardiac output occasionally in all rats or only in some individuals. To this end, cocaine was administered several times to rats and the mean change in cardiac output in each rat was used to differentiate two groups depending upon the presence or absence of cardiac output depression. Because other local anesthetics may produce cardiodepression as measured by decreased cardiac output, stroke volume and myocardial contractility (17,18,19,20), we sought to determine whether the difference in responsiveness to cocaine could be mimicked by an equipotent local anesthetic dose (10 mg/Kg, i.v.) of procaine (21). Mark M. Knuepfer, Ph.D., Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, 1402 S. Grand Boulevard, St. Louis, Missouri 63104 0024-3205/93 $6.00 + .00 Copyright © 1992 Pergamon Press Ltd. All rights reserved.
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Methods
Male Sprague-Dawley rats (300-420 g) were surgically prepared using aseptic techniques under pentobarbital anesthesia (50 mg/Kg) for cardiac output determination (N=32). A miniature pulsed Doppler flow probe was implanted on the ascending aorta as described earlier (22,23). Ten days later, cannulas were inserted into left femoral blood vessels for measurement of arterial pressure and venous administration of drugs. Rats were allowed to recover for an additional 2 days before administration of cocaine or procaine. Rats were acclimated for 3 to 6 hours in a translucent Plexiglas test cage one day before the beginning of the study and thereafter for one hour every morning prior to drug administration. Cocaine was administered twice daily with an interdose interval of 3-5 hours. Blood flow was estimated continuously using a 20 MHz pulsed Doppler flowmeter (University of Iowa, Department of Bioengineering) with either a 62.5 kHz or a 100 kHz sampling frequency. Blood flows which appeared unstable during an experiment possibly due to potential aliasing of the flow signal (24) were omitted. Use of a higher sampling frequency (100 kHz), antialiasing and auto tracking reduced the occurrence of unstable flow signals and provided regular pulsatile flow signals of up to 28 kHz shift. Data were displayed on a chart recorder and stored magnetically with a microcomputer using a data acquisition and analysis program (PC Chart Recorder). Arterial pressure, heart rate, and ascending aortic blood flow were measured continuously in freely-moving conscious rats. Changes in cardiac output, systemic vascular resistance and stroke volume were calculated as described earlier (22,23). Rats were given cocaine (0.5, 1 and 5 mg/Kg, i.v.) injected in a volume of 0.5-0.6 ml over 45 sec. Differences in cardiac output responses between individuals were most prevalent at the 5 mg/Kg dose. Rats were classified as responders (R) if they had consistent decreases in cardiac output after several cocaine treatments (minimum of 3 trials), i.e. the mean change in cardiac output at any defined time period within 5 minutes after cocaine administration (5 mg/Kg) was negative by more than 15%. Alternatively, rats which did not meet this criterion were classified as nonresponders (NR). An equipotent local anesthetic dose (21) of procaine (10 mg/Kg i.v.) was administered to determine if the observed cardiodepression was a result of anesthesia. Due to previous studies defining time-dependent differences in the responses to cocaine (16,25,26), initial peak pressor responses were compared with a Student's t test (pairwise where appropriate) whereas effects at 1, 3, and 5 minutes after drug administration and peak responses at different doses of cocaine were compared with an analysis of variance. Data are expressed as mean + S.EM., and differences were considered significant ifp < 0.05. Results
Conscious, instrumented rats had a resting mean arterial pressure and heart rate of 120.4 + 1.5 mmHg and 402 + 6.2 b/min, respectively. Cocaine administration (0.5, 1 and 5 mg/Kg, i.v., infusion over 45s) elicited dose-related pressor responses during both the initial peak and sustained period, and bradycardia during the sustained response period (1 to 5 minutes after dosing) (Fig. 1). Estimated cardiac output was often elevated but in many rats, at higher doses, a decrease in cardiac output was observed occurring within one minute after the onset of cocaine infusion. The cardiac output data for all rats combined did not follow a dose-response relationship (ANOVA). Since the 5 mg/Kg dose appeared to identify separate groups without being overtly toxic, yet a 10 mg/Kg dose was lethal in approximately 50% of animals (unpublished data), we continued our studies using a dose of 5 mg/Kg to separate rats as to their responsiveness to cocaine. The dose related responses to cocaine in responder rats (those with a mean decrease in cardiac output of at least 15% with multiple trials of 5 mg/Kg cocaine) were compared to those of nonresponders (Fig. 1).
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FIG. 1 Cardiovascular responses occurring at the time of the peak increase in arterial pressure (within 1 min after beginning cocaine infusion) at three doses of cocaine (0.5, 1 and 5 mg/Kg, Lv.). There were significant differences at the 1 and 5 mg/Kg dose level between responders (n=10) and non-responders (n=l 1) for cardiac output (CO) and systemic vascular resistance (SysVR). No difference was observed over all doses for mean arterial pressure (AP) or heart rate (HR). Of all the rats, 1 had a decrease (<-15%) in cardiac output at 0.5 mg/Kg, 4 had a fall at 1 mg/Kg and 12 had a decrease at 5 mg/Kg. The cardiac output, systemic vascular resistance and stroke volume (data not shown) responses were different at both the 1 and 5 mg/Kg dose. Studies employing 5 mg/Kg identified 8 of the first 20 rats tested as responders, as defined by the acute, reversible fall in cardiac output (Fig. 2). As previously described, the cardiovascular responses to cocaine consisted of two phases, a substantial brief pressor response occurring within the first minute (referred to as peak response) followed by a modest sustained pressor response (measured at 1, 3, and 5 rain after cocaine) associated with bradycardia (16,25,26). The pressor and bradycardic responses to cocaine were virtually identical in the two groups, despite the dramatic differences in cardiac output especially during the early time periods (Fig. 2). Therefore, rats in which cardiac output fell acutely had an apparent compensatory increase in systemic vascular resistance. No differences were found in body weight, baseline mean arterial pressure, heart rate, or mean kHz Doppler shift between the groups (data not shown). A second group of rats (3 from the first study described above) comprised of 6 responders and 9 nonresponders were used to compare the effects of cocaine with those of procaine (Fig. 3). The pressor and bradycardic effects of cocaine administration were not different between the two groups during either the peak or sustained response period. As in the previous study, the responder group demonstrated a decrease in cardiac output and exaggerated systemic vascular resistance responses to cocaine during both periods. Procaine, at an equipotent dose for inhibiting motoneurons
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FIG. 2 Cardiovascular responses to cocaine (5 mg/Kg, i . v . , administered over 45 sec beginning at arrow) in rats with a fall in cardiac output (responders or R, solid line, n=8) and those without significant decrements in cardiac output (nonresponders or NR, dashed line, n=12) expressed as change in mean arterial pressure (AP in mmHg) and heart rate (HR in beats/min) and percent change in cardiac output (CO). Data were obtained at 1 sec intervals and average changes (each 10 sec during first 15 minutes and each minute during the next 15 minutes) are expressed as compared to a control period obtained for 2 minutes before injection. Standard errors are shown at the peak pressor and cardiac output response and at 5 minute intervals after the onset of cocaine administration. (21), was administered to determine whether the cardiodepressive effect was due to inhibition of nerve conduction. Procaine (10 mg/Kg L v . ) elicited significantly smaller pressor responses compared to cocaine (Fig. 3). In contrast to cocaine, procaine elicited tachycardia and an increase in cardiac output at all time periods in responder rats. In nonresponders, procaine produced little effect on cardiac output during the sustained pressor response. Discussion Our results suggest that rats respond in a differential manner to cocaine. The majority of rats had little change or a slight increase in cardiac output after cocaine (5 mg/Kg) whereas 44% of rats had an average fail in cardiac output of at least 15%. The decrease in cardiac output was reproducible within individual rats. Responses observed with doses of cocaine lower than 5 mg/Kg
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FIG. 3 Effects of intravenous cocaine (5 mg/Kg, open symbols) or procaine (10 mg/Kg, filled symbols) in conscious rats with cardiodepression (Responders, squares and solid lines, n--6) and without cardiodepression (Nonresponders, circles and dashed lines, n=9) on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), and systemic vascular resistance (SysVR). Data, expressed as changes from control values, are shown at the peak pressor response (within the first minute) and at 1, 3, and 5 minutes (sustained response period) after beginning drug administration. The peak pressor response was often, but not always, coincident with the peak fall in cardiac output. Significant differences in responses between responders and nonresponders are denoted with *. In responders, the effects of procaine which are significantly different from that of cocaine are denoted by +. Although not shown, comparison of the CO and SysVE responses to procaine between these subgroups indicated significant differences during the sustained response period, also. were not consistent since fewer rats experienced a decrease in cardiac output. We have also been able to identify a subset of rats with a decrease in cardiac output following cocaine administration at a dose ofO.5 mg/Kg, i.v. when administered over 5 s (unpublished results). These data suggest that the threshold for the negative cardiac output response in the responder subset of rats is dependent on the rate of rise of plasma cocaine levels and not necessarily on the absolute dose. The 5 mg/Kg dose is apparently not far below the lethal dose for all rats since both responders and non-responders experienced significant mortality at higher intravenous doses. Other studies describing the pressor and heart rate effects of cocaine in conscious rats and squirrel monkeys have not identified differential responses to cocaine (27,28,29,30). The pressor responses in responders and nonresponders were also similar in our study due to a greater increase in systemic vascular resistance in those rats experiencing a decrease in cardiac output. The dichotomous effects of cocaine in responder and nonresponder rats may be described by either exaggerated cardiodepression or systemic vasoconstriction on the part of the responder rats. However,
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the differential effects are not likely to be simply attributed to exaggerated systemic vasoconstriction since: (1) afterload has little effect on cardiac output in the normal heart unless arterial pressure rises well above normal operating range (>175 mmHg) (31), (2) the cocaine-induced increases in arterial pressure were not different in the two groups of rats and (3) calcium channel antagonists prevent the fall in cardiac output while only attenuating the increase in systemic vascular resistance (32). Although the heart rate responses were not different in the two groups of rats, it is possible that the differential cardiac and systemic vascular effects of cocaine may be attributed to alterations in baroreflex sensitivity. Cocaine has been reported to depress baroreflex function in vitro (41). However, baroreflexes are apparently functioning in both responder and nonresponder rats since both have similar bradycardiac responses 1 to 5 minutes following cocaine administration. This bradycardic response is likely baroreflex mediated since it can be prevented by pentolinium and attenuated by atropine (25). Also, we have observed no differences in the pressor or baroreflex heart rate responses to multiple doses of phenylephrine or nitroprusside in a separate study of responder and nonresponder rats (unpublished data). We sought to determine whether the cardiac output effect was a result of differential sensitivity to the local anesthetic properties of cocaine. For example, differences in spontaneous or evoked sympathetic neuronal activity that are suppressed by inhibition of sodium channel activity may result in differential suppression of cardiac function. In order to compare the relative toxicity of cocaine and procaine, we took into account several studies indicating a difference in anesthetic potency of these agents. Procaine has been shown to be approximately ½ as potent in reducing nerve conduction in the isolated gastrocnemius (21), 6-7 times less potent in reducing myocardial contractile force (18), 3-4 times less potent in producing convulsions (17) and 3 times less potent in producing respiratory failure (33) compared to cocaine. Therefore, procaine is 2-7 times less potent by several different indices of toxicity as a local anesthetic. We were unable to mimic the cocaine-induced effects in responder rats with procaine treatment. Even when one compares the peak effects of 1 mg/Kg cocaine (Fig. 1) with the effects of 10 mg/Kg procaine (Fig. 3), it is clear that procaine does not produce an acute decrease in cardiac output nor increase in systemic vascular resistance. In fact, we observed a significantly greater increase in cardiac output to procaine after the peak pressor response in responder rats. These data suggest a differential sensitivity to local anesthesia during the sustained, modest pressor response but not during the peak increase in arterial pressure or decrease in cardiac output. Although our study appears to be the first description of the effects of cocaine administration on cardiac output, stroke volume and systemic vascular resistance in conscious rats, studies in canines have examined similar parameters. Using various indices most investigators have reported impairment of cardiac function (8,9,10,11,12,13,18) although some describe an enhancement of cardiac activity in response to cocaine (14,15). These studies did not generally note a differential cardiac responsiveness to cocaine, however, due to the short-lasting response (<1 min.) and the fact that it may not occur each time cocaine is administered, it may have been overlooked. Nevertheless, Stewart and coworkers (18) did note inconsistent alterations in myocardial contractile force in response to cocaine in dogs, in contrast to better correlations recorded using any of five other local anesthetics. Clinical descriptions of myocardial aberrations associated with cocaine use have been described as unrelated to dose, route, frequency of administration or excessive risk factors for cardiac disease (1,34). While the factors which underlie an individual's enhanced risk for experiencing severe cardiac and hemodynamic complications are unknown, they must exist given the relatively small number of abusers who experience severe cardiovascular complications (2,4,5,6,7). Similarly, cocaine does not elicit a decrease in cardiac output and excessive systemic vasoconstriction in all
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rats. Therefore, responding rats may be representative of a subpopulation of animals which have an elevated risk of developing cardiac and hemodynamic abnormalities after cocaine administration. In preliminary studies, we have noted an increase in the frequency of focal lesions consisting of myofibrillar and mitochondrial disruption within myocardiocytes characteristically seen in responders when compared to nonresponders after cocaine administration (16). Others have reported widely variable myocardial cardiomyopathies in rats (35) and humans (1) after repeated cocaine use. We suggest that the functional deficits in myocardial performance elicited by cocaine in some rats may be related to the ultrastructurai damage to myocardiocytes. These data, plus the lack of differences in age, body weight, resting arterial pressure, heart rate, and Doppler flow signals, suggest that unique populations exist that may be more likely to experience deleterious cardiac effects of cocaine. Another possible explanation for differential responsiveness would be an inadvertent denervation of the myocardium in some rats caused by the placement of the aortic flow probe as suggested by others (36). This is unlikely since we have observed a spike in renal sympathetic nerve activity that only occurs in responders and immediately precedes or coincides with the acute fall in cardiac output (unpublished observations). Furthermore, the marked ultrastructural aberrations that we have observed only in responders (16) have also been described in a subset of rats without instrumentation for cardiac output determination (35) and appears to exist in humans also (1). Susceptibility to cardiodepression has also been described in a subset of dogs in response to exercise-induced stress, after recovering from a healed myocardial infarction (i.e. myocardial ischemia in the presence of heightened sympathetic nerve activity) (37) suggesting that there may be an autonomic imbalance that predisposes animals to cocaine or stress-induced cardiodepression. The exact mechanism responsible for the differential cardiac and vascular sensitivity to cocaine in these rats is unclear at this time. It has been suggested by others that the cocaine-induced cardiodepression elicited in dogs is associated with a reduction in coronary blood flow (9,13,38). We have reported that the fall in cardiac output is temporally correlated with coronary vasoconstriction in anesthetized rats (39), however the decrease in coronary blood flow does not appear to be a causative factor in the cocaine-induced decrease in cardiac output, at least in anesthetized rats (submitted for publication). Kiritsy-Roy and coworkers (40) reported that ganglionic blockade with chlorisondamine prevented the maximum cocaine-induced pressor and heart rate effects as well as the rise in plasma catecholamine levels in conscious rats. We have reported that the peak increase in arterial pressure associated with the cardiodepression is likely to be mediated by the CNS since it can be attenuated by pentolinium (16,25). In the latter study we observed an initial brief spike in renal sympathetic nerve activity in some but not all rats, indicating that in some rats cocaine elicits a brief sympathoexcitation preceding the long-lasting sympathoinhibition (25). While speculative at this point, these data suggest that the differential cardiac and systemic vascular responses observed in the responder and nonresponder rats may be related to differences in the presence or absence of the initial sympathoexcitation.
Acknowledgements We gratefully acknowledge the technical assistance of Mr. David Wehner and the valuable suggestions of Drs. Vernon W. Fischer and Thomas C. Westfall. We appreciate the use of software designed for data analysis (PC Chart Recorder) written by Drs. A. Wallace and E. Lankford. Portions of this work were published in abstract form (FASEB J. 5:A1437, 1991) and in a review article (NIDA Monograph 108:55-73, 1991). This work was supported by USPHS Grants DA05180 and HL38299.
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Pergamon Press
DICHOTOMOUS CARDIAC AND SYSTEMIC VASCULAR RESPONSES TO COCAINE IN CONSCIOUS RATS Carrie A. Branch and Mark M. Knuepfer 1 Departments of Pathology, and of 1pharmacological and Physiological Science St. Louis University School of Medicine (Received in final form October 29, 1992)
Summary This study examined the effects of cocaine on cardiac output in conscious freelymoving rats. Although pressor responses were similar at all doses, 14 of 32 rats had consistent declines in cardiac output (> 15%) and greater increases in systemic vascular resistance after administration of cocaine (5 mg/Kg, i.v.). Procaine (10 mg/Kg i.v.) did not mimic this effect in either subgroup. We propose that a subpopulation of rats exists with an enhanced susceptibility to cocaine-induced cardiac and systemic vascular alterations at higher doses.
Cocaine abuse has been associated with a wide variety of cardiac and hemodynamic alterations including myocardial ischemia and infarction, arrhythmias and sudden death, cardiomyopathy, accelerated atherosclerosis and hypertension (1,2). Given that 3-6 million Americans use cocaine regularly (3), it appears that certain individuals are especially at risk for severe cocaine-induced cardiovascular abnormalities. Although factors such as tolerance, sensitization, metabolism, multidrug use, premature coronary atherosclerosis, smoking, and variation in cellular receptors have been suggested to underlie this susceptibility (2,4,5,6,7), the mechanism(s) is/are unknown. While laboratory studies show that cocaine produces a pressor response and impairs cardiac function in most (8,9,10,11,12,18), but not all reports (14,15), an animal model which exhibits variability in susceptibility to cocaine-induced cardiac and hemodynamic effects is not yet available. Recently, we reported that cocaine occasionally induces an acute decrease in cardiac output in conscious, freely-moving rats using pulsed Doppler flowmetry (16). This response was observed in some rats at a dose of 5 mg/Kg, i.v., and in a few rats at 1 mg/Kg. In the present study, we sought to determine whether cocaine's effects on cardiac output are consistent within individual rats; i.e. does repeated cocaine administration (5 mg/Kg, i.v.) produce a decrease in cardiac output occasionally in all rats or only in some individuals. To this end, cocaine was administered several times to rats and the mean change in cardiac output in each rat was used to differentiate two groups depending upon the presence or absence of cardiac output depression. Because other local anesthetics may produce cardiodepression as measured by decreased cardiac output, stroke volume and myocardial contractility (17,18,19,20), we sought to determine whether the difference in responsiveness to cocaine could be mimicked by an equipotent local anesthetic dose (10 mg/Kg, i.v.) of procaine (21). Mark M. Knuepfer, Ph.D., Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, 1402 S. Grand Boulevard, St. Louis, Missouri 63104 0024-3205/93 $6.00 + .00 Copyright © 1992 Pergamon Press Ltd. All rights reserved.
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Methods
Male Sprague-Dawley rats (300-420 g) were surgically prepared using aseptic techniques under pentobarbital anesthesia (50 mg/Kg) for cardiac output determination (N=32). A miniature pulsed Doppler flow probe was implanted on the ascending aorta as described earlier (22,23). Ten days later, cannulas were inserted into left femoral blood vessels for measurement of arterial pressure and venous administration of drugs. Rats were allowed to recover for an additional 2 days before administration of cocaine or procaine. Rats were acclimated for 3 to 6 hours in a translucent Plexiglas test cage one day before the beginning of the study and thereafter for one hour every morning prior to drug administration. Cocaine was administered twice daily with an interdose interval of 3-5 hours. Blood flow was estimated continuously using a 20 MHz pulsed Doppler flowmeter (University of Iowa, Department of Bioengineering) with either a 62.5 kHz or a 100 kHz sampling frequency. Blood flows which appeared unstable during an experiment possibly due to potential aliasing of the flow signal (24) were omitted. Use of a higher sampling frequency (100 kHz), antialiasing and auto tracking reduced the occurrence of unstable flow signals and provided regular pulsatile flow signals of up to 28 kHz shift. Data were displayed on a chart recorder and stored magnetically with a microcomputer using a data acquisition and analysis program (PC Chart Recorder). Arterial pressure, heart rate, and ascending aortic blood flow were measured continuously in freely-moving conscious rats. Changes in cardiac output, systemic vascular resistance and stroke volume were calculated as described earlier (22,23). Rats were given cocaine (0.5, 1 and 5 mg/Kg, i.v.) injected in a volume of 0.5-0.6 ml over 45 sec. Differences in cardiac output responses between individuals were most prevalent at the 5 mg/Kg dose. Rats were classified as responders (R) if they had consistent decreases in cardiac output after several cocaine treatments (minimum of 3 trials), i.e. the mean change in cardiac output at any defined time period within 5 minutes after cocaine administration (5 mg/Kg) was negative by more than 15%. Alternatively, rats which did not meet this criterion were classified as nonresponders (NR). An equipotent local anesthetic dose (21) of procaine (10 mg/Kg i.v.) was administered to determine if the observed cardiodepression was a result of anesthesia. Due to previous studies defining time-dependent differences in the responses to cocaine (16,25,26), initial peak pressor responses were compared with a Student's t test (pairwise where appropriate) whereas effects at 1, 3, and 5 minutes after drug administration and peak responses at different doses of cocaine were compared with an analysis of variance. Data are expressed as mean + S.EM., and differences were considered significant ifp < 0.05. Results
Conscious, instrumented rats had a resting mean arterial pressure and heart rate of 120.4 + 1.5 mmHg and 402 + 6.2 b/min, respectively. Cocaine administration (0.5, 1 and 5 mg/Kg, i.v., infusion over 45s) elicited dose-related pressor responses during both the initial peak and sustained period, and bradycardia during the sustained response period (1 to 5 minutes after dosing) (Fig. 1). Estimated cardiac output was often elevated but in many rats, at higher doses, a decrease in cardiac output was observed occurring within one minute after the onset of cocaine infusion. The cardiac output data for all rats combined did not follow a dose-response relationship (ANOVA). Since the 5 mg/Kg dose appeared to identify separate groups without being overtly toxic, yet a 10 mg/Kg dose was lethal in approximately 50% of animals (unpublished data), we continued our studies using a dose of 5 mg/Kg to separate rats as to their responsiveness to cocaine. The dose related responses to cocaine in responder rats (those with a mean decrease in cardiac output of at least 15% with multiple trials of 5 mg/Kg cocaine) were compared to those of nonresponders (Fig. 1).
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Cocaine-induced
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FIG. 1 Cardiovascular responses occurring at the time of the peak increase in arterial pressure (within 1 min after beginning cocaine infusion) at three doses of cocaine (0.5, 1 and 5 mg/Kg, Lv.). There were significant differences at the 1 and 5 mg/Kg dose level between responders (n=10) and non-responders (n=l 1) for cardiac output (CO) and systemic vascular resistance (SysVR). No difference was observed over all doses for mean arterial pressure (AP) or heart rate (HR). Of all the rats, 1 had a decrease (<-15%) in cardiac output at 0.5 mg/Kg, 4 had a fall at 1 mg/Kg and 12 had a decrease at 5 mg/Kg. The cardiac output, systemic vascular resistance and stroke volume (data not shown) responses were different at both the 1 and 5 mg/Kg dose. Studies employing 5 mg/Kg identified 8 of the first 20 rats tested as responders, as defined by the acute, reversible fall in cardiac output (Fig. 2). As previously described, the cardiovascular responses to cocaine consisted of two phases, a substantial brief pressor response occurring within the first minute (referred to as peak response) followed by a modest sustained pressor response (measured at 1, 3, and 5 rain after cocaine) associated with bradycardia (16,25,26). The pressor and bradycardic responses to cocaine were virtually identical in the two groups, despite the dramatic differences in cardiac output especially during the early time periods (Fig. 2). Therefore, rats in which cardiac output fell acutely had an apparent compensatory increase in systemic vascular resistance. No differences were found in body weight, baseline mean arterial pressure, heart rate, or mean kHz Doppler shift between the groups (data not shown). A second group of rats (3 from the first study described above) comprised of 6 responders and 9 nonresponders were used to compare the effects of cocaine with those of procaine (Fig. 3). The pressor and bradycardic effects of cocaine administration were not different between the two groups during either the peak or sustained response period. As in the previous study, the responder group demonstrated a decrease in cardiac output and exaggerated systemic vascular resistance responses to cocaine during both periods. Procaine, at an equipotent dose for inhibiting motoneurons
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Cocaine-induced Cardiodepression
Responder
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Non-Resp
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FIG. 2 Cardiovascular responses to cocaine (5 mg/Kg, i . v . , administered over 45 sec beginning at arrow) in rats with a fall in cardiac output (responders or R, solid line, n=8) and those without significant decrements in cardiac output (nonresponders or NR, dashed line, n=12) expressed as change in mean arterial pressure (AP in mmHg) and heart rate (HR in beats/min) and percent change in cardiac output (CO). Data were obtained at 1 sec intervals and average changes (each 10 sec during first 15 minutes and each minute during the next 15 minutes) are expressed as compared to a control period obtained for 2 minutes before injection. Standard errors are shown at the peak pressor and cardiac output response and at 5 minute intervals after the onset of cocaine administration. (21), was administered to determine whether the cardiodepressive effect was due to inhibition of nerve conduction. Procaine (10 mg/Kg L v . ) elicited significantly smaller pressor responses compared to cocaine (Fig. 3). In contrast to cocaine, procaine elicited tachycardia and an increase in cardiac output at all time periods in responder rats. In nonresponders, procaine produced little effect on cardiac output during the sustained pressor response. Discussion Our results suggest that rats respond in a differential manner to cocaine. The majority of rats had little change or a slight increase in cardiac output after cocaine (5 mg/Kg) whereas 44% of rats had an average fail in cardiac output of at least 15%. The decrease in cardiac output was reproducible within individual rats. Responses observed with doses of cocaine lower than 5 mg/Kg
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No.
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Cocaine-induced Cardiodepression
1993
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FIG. 3 Effects of intravenous cocaine (5 mg/Kg, open symbols) or procaine (10 mg/Kg, filled symbols) in conscious rats with cardiodepression (Responders, squares and solid lines, n--6) and without cardiodepression (Nonresponders, circles and dashed lines, n=9) on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), and systemic vascular resistance (SysVR). Data, expressed as changes from control values, are shown at the peak pressor response (within the first minute) and at 1, 3, and 5 minutes (sustained response period) after beginning drug administration. The peak pressor response was often, but not always, coincident with the peak fall in cardiac output. Significant differences in responses between responders and nonresponders are denoted with *. In responders, the effects of procaine which are significantly different from that of cocaine are denoted by +. Although not shown, comparison of the CO and SysVE responses to procaine between these subgroups indicated significant differences during the sustained response period, also. were not consistent since fewer rats experienced a decrease in cardiac output. We have also been able to identify a subset of rats with a decrease in cardiac output following cocaine administration at a dose ofO.5 mg/Kg, i.v. when administered over 5 s (unpublished results). These data suggest that the threshold for the negative cardiac output response in the responder subset of rats is dependent on the rate of rise of plasma cocaine levels and not necessarily on the absolute dose. The 5 mg/Kg dose is apparently not far below the lethal dose for all rats since both responders and non-responders experienced significant mortality at higher intravenous doses. Other studies describing the pressor and heart rate effects of cocaine in conscious rats and squirrel monkeys have not identified differential responses to cocaine (27,28,29,30). The pressor responses in responders and nonresponders were also similar in our study due to a greater increase in systemic vascular resistance in those rats experiencing a decrease in cardiac output. The dichotomous effects of cocaine in responder and nonresponder rats may be described by either exaggerated cardiodepression or systemic vasoconstriction on the part of the responder rats. However,
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the differential effects are not likely to be simply attributed to exaggerated systemic vasoconstriction since: (1) afterload has little effect on cardiac output in the normal heart unless arterial pressure rises well above normal operating range (>175 mmHg) (31), (2) the cocaine-induced increases in arterial pressure were not different in the two groups of rats and (3) calcium channel antagonists prevent the fall in cardiac output while only attenuating the increase in systemic vascular resistance (32). Although the heart rate responses were not different in the two groups of rats, it is possible that the differential cardiac and systemic vascular effects of cocaine may be attributed to alterations in baroreflex sensitivity. Cocaine has been reported to depress baroreflex function in vitro (41). However, baroreflexes are apparently functioning in both responder and nonresponder rats since both have similar bradycardiac responses 1 to 5 minutes following cocaine administration. This bradycardic response is likely baroreflex mediated since it can be prevented by pentolinium and attenuated by atropine (25). Also, we have observed no differences in the pressor or baroreflex heart rate responses to multiple doses of phenylephrine or nitroprusside in a separate study of responder and nonresponder rats (unpublished data). We sought to determine whether the cardiac output effect was a result of differential sensitivity to the local anesthetic properties of cocaine. For example, differences in spontaneous or evoked sympathetic neuronal activity that are suppressed by inhibition of sodium channel activity may result in differential suppression of cardiac function. In order to compare the relative toxicity of cocaine and procaine, we took into account several studies indicating a difference in anesthetic potency of these agents. Procaine has been shown to be approximately ½ as potent in reducing nerve conduction in the isolated gastrocnemius (21), 6-7 times less potent in reducing myocardial contractile force (18), 3-4 times less potent in producing convulsions (17) and 3 times less potent in producing respiratory failure (33) compared to cocaine. Therefore, procaine is 2-7 times less potent by several different indices of toxicity as a local anesthetic. We were unable to mimic the cocaine-induced effects in responder rats with procaine treatment. Even when one compares the peak effects of 1 mg/Kg cocaine (Fig. 1) with the effects of 10 mg/Kg procaine (Fig. 3), it is clear that procaine does not produce an acute decrease in cardiac output nor increase in systemic vascular resistance. In fact, we observed a significantly greater increase in cardiac output to procaine after the peak pressor response in responder rats. These data suggest a differential sensitivity to local anesthesia during the sustained, modest pressor response but not during the peak increase in arterial pressure or decrease in cardiac output. Although our study appears to be the first description of the effects of cocaine administration on cardiac output, stroke volume and systemic vascular resistance in conscious rats, studies in canines have examined similar parameters. Using various indices most investigators have reported impairment of cardiac function (8,9,10,11,12,13,18) although some describe an enhancement of cardiac activity in response to cocaine (14,15). These studies did not generally note a differential cardiac responsiveness to cocaine, however, due to the short-lasting response (<1 min.) and the fact that it may not occur each time cocaine is administered, it may have been overlooked. Nevertheless, Stewart and coworkers (18) did note inconsistent alterations in myocardial contractile force in response to cocaine in dogs, in contrast to better correlations recorded using any of five other local anesthetics. Clinical descriptions of myocardial aberrations associated with cocaine use have been described as unrelated to dose, route, frequency of administration or excessive risk factors for cardiac disease (1,34). While the factors which underlie an individual's enhanced risk for experiencing severe cardiac and hemodynamic complications are unknown, they must exist given the relatively small number of abusers who experience severe cardiovascular complications (2,4,5,6,7). Similarly, cocaine does not elicit a decrease in cardiac output and excessive systemic vasoconstriction in all
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rats. Therefore, responding rats may be representative of a subpopulation of animals which have an elevated risk of developing cardiac and hemodynamic abnormalities after cocaine administration. In preliminary studies, we have noted an increase in the frequency of focal lesions consisting of myofibrillar and mitochondrial disruption within myocardiocytes characteristically seen in responders when compared to nonresponders after cocaine administration (16). Others have reported widely variable myocardial cardiomyopathies in rats (35) and humans (1) after repeated cocaine use. We suggest that the functional deficits in myocardial performance elicited by cocaine in some rats may be related to the ultrastructurai damage to myocardiocytes. These data, plus the lack of differences in age, body weight, resting arterial pressure, heart rate, and Doppler flow signals, suggest that unique populations exist that may be more likely to experience deleterious cardiac effects of cocaine. Another possible explanation for differential responsiveness would be an inadvertent denervation of the myocardium in some rats caused by the placement of the aortic flow probe as suggested by others (36). This is unlikely since we have observed a spike in renal sympathetic nerve activity that only occurs in responders and immediately precedes or coincides with the acute fall in cardiac output (unpublished observations). Furthermore, the marked ultrastructural aberrations that we have observed only in responders (16) have also been described in a subset of rats without instrumentation for cardiac output determination (35) and appears to exist in humans also (1). Susceptibility to cardiodepression has also been described in a subset of dogs in response to exercise-induced stress, after recovering from a healed myocardial infarction (i.e. myocardial ischemia in the presence of heightened sympathetic nerve activity) (37) suggesting that there may be an autonomic imbalance that predisposes animals to cocaine or stress-induced cardiodepression. The exact mechanism responsible for the differential cardiac and vascular sensitivity to cocaine in these rats is unclear at this time. It has been suggested by others that the cocaine-induced cardiodepression elicited in dogs is associated with a reduction in coronary blood flow (9,13,38). We have reported that the fall in cardiac output is temporally correlated with coronary vasoconstriction in anesthetized rats (39), however the decrease in coronary blood flow does not appear to be a causative factor in the cocaine-induced decrease in cardiac output, at least in anesthetized rats (submitted for publication). Kiritsy-Roy and coworkers (40) reported that ganglionic blockade with chlorisondamine prevented the maximum cocaine-induced pressor and heart rate effects as well as the rise in plasma catecholamine levels in conscious rats. We have reported that the peak increase in arterial pressure associated with the cardiodepression is likely to be mediated by the CNS since it can be attenuated by pentolinium (16,25). In the latter study we observed an initial brief spike in renal sympathetic nerve activity in some but not all rats, indicating that in some rats cocaine elicits a brief sympathoexcitation preceding the long-lasting sympathoinhibition (25). While speculative at this point, these data suggest that the differential cardiac and systemic vascular responses observed in the responder and nonresponder rats may be related to differences in the presence or absence of the initial sympathoexcitation.
Acknowledgements We gratefully acknowledge the technical assistance of Mr. David Wehner and the valuable suggestions of Drs. Vernon W. Fischer and Thomas C. Westfall. We appreciate the use of software designed for data analysis (PC Chart Recorder) written by Drs. A. Wallace and E. Lankford. Portions of this work were published in abstract form (FASEB J. 5:A1437, 1991) and in a review article (NIDA Monograph 108:55-73, 1991). This work was supported by USPHS Grants DA05180 and HL38299.
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