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Circulation. 1996;94:534-541

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(Circulation. 1996;94:534-541.)
© 1996 American Heart Association, Inc.

Articles

Mechanism of the Systemic, Left Ventricular, and Coronary Vascular Tolerance to a Binge of Cocaine in Conscious Dogs

Richard P. Shannon, MD; Pedro Lozano, MD; Qing Cai, MD; W. Thomas Manders, BA; You-tang Shen, MD

the Cardiovascular Division (R.P.S.), New England Regional Primate Research Center, Harvard Medical School; Section of Cardiology (R.P.S., P.L., Q.C., W.T.M.), Brockton/West Roxbury VA Medical Center, West Roxbury, Mass; and Merck Research Laboratories (Y.-t.S.), West Point, Pa.

Correspondence to Richard P. Shannon, MD, Cardiovascular Division, West Roxbury VA Medical Center, 1400 VFW Pkwy, West Roxbury, MA 02132.


*    Abstract
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 *Abstract
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Background Prior experimental studies have emphasized the cardiovascular effects of acute, single doses of cocaine. However, cardiovascular complications are most often reported in chronic users, who have been exposed to repetitive doses of cocaine. It remains unclear whether there is tolerance or sensitization to the systemic, left ventricular, and coronary hemodynamic effects of a binge of cocaine.

Methods and Results We studied 11 conscious, chronically instrumented dogs to determine the systemic pressor, inotropic, chronotropic, and coronary vascular resistance responses to cocaine (1 mg/kg IV) administered every 25 minutes for five doses. There was progressive tolerance to the systemic pressor (mean arterial pressure: first dose, +42±4% from 97±2 mm Hg; fifth dose, +8±3% from 116±7 mm Hg; P<.01) and heart rate (first dose, +45±8% from 93±5 bpm; fifth dose, +8±2% from 109±9 bpm; P<.01) responses and abolition of the positive inotropic (left ventricular dP/dt: first dose, +19±4% from 2824±75 mm Hg/s; fifth dose, -3±5% from 2531±436 mm Hg/s; P<.01) and coronary vasoconstrictor (coronary vascular resistance: first dose, +38±9% from 1.9 mm Hg·mL-1·min-1; fifth dose, -7±2% from 2.6±0.2 mm Hg·mL-1·min-1; P<.01) responses to a binge of cocaine despite progressive increases in peak plasma cocaine concentrations. In contrast, both the plasma norepinephrine and epinephrine responses were attenuated with repetitive exposure to cocaine, whereas myocardial {alpha}- and ß-adrenergic responsiveness was maintained.

Conclusions Repetitive cocaine administration is associated with the development of early and progressive tolerance to systemic, left ventricular, and coronary vascular effects of cocaine. The mechanism of the tolerance involves neither impaired myocardial nor coronary vascular responsiveness to adrenergic stimulation but, rather, attenuated catecholamine responses to repetitive cocaine administration.


Key Words: cocaine • catecholamines • contractility • circulation


*    Introduction
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 *Introduction
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 down arrowResults
 down arrowDiscussion
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Despite increasing interest and intense study, the mechanisms underlying the toxicity of chronic cocaine administration remain incompletely understood. A major limitation in prior studies has been the emphasis on establishing the consequences and mechanisms of acute cocaine administration in both humans1 2 3 4 5 6 and experimental models.6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 However, illicit cocaine users rarely consume a single dose of the drug, and the majority of the cardiac complications have been observed in chronic users and frequently after a binge.23 24 25 26 27 28 Furthermore, there have been no experimental studies in either humans or animals that have demonstrated evidence of myocardial ischemia after acute cocaine administration in doses consumed by chronic users. Only multiple, large, and repetitive doses, resulting in sublethal levels of cocaine, have been shown to produce pathological myocardial injury.29 30 However, the consequences of chronic cocaine administration may be both qualitatively and quantitatively different from those of acute cocaine administration. Specifically, Wilkerson et al31 showed that the pharmacokinetics of multiple repetitive doses of cocaine result in cumulative increases in plasma cocaine levels that are more than the sum of the individual effects.

There is extensive literature describing the effects of chronic cocaine administration on behavioral responses in experimental models. Similarly, there are limited data on the pressor and chronotropic responses after repetitive doses of cocaine in both humans32 33 34 and experimental models.35 36 37 38 39 40 41 These studies have yielded conflicting results, with most,32 33 34 35 36 but not all,36 37 studies showing the development of acute tolerance to the blood pressure or chronotropic responses. However, there are no data on the effects of multiple repetitive doses of cocaine on left ventricular (LV) systolic performance or coronary hemodynamics in vivo. It is critical to examine these cardiac responses after a binge of cocaine, given that the clinically described toxicities of cocaine pertain to effects on myocardial contractile performance and coronary vasoconstriction.

Accordingly, the purpose of the present study was to determine whether sensitization or tolerance develops to the LV and coronary hemodynamic responses to a binge of cocaine in conscious dogs. We defined a binge of cocaine as five repetitive doses (1 mg/kg) of intravenous cocaine with successive doses administered as the hemodynamic responses waned to the previous dose. A second goal was to determine whether the mechanism of the altered response to a binge of cocaine involved alterations in endogenous catecholamine release observed after acute cocaine administration11 12 20 or whether the observed responses could be attributed to altered myocardial end-organ responsiveness.


*    Methods
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 *Methods
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Eleven mongrel dogs of either sex (25 to 30 kg) were sedated with xyalazine (10 mg/kg) and anesthetized with halothane (1 to 1.5 vol%). Through an incision in the fifth left intercostal space, Tygon catheters were placed in the descending thoracic aorta and left atrium, and a Silastic catheter was placed in the coronary sinus. A solid-state miniature pressure transducer (Konigsberg Instruments) was implanted in the LV through an apical approach for the high-fidelity recordings of LV pressure. A Doppler ultrasonic flow probe was placed on the proximal portion of the left circumflex coronary artery for the continuous measurement of coronary blood flow velocities. A bipolar pacing lead was sutured to the surface of the left atrial appendage to control heart rate. All catheters were tunneled subcutaneously and externalized infrascapularly, after which the thoracotomy was closed in layers and the thoracic cavity was evacuated of air. All animals received analgesics as needed for the first 72 hours, and Keflin (1 g, IV) was administered daily for 7 days. The dogs were allowed to recover from the surgical procedure for 2 weeks, during which they were trained to lie quietly on the experimental table in a conscious, unrestrained state. Catheters were flushed daily and filled with a 50% heparin solution to maintain patency. Animals used in this study were maintained in accordance with the guidelines of the Committee on Animals of Harvard Medical School and the NIH Guide for the Care and Use of Laboratory Animals (Department of Health and Human Services publication No. NIH 85-23, revised 1985).20 21 22

Experimental Measurements
Aortic and left atrial pressures were measured with the use of the chronically implanted catheters with Statham strain-gauge manometers, which were calibrated with a mercury manometer before each experiment. LV pressure was measured with the solid-state miniature pressure transducer calibrated with a mercury manometer in vitro (10 mV=200 mm Hg) and in vivo with aortic and left atrial pressures. Left circumflex coronary artery blood flow velocity was measured with a Doppler flow probe that measured the shift in Doppler frequency in kHz. Measurements of arterial and coronary sinus oxygen contents, hemoglobin, and oxygen saturations were made with an IL-482 Co-Oximeter System (Instrumentation Laboratories).

Experimental Protocol
All experimental studies were conducted in the fully conscious state after the dog had recovered completely from surgery.20 21 22 Each dog received intravenous infusions of cocaine hydrochloride (1 mg/kg over 1 minute) dissolved in normal saline and administered via a peripheral vein at a rate of 3.82 mL/min every 25 minutes for a total of five doses to mimic a binge of cocaine. The individual dose was chosen as the maximally tolerated dose in a conscious dog that did not result in uncontrollable agitation based on our prior studies20 21 22 and is in keeping with doses used in human studies of the tolerance to chronic cocaine.33 34 Hemodynamic measurements were recorded continuously throughout the administration of the binge in intrinsic sinus rhythm and with heart rate held constant at 150 bpm at baseline and 2.5, 5, 10, 15, and 20 minutes after each of the five doses of cocaine. On a different day, 4 of the 11 dogs received infusions of normal saline (3.82 mL/min) every 25 minutes for five doses as a control for the influence of time and intravenous fluid administration on the resting hemodynamics in a conscious dog subjected to this 3-hour protocol. In 6 dogs, isoproterenol (0.05 to 0.4 µg·kg-1·min-1) was administered before the first dose of cocaine and at 20 minutes after the fifth dose to allow assessment of changes in myocardial ß-adrenergic responsiveness. Isoproterenol was chosen because its metabolism is not dependent on reuptake mechanisms known to be inhibited by cocaine. On a different day, in the other 5 dogs, phenylephrine (1 to 10 µg·kg-1·min-1) was administered intravenously before the first dose of cocaine and 25 minutes after the fifth dose of cocaine to assess systemic pressor and coronary vasoconstrictor responsiveness to {alpha}-adrenergic stimulation. Plasma levels of norepinephrine and epinephrine were sampled from the arterial catheter at baseline and at 5 minutes after the first, third, and fifth doses of cocaine and were measured with the use of the radioimmunoassay of Peuler and Johnson.42 Plasma levels of cocaine were drawn in gray-topped tubes containing sodium fluoride to inhibit plasma pseudocholinesterase activity at 2.5 and 25 minutes after the first, third, and fifth doses of cocaine and were assayed as described previously.43 Samples for arterial and coronary sinus oxygen contents were drawn simultaneously in heparinized 3-mL syringes with heart rate held constant at 150 bpm at baseline and 5 and 20 minutes after the first, third, and fifth doses of cocaine. These time points were based on prior studies from our laboratory20 22 43 that have characterized the time course of the metabolic and neurohumoral responses to intravenous cocaine in conscious dogs.

Data Analysis
The hemodynamics were recorded simultaneously with a multichannel magnetic tape recorder (Honeywell 101) and played back on a strip-chart recorder (Gould 3800). Continuous recordings of LV dP/dt were derived from the LV pressure signals with operational amplifiers connected as differentiators. The differentiators were calibrated directly by substituting a triangular wave signal of known slope for the pressure signal. A cardiotachometer triggered from the LV pressure waveform was used to continuously record heart rate. Mean arterial pressure was derived through the use of an electronic filter applied to the phasic arterial pressure signal. The mean left circumflex coronary blood flow velocities were similarly derived from the phasic signals with a similar filtering system. Mean left circumflex flow in milliliters per minute was calculated as the product of the measured velocity in centimeters per second and the internal cross-sectional area of the coronary artery at the site of implantation of the Doppler flowmeter, obtained when the animal was euthanized. This technique for measuring the coronary blood flow response to cocaine compares favorably with direct measures of coronary blood flow based on Transonics or microsphere techniques.22 The mean coronary artery vascular resistance was calculated as the quotient of the mean arterial pressure and the coronary blood flow and is expressed in millimeters of mercury per milliliter per minute. An index of myocardial oxygen consumption was calculated as the product of the coronary artery blood flow and the arteriocoronary sinus oxygen content difference21 22 and expressed as milliliters of O2 consumed per minute. An index of myocardial oxygen delivery was calculated as the product of coronary blood flow and the arterial oxygen content and was expressed in milliliters of O2 delivered per minute. An index of oxygen extracted across the coronary circulation was calculated as the quotient of the arteriocoronary sinus oxygen content difference and the arterial oxygen content and was expressed as percent extracted.

Statistical Analysis
All analyses were performed with a BMDP Biomedical Computer Program. The significant differences in the measured parameters over time, either absolute or percent change, were assessed with a repeated-measures ANOVA. This was followed, where necessary, by a Student's t test, corrected for multiple comparisons (Bonferroni), to compare each subsequent dose response with the first dose. The plasma norepinephrine and epinephrine responses were compared with the use of a Student's t test for paired data, and a Bonferroni correction was applied when multiple comparisons were made. The data are reported as mean±SEM.


*    Results
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 up arrowMethods
 *Results
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Hemodynamic Responses to Binge Cocaine Administration
Table 1Down demonstrates the baseline and peak hemodynamic effects of intravenous cocaine after each of the five doses of cocaine (1 mg/kg). There was a prompt and significant increase (36%) in LV systolic pressure from 118±2 to 161±3 mm Hg, peaking at 2.5 minutes. However, the subsequent rise in LV systolic pressure was markedly attenuated after the second (14%), third (8%), fourth (7%), and fifth (7%) doses of cocaine (Fig 1Down). Similarly, LV end-diastolic pressure increased within the first 2.5 minutes by 14±4 mm Hg from 4±1 mm Hg after the first dose, yet the response was progressively attenuated after subsequent doses. The mean arterial pressure rose by 40±3 mm Hg after the first dose, but the response was rapidly attenuated so that, by the fifth dose, mean arterial pressure rose by only 11±4 mm Hg (P<.01, Fig 1Down). However, there was an increase in the baseline mean arterial pressure with each dose from 97±3 mm Hg at baseline to 114±4 mm Hg before the second dose, 113±5 mm Hg before the third dose, 112±6 mm Hg before the fourth dose, and 116±7 mm Hg before the fifth dose. To be certain that the attenuated response to repeated cocaine exposure was not a consequence of the increase in mean arterial pressure before each dose, three dogs were studied on a separate day at a normal baseline mean arterial pressure (98±4 mm Hg) and after the baseline mean arterial pressure was increased by {approx}20 mm Hg through infusion of phenylephrine (2 to 3 µg·kg-1·min-1). The peak increase and time course of the mean arterial pressure response to cocaine were similar before (+36±6 mm Hg) and after (+34±7 mm Hg) the increase in baseline mean arterial pressure, suggesting that the impaired pressor response after repeated cocaine exposure was not a consequence of the increase in baseline mean arterial pressure.


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  		Table 1. Peak Responses to Binge Cocaine: LV, Systemic, and Coronary Vascular Responses



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  		Figure 1. Left ventricular and systemic pressure responses to binge cocaine after the first, third, and fifth doses. There was early and progressive attenuation in the pressor response to each dose (P<.01 compared with the first dose). LVP indicates left ventricular pressure; MAP, mean arterial pressure.

Fig 2Down reveals the impact of a binge of cocaine on LV contractility and heart rate. Initially, there was a 19±3% increase in LV dP/dt, which was progressively attenuated after repeated cocaine administration, so that by the fifth dose, not only was the baseline LV dP/dt depressed (2531±436 mm Hg/s) but there also was actual further decline in LV dP/dt after the fifth dose (-3±5%, P<.01 compared with the first dose). Similarly, there was a marked attenuation in the heart rate response to repeated cocaine exposure, which was evident and near maximal by the second dose (Table 1Up). Initially, peak heart rates were as high as 133±7 bpm from 93±5 bpm and, subsequently, 111±6 bpm after repeated cocaine administration. The attenuation in the heart rate response to repeated cocaine administration was not a consequence of the increase in baseline heart rate as the chronotropic response to cocaine was not attenuated when baseline heart rate was increased to 110 bpm by atrial pacing. Thus, the binge of cocaine resulted in a loss of the positive inotropic and an attenuation of the positive chronotropic responses observed with a single dose of cocaine.



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  		Figure 2. Inotropic (left ventricular dP/dt) and chronotropic (heart rate) responses to binge cocaine after the first, third, and fifth doses. There was early and progressive attenuation in both responses (P<.01 compared with the first dose).

To be certain that the attenuated inotropic response to binge cocaine was not a consequence of the impaired heart rate response, we also examined the LV dP/dt response to binge cocaine administration with heart rate held constant at 150 bpm through left atrial pacing. There was, nevertheless, progressive attenuation in the LV dP/dt response from +17±4% after the first dose to +7±2% after the third dose to -6±3% after the fifth dose.

Fig 3Down reveals the effects of repeated cocaine exposure on the coronary blood flow and coronary vasoconstrictor responses. The peak coronary blood flow response (+20±4%) after the first dose tended to be less after subsequent doses of cocaine but not significantly so. However, although there was a progressive increase in baseline coronary vascular resistance (2.6±0.2 from 1.93±0.1 mm Hg·mL-1·min-1), there was progressive attenuation in the coronary vasoconstrictor response to a binge of cocaine from a +38±5% increase after the first dose to -7±2% after the fifth dose (P<.01 compared with the first dose). The attenuation in response was not a consequence of the increase in baseline coronary vascular resistance, as the increase in resistance in response to cocaine was comparable (+34±5%) when baseline resistance was increased through pretreatment with phenylephrine (2 to 3 µg·kg-1·min-1, three dogs on a separate occasion) compared with the response observed after the first dose of cocaine. Thus, there was a significant decline in the coronary vasoconstrictor response to cocaine with each subsequent dose, suggesting tolerance to binge cocaine administration. It should be noted that equivolume infusions of saline with the same binge protocol had no significant effect on any of the measured baseline parameters.



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  		Figure 3. Coronary vascular responses to binge cocaine as assessed through coronary blood flow (CBF) and vascular resistance (CVR) responses. Although the peak increases in CBF responses were comparable, the CBF remained elevated after the fifth dose as the CVR response was rapidly and progressively attenuated (P<.01 compared with the first dose).

Alterations in Oxygen Consumption Response After a Binge of Cocaine
To determine whether the attenuated response to the coronary vasoconstrictor effects of binge cocaine was due to greater oxygen consumption responses, we measured the myocardial oxygen consumption, oxygen delivery, and oxygen extraction responses during the binge of cocaine with heart rate held constant at 150 bpm through atrial pacing. Table 2Down shows the baseline and peak responses after the first, third, and fifth doses. There was an initial increase in arterial oxygen content from 16.2±0.5 to 18.1±0.6 vol%, which occurred as a consequence of a significant increase in circulating hemoglobin concentration from 12.0±0.5 to 13.9±0.4 g/dL (P<.05) after the first dose of cocaine. However, with repeated doses of cocaine, the increase in both arterial oxygen content (third dose, +0.3±0.7 mL O2/100 mL; fifth dose, +0.4±0.4 mL O2/100 mL) and circulating hemoglobin concentration (third dose, 0.6±0.3 g/dL; fifth dose, 0.1±0.3 g/dL) were progressively less compared with the first dose. In contrast, the decline in coronary sinus oxygen content was not statistically different from the first through the fifth dose of cocaine. Both the peak myocardial oxygen consumption and the oxygen delivery responses were significantly less with repeated cocaine doses (Table 2Down). Thus, the progressive attenuation in the coronary vasoconstrictor response to binge cocaine could not be attributed to greater metabolically induced coronary vasodilation.


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  		Table 2. Peak Coronary Vascular and MO2 Responses to Binge Cocaine

Mechanisms of Tolerance to a Binge of Cocaine
In five dogs, the baseline and plasma cocaine concentrations at 2.5 minutes after the infusion were measured during the first, third, and fifth doses of cocaine (Table 3Down). Both the baseline and the 2.5-minute plasma cocaine concentrations increased with each dose, so that the 2.5-minute level after the fifth dose (1431±179 ng/mL) was greater than twice the 2.5-minute level after the first dose (678±127 ng/mL). Thus, there was a progressive increase in both baseline plasma cocaine levels and plasma cocaine responses during the binge protocol.


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  		Table 3. Plasma Cocaine Levels During a Binge of Cocaine

Fig 4Down shows the inotropic and chronotropic responses to increasing doses of isoproterenol before and after binge cocaine administration. There was no significant difference in the dose-response relation, suggesting preservation in the myocardial inotropic and chronotropic responses to ß-adrenergic stimulation. Fig 5Down reveals the coronary vasoconstrictor response to increasing doses of phenylephrine before and after binge cocaine administration. There was a tendency for enhanced coronary vasoconstriction to phenylephrine challenge after binge cocaine, although the difference did not reach statistical significance. Thus, altered {alpha}- and ß-adrenergic end-organ responsiveness was not responsible for the tolerance observed to the LV, systemic, and coronary vascular responses to repeated cocaine administration.



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  		Figure 4. Myocardial ß-adrenergic responsiveness to isoproterenol was not different before and after binge cocaine administration, suggesting that myocardial desensitization was not the mechanism of the cardiovascular tolerance to binge cocaine. LV indicates left ventricular.



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  		Figure 5. Coronary vasoconstrictor responses to phenylephrine were not different before and after binge cocaine, suggesting that impaired {alpha}-adrenergic responsiveness was not the mechanism of the cardiovascular tolerance to binge cocaine. CVR indicates coronary vascular resistance.

Table 4Down shows the arterial plasma norepinephrine and epinephrine responses to repeated cocaine administration. There was progressive attenuation in the increase in norepinephrine and epinephrine levels observed after repeated cocaine administration compared with the first response. In fact, there was no significant increase in plasma epinephrine levels after the fifth dose of cocaine compared with the near-doubling of circulating epinephrine levels observed after the first dose. Thus, the plasma catecholamine response to a binge of cocaine was markedly attenuated, similar to the attenuated hemodynamic responses.


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  		Table 4. Plasma Catecholamine Response Levels During a Binge of Cocaine


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
In the present study, we observed for the first time that the LV and coronary hemodynamic responses to a binge of cocaine were markedly and progressively attenuated in conscious, chronically instrumented dogs. In general, tolerance to cocaine was manifest on rechallenge after a single dose, although progressive decline in the hemodynamic and neurohumoral response to cocaine was observed with subsequent doses. Furthermore, the tolerance was not a function of the increase in baseline hemodynamic measurements before subsequent cocaine doses as the acute hemodynamic effects of cocaine were maintained when baseline hemodynamics were increased independent of cocaine. Finally, the mechanism of tolerance to the LV and systemic effects of repeated cocaine administration did not involve end-organ desensitization to the adrenergic effects of cocaine (Figs 4Up and 5Up) but rather attenuated cocaine-induced catecholamine release as demonstrated by declines in plasma norepinephrine and epinephrine responses with repeated cocaine administration (Table 4Up).

Prior studies that have investigated the effects of repeated exposure to cocaine have been focused on the behavioral tolerance that develops. Studies that have explored cardiovascular tolerance have been limited to the study of heart rate and blood pressure responses to which tolerance has been demonstrated in some but not all studies. For example, Fischman et al33 demonstrated attenuation in the heart rate response to intravenous cocaine 1 hour after intranasal administration of the drug in chronic users. Foltin et al37 reported tolerance to the chronotropic but not the systemic pressor response to cocaine, whereas Kumor et al36 found neither heart rate nor blood pressure attenuation. Ambre et al35 used a more complex drug administration protocol and found that the chronotropic effects of cocaine were attenuated after rechallenge at 4 hours but not 20 hours. These differences are likely due to different dosing regimens used to induce tolerance. Similar conflicting data are observed in experimental models. Tella et al14 reported no tolerance to the chronotropic or pressor effects of cocaine (0.3 mg/kg) administered at daily intervals for 5 days in squirrel monkeys, whereas Matsuzaki et al39 noted attenuated heart rate responses to intravenous cocaine (2 to 4 mg/kg) after 24 hours. With isolated perfused rat hearts, Avakian et al41 reported that chronic daily cocaine administration for 8 weeks resulted in attenuated heart rate responses to epinephrine but had no effects on coronary blood flow. Thus, there is no consensus as to the magnitude or the mechanisms by which repeated doses of cocaine elicit cardiovascular tolerance. Furthermore, there are few data as to whether tolerance extends to the inotropic and coronary vascular effects of cocaine, which are the parameters most relevant when considering the potential cardiovascular toxicities in humans. These data cannot be extrapolated from the heart rate and blood pressure data alone.

In the present study, we used a dose of cocaine previously shown in our laboratory to induce potent and reproducible cardiovascular effects on both LV function and coronary circulation.20 21 22 We administered this dose at 25-minute intervals, which represented the time over which the principal effects of an acute 1-mg/kg dose of cocaine dissipate in a conscious dog. Notably, tolerance to the inotropic, chronotropic, systemic pressor, and coronary vasoconstrictor responses to intravenous cocaine was evident after two doses and was progressive with repetitive dosing. Importantly, there have been no prior studies that have examined the effects of repeated doses of cocaine on LV and coronary hemodynamics in a relevant large animal model or human study. Furthermore, the work of Brogan et al4 has suggested a residual coronary vasoconstrictor response to acute cocaine in humans that was attributed to the accumulation of the major metabolite of cocaine, benzyolecognine. On the basis of these data, it might be hypothesized that sensitization to the coronary effects of cocaine can be observed as the plasma levels of both cocaine and benzyolecognine increase. However, this was not the case. Although there was a significant increase in baseline coronary vascular resistance and in myocardial oxygen extraction with progressive cocaine dosing, the response to each dose was attenuated despite achieving greater plasma cocaine levels (Table 3Up), which is consistent with the development of functional tolerance to the coronary vasoconstrictor effects. There was frank coronary vasodilation to cocaine during the fifth dose, which was not attributable to greater myocardial oxygen requirements (Table 2Up).

It is interesting to note that repeated exposure to cocaine in a binge resulted in increases in baseline mean arterial pressure and heart rate and slight decreases in LV dP/dt. This was associated with progressive increases in baseline cocaine (Table 3Up) and catecholamine levels (Table 4Up) before each dose. There also were significant increases in baseline coronary vascular resistance and increases in myocardial oxygen extraction, suggesting that the increase in coronary vascular resistance was sufficient to limit myocardial oxygen delivery at this level of myocardial oxygen demand. This is in contrast to the effects of an acute single dose of cocaine,21 22 in which oxygen delivery was sufficient to meet myocardial oxygen demands despite significant coronary vasoconstriction. One difference is that the increase in circulating hemoglobin concentration observed after acute cocaine administration22 was attenuated with repeated exposure, with the resultant decline in oxygen delivery despite comparable coronary blood flow responses. Thus, the effects of binging were associated with a greater imbalance in myocardial oxygen supply and demand at baseline than has been observed in the conscious canine model after a single dose.

We have also shown previously22 that the degree of coronary artery vasoconstriction associated with a single intravenous dose of cocaine is inversely related to the associated increase in myocardial oxygen consumption. These observations are consistent with previous studies demonstrating the competing influences of sympathetic stimulation on myocardial metabolic demands, leading to vasodilation, and direct effects on coronary smooth muscle, leading to coronary vasoconstriction. However, this inverse relation is lost during a binge. Specifically, the attenuation in the coronary vasoconstrictor response and the ultimate coronary vasodilation seen during the infusion of the fifth dose in the binge occurred despite significantly lower myocardial oxygen consumption responses and increases in coronary sinus oxygen content. This suggests that repeated cocaine exposure leads to the elaboration of a vasodilator substance, perhaps nitric oxide, that antagonizes the limited sympathetic effects of cocaine on the coronary vascular response. It is also conceivable that nitric oxide mediates the impaired cocaine-induced sympathetic effects on inotropic and chronotropic effects. However, further studies are necessary to examine this potential mechanism.

There are three major mechanisms by which tolerance may occur to the effects of binge cocaine administration. First, there is the possibility that plasma cocaine levels do not rise with repeated exposure due to enhanced drug metabolism. However, work by Wilkerson et al31 suggested that repeated cocaine exposure results in greater increases in plasma cocaine levels as endogenous pseudocholinesterase activity becomes saturated. Indeed, we observed that plasma cocaine levels rose significantly with repeated exposure, arguing that the observed tolerance was not due to enhanced metabolism. We did not measure the major metabolite of cocaine, benzyolecognine, nor were these measurements made under steady-state conditions, so we cannot conclude that the pharmacokinetics of cocaine were altered. However, we can conclude that the impaired LV and coronary vascular responses to a binge of cocaine were not a consequence of decreased plasma cocaine concentrations.

A second possibility involves myocardial adrenergic desensitization to {alpha}- and ß-adrenergic stimulation. Increased neural synaptic concentrations of norepinephrine could, in theory, lead to {alpha}- and ß-adrenergic receptor downregulation and desensitization with subsequent myocardial and coronary vascular hyporesponsiveness to repeated cocaine administration. However, we observed that the myocardial inotropic and chronotropic responses to isoproterenol administered before and after the binge were unchanged, suggesting that myocardial ß-adrenergic responsiveness was preserved. It should be noted that isoproterenol was chosen as the ß-agonist because it is not metabolized by neuronal reuptake mechanisms, which are a pharmacological target of cocaine. However, the effects of intravenous infusion of isoproterenol in a conscious dog are complex and involve the combined effects of direct ß-receptor stimulation and baroreflex stimulation due to decreases in arterial pressure. Thus, it is conceivable that there was myocardial ß-adrenergic receptor desensitization that was compensated for by enhanced baroreflex responses. However, Andressen et al48 demonstrated that cocaine impairs arterial baroreceptor responses, which would argue against this possibility. In support of these observations, we observed an attenuated heart rate response to the hypotension induced by nitroglycerin (120 µg IV) in two dogs, suggesting that baroreflex-mediated chronotropic responses were impaired, not enhanced. Furthermore, we observed that the coronary vascular response to {alpha}-adrenergic stimulation with phenylephrine tended to be greater after binge cocaine, suggesting that {alpha}-adrenergic responses were not desensitized. Here, it is conceivable that impaired baroreflex responses48 could lead to less sympathoinhibition during phenylephrine infusion, resulting in enhanced {alpha}-adrenergic coronary vascular effects. In this regard, the bradycardic response to phenylephrine infusion tended to be less (-18±5 bpm) after the binge of cocaine compared with before the binge (-26±7 bpm). However, it is unlikely that our findings reflect significant {alpha}-adrenergic desensitization, which would result in impaired rather than enhanced coronary vasoconstrictor responses to phenylephrine. Taken together, these data suggest that impaired adrenergic end-organ responsiveness does not likely account for the LV and coronary vascular tolerance observed after a binge of cocaine. These findings of preserved myocardial adrenergic responsiveness are in contrast to the observations of Avakian et al,41 who observed an attenuated chronotropic response to epinephrine in vitro after chronic cocaine exposure, and Jones and Tackett,49 who observed impaired responses to norepinephrine in in vitro vascular preparations. In our study, we used a binge of cocaine but did not investigate the effects of chronic daily cocaine administration.

A third potential mechanism to account for the functional tolerance to binge cocaine is impaired central or peripheral sympathetic stimulation, given that the inotropic, chronotropic, and coronary vasoconstrictor effects of cocaine are dependent on the integrity of the autonomic nervous system.8 20 Prior studies45 46 have suggested that tolerance to the chronotropic effects of neurally released norepinephrine in the presence of cocaine is due to stimulation of presynaptic {alpha}2-receptors. Importantly, these observations were made in pentobarbital-anesthetized cats45 after spinal cord transection and in response to stellate ganglion stimulation. However, we observed significant attenuation in both endogenous norepinephrine and epinephrine responses during the binge exposure, suggesting attenuated central stimulatory effects, including adrenal medullary release of epinephrine, which has been shown to play a critical role in the response to cocaine.11 12 20 47 Thus, although cardiac presynaptic {alpha}2-receptor mechanisms might be invoked to explain the norepinephrine response, they are insufficient to explain the attenuated epinephrine response. An alternative autonomic mechanism that could result in attenuated sympathetic stimulation involves enhanced parasympathetic tone. Parasympathetic tone is known to modulate catecholamine release at both preganglionic and postganglionic sites. We have shown previously that both the chronotropic20 and coronary vascular21 responses to cocaine are attributable to combined parasympathetic withdrawal and sympathetic release. It is conceivable that impaired parasympathetic withdrawal during the binge of cocaine could oppose catecholamine release, from both sympathetic neurons and the adrenal medulla. However, further studies are required to clarify the role of presynaptic versus central mechanisms in the attenuated catecholamine responses after a binge of cocaine.

In conclusion, a binge of cocaine results in cardiovascular tolerance to the inotropic, chronotropic, systemic pressor, and coronary vasoconstrictor responses to cocaine in conscious dogs. The mechanism does not involve altered myocardial responsiveness to catecholamines but, rather, attenuated sympathetic responses to repeated cocaine administration. Whether further tolerance is observed after chronic cocaine administration remains to be determined.


*    Acknowledgments
 
This work was supported in part by US Public Health Service grants NIDA-06306, HL-38070, and RR-00168. Dr Shannon was the recipient of a Clinician-Scientist Award from the American Heart Association. We wish to thank Stephen F. Vatner, MD, for his assistance in the conduct of this work and Gail Smygelski for her expert assistance in manuscript preparation.

Received October 12, 1995; revision received February 5, 1996; accepted February 16, 1996.


*    References
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 *References
 

  1. Lange RA, Cigarroa RG, Yancy CW, Willard JE, Popma JJ, Sills MN, McBride W, Kim AS, Hillis LD. Cocaine-induced coronary-artery vasoconstriction. N Engl J Med.. 1989;321:1557-1561.[Abstract]
  2. Lange RA, Cigarroa RG, Flores ED, McBride W, Kim AS, Wells PJ, Bedotto JB, Danziger RS, Hillis LD. Potentiation of cocaine induced coronary vasoconstriction by beta adrenergic blockade. Ann Intern Med.. 1990;112:897-903.
  3. Brogan WC III, Lange RA, Kim AS, Moliterno DJ, Hillis LD. Alleviation of cocaine-induced coronary vasoconstriction by nitroglycerin. J Am Coll Cardiol.. 1991;18:581-586.[Abstract]
  4. Brogan WC, Lange RA, Glamann DE, Hillis LD. Recurrent coronary vasocontraction caused by intranasal cocaine: possible role of metabolites. Ann Intern Med.. 1992;116:556-561.
  5. Flores ED, Lange RA, Cigarroa RG, Hillis LD. Effect of cocaine on coronary artery dimensions in atherosclerotic coronary artery disease: enhanced vasoconstriction of sites of significant stenosis. J Am Coll Cardiol.. 1990;16:74-79.[Abstract]
  6. Kloner RA, Hale S, Alker K, Rezkalla S. The effects of acute and chronic cocaine use on the heart. Circulation.. 1992;85:407-419.[Abstract/Free Full Text]
  7. Abel FL, Wilson SP, Shao RR, Fennell WH. Cocaine depressed the canine myocardium. Circ Shock.. 1989;28:309-319.[Medline] [Order article via Infotrieve]
  8. Wilkerson RD. Cardiovascular effects of cocaine in conscious dogs: importance of fully functional autonomic and central nervous systems. J Pharmacol Exp Ther.. 1988;246:466-471.[Abstract/Free Full Text]
  9. Fraker TD, Temesy-Armos PN, Brewster PS, Wilkerson RD. Mechanism of cocaine-induced myocardial depression in dogs. Circulation.. 1990;81:1012-1021.[Abstract/Free Full Text]
  10. Billman GE. Mechanisms responsible for the cardiotoxic effects of cocaine. FASEB J.. 1990;4:2469-2475.[Abstract]
  11. Trouve R, Nahas GG, Maner WM. Catecholamines, cocaine toxicity, and their antidotes in the rat. Proc Soc Exp Biol Med.. 1991;196:184-192.[Abstract]
  12. Schwartz AB, Boyle W, Janzen D, Jones RT. Acute effects of cocaine on catecholamines and cardiac electrophysiology in the conscious dog. Can J Cardiol.. 1988;4:188-192.[Medline] [Order article via Infotrieve]
  13. Knuepfer MM, Branch CA, Fischer VW. Mechanisms of cardiac and vascular response to cocaine. In: Thadani P, ed. Cardiovascular Toxicity of Cocaine: Underlying Mechanisms. NIDA Res Monogr.. 1991;108:55-73.
  14. Tella SR, Schindler CW, Goldberg SR. Cardiovascular effects of cocaine in squirrel monkeys. In: Thadani P, ed. Cardiovascular Toxicity of Cocaine: Underlying Mechanisms. NIDA Res Monogr.. 1991;108:74-91.
  15. Gillis RA, Bachenheimer LC, Dretchen KL, Erzouki HK, Hernandez YM, Jain RK, Jain MK, Kuhn FE, Guest J, Schaer GL. Role of the sympathetic nervous system in the cardiovascular effects of cocaine. In: Thadani P, ed. Cardiovascular Toxicity of Cocaine: Underlying Mechanisms. NIDA Res Monogr.. 1991;108:92-109.
  16. Hale SL, Alker KJ, Razkalia S, Figures G, Kloner R. Adverse effects of cocaine on cardiovascular dynamics, myocardial blood flow, and coronary artery diameter in an experimental model. Am Heart J.. 1989;118:927-933.[Medline] [Order article via Infotrieve]
  17. Kuhn FE, Johnson ME, Gillis RA, Visner MS, Schaer GL. Effects of cocaine on the coronary circulation and systemic hemodynamics in dogs. J Am Coll Cardiol.. 1990;16:1481-1491.[Abstract]
  18. Clarkson CW, Chang C, Stolfi A, George WJ, Yamasaki S, Pickoff AS. Electrophysiological effects of high cocaine concentrations on intact canine heart: evidence for modulation by both heart rate and autonomic nervous system. Circulation.. 1993;87:950-962.[Abstract/Free Full Text]
  19. Liu CP, Tunin C, Kass DA. Transient time course of cocaine-induced cardiac depression versus sustained peripheral vasoconstriction. J Am Coll Cardiol.. 1993;21:260-268.[Abstract]
  20. Stambler BS, Komamura K, Ihara T, Shannon RP. Acute intravenous cocaine causes transient expression followed by enhanced left ventricular function in conscious dogs. Circulation.. 1993;87:1687-1697.[Abstract/Free Full Text]
  21. Shannon RP, Stambler BS, Komamura K, Ihara T, Vatner SF. Cholinergic modulation of the coronary vasoconstriction induced by cocaine in conscious dogs. Circulation.. 1993;87:939-949.[Abstract/Free Full Text]
  22. Shannon RP, Manders WT, Shen Y-T. Role of blood doping in the coronary vasoconstrictor response to cocaine. Circulation.. 1995;92:96-105.[Abstract/Free Full Text]
  23. Chakko S, Fernandez A, Mellman TA, Milanes FJ, Kessler KM, Myerburg RJ. Cardiac manifestations of cocaine abuse: a cross-sectional study of asymptomatic men with a history of long-term abuse of crack cocaine. J Am Coll Cardiol.. 1992;20:1168-1174.[Abstract]
  24. Isner JM, Chokshi SK. Cocaine-induced myocardial infarction: clinical observations and pathogenetic considerations. In: Thadani P, ed. Cardiovascular Toxicity of Cocaine: Underlying Mechanisms. NIDA Res Monogr.. 1991;108:121-130.
  25. Nademanee K. Prevalence of myocardial ischemia in cocaine addicts. In: Thadani P, ed. Cardiovascular Toxicity of Cocaine: Underlying Mechanisms. NIDA Res Monogr.. 1991;108:116-120.
  26. Weiner RS, Lockhart JT, Schwartz RG. Dilated cardiomyopathy and cocaine abuse. Am J Med.. 1986;81:699-701.[Medline] [Order article via Infotrieve]
  27. Chokshi SK, Moore R, Pandian NG, Isner JM. Reversible cardiomyopathy associated with cocaine intoxication. Ann Intern Med.. 1989;111:1039-1040.
  28. Peng S, French WJ, Pelikan PCD. Direct cocaine cardiotoxicity demonstrated by endomyocardial biopsy. Arch Pathol Lab Med.. 1989;113:842-845.[Medline] [Order article via Infotrieve]
  29. Maillet M, Chiarasini D, Nahas G. Myocardial damage induced by cocaine administration of a week's duration in the rat. Adv Biosci.. 1991;80:187-197.
  30. Nunez BD, Wang Y, Nunez MM, Sellke FW, Ross J, Sysulic V, Paik GY, Carrozza JP, Morgan JP. Cocaine-induced microvascular spasm in Yucatan miniature swine in vivo and in vitro evidence of spasm. Circ Res.. 1994;74:281-290.[Abstract/Free Full Text]
  31. Wilkerson RD, Temesy-Armos PN, Fraker TD. Pharmacokinetics and time-action profile of cocaine in dogs. In: Thadani P, ed. Cardiovascular Toxicity of Cocaine: Underlying Mechanisms. NIDA Res Monogr.. 1991;108:28-40.
  32. Fischman MW, Schuster CR. Cocaine self-administration in humans. Fed Proc.. 1982;41:241-246.[Medline] [Order article via Infotrieve]
  33. Fischman MW, Schuster CR, Javaid J, Hatano Y, Davis J. Acute tolerance development to the cardiovascular and subjective effects of cocaine. J Pharmacol Exp Ther.. 1985;235:677-682.[Abstract/Free Full Text]
  34. Foltin RW, Fischman MW. Smoked and intravenous cocaine in humans: acute tolerance, cardiovascular and subjective effects. J Pharmacol Exp Ther.. 1991;257:247-261.[Abstract/Free Full Text]
  35. Ambre JJ, Connelly TJ, Ruo T, Henthorn TK. Acute tolerance to the chronotropic effect of cocaine in humans. In: Thadani P, ed. Cardiovascular Toxicity of Cocaine: Underlying Mechanisms. NIDA Res Monogr.. 1991;108:41-54.
  36. Kumor K, Sherer M, Thompson L, Cone E, Mahaffey J, Jaffe JH. Lack of cardiovascular tolerance during intravenous cocaine infusions in human volunteers. Life Sci.. 1988;42:2063-2071.[Medline] [Order article via Infotrieve]
  37. Foltin RW, Fischman MW, Pedroso JJ, Pearlson GD. Repeated intranasal cocaine administration: lack of tolerance to pressor effects. Drug Alcohol Depend.. 1988;22:169-177.[Medline] [Order article via Infotrieve]
  38. Katz JL, Griffiths JW, Sharpe LG, de Souza EB, Witkin JM. Cocaine tolerance and cross-tolerance. J Pharmacol Exp Ther.. 1992;264:183-192.[Abstract/Free Full Text]
  39. Matsuzaki M, Springler PJ, Misra AL, Mule SJ. Cocaine: tolerance to its convulsant and cardiorespiratory stimulating effects in the monkey. Life Sci.. 1976;19:193-203.[Medline] [Order article via Infotrieve]
  40. Tarizzo V, Rubio MC. Effects of cocaine on several adrenergic system parameters. Gen Pharmacol.. 1985;16:71-74.[Medline] [Order article via Infotrieve]
  41. Avakian EV, LeRoy M, St. John AK, Sayre FW, Malone MH. Effects of chronic cocaine in isolated perfused rat hearts. Life Sci.. 1990;46:1569-1574.[Medline] [Order article via Infotrieve]
  42. Peuler JD, Johnson GA. Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine. Life Sci.. 1977;21:625-636.[Medline] [Order article via Infotrieve]
  43. Kugelmas AD, Shannon RP, Yeo EL, Ware JA. Intravenous cocaine induces platelet activation in the conscious dog. Circulation.. 1995;91:1336-1340.[Abstract/Free Full Text]
  44. Zimring HJ, Fitzgerald RL, Engler RL, Ito BR. Intracoronary versus intravenous effects of cocaine on coronary flow on ventricular function. Circulation.. 1994;89:1819-1828.[Abstract/Free Full Text]
  45. Jain RK, Jain MK, Bachenheimer LC, Visner MS, Hamosh P, Tracy CM, Gillis RA. Factors determining whether cocaine will potentiate the cardiac effects of neurally released norepinephrine. J Pharmacol Exp Ther.. 1990;252:147-153.[Abstract/Free Full Text]
  46. Cousineau D, Goresky CA, Rose CP. Decreased basal cardiac norepinephrine release after neuronal uptake inhibition in dogs. Circ Res.. 1986;58:859-866.[Abstract/Free Full Text]
  47. Chiueh CC, Kopin IJ. Centrally mediated releases by cocaine of endogenous epinephrine and norepinephrine from the sympathoadrenal medullary system of unanesthetized rats. J Pharmacol Exp Ther.. 1978;205:148-154.[Abstract/Free Full Text]
  48. Andressen MC, Yang M, Nelson SH, Steinsland S. Cocaine inhibits baroreflex control of blood pressure by actions at arterial baroreceptors. Am J Physiol. 1990;258(Heart Circ Physiol 27):H1244-H1249.
  49. Jones LF, Tackett RL. Chronic cocaine treatment enhances the responsiveness of the left anterior descending coronary artery and the femoral artery to vasoactive substances. J Pharmacol Exp Ther.. 1990;255:1366-1370.[Abstract/Free Full Text]



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