Effect of cocaine on the coronary circulation and systemic hemodynamics in dogs (original) (raw)

Cocaine and Ethanol: Combined Effects on Coronary Artery Blood Flow and Myocardial Function in Dogs

Academic Emergency Medicine, 2009

Objectives: In combination, cocaine and ethanol are more cardiotoxic than is either substance alone. These substances together constitute a drug abuse combination that commonly results in fatality. Previously the authors have demonstrated that cardiotoxicity of cocaine and ethanol is in part due to synergistic myocardial-depressant effects. However, it remains unclear whether this myocardial depression is associated with concomitant adverse effects on coronary blood flow in relation to these substances. The aim of this study was to investigate combined effects of cocaine and ethanol on myocardial blood flow, in relation to indices of myocardial function. Methods: Anesthetized dogs were instrumented for hemodynamic monitoring with Doppler flow probes placed on the circumflex and left anterior descending (LAD) coronary arteries. Dogs were randomized to three groups (each n = 6): ethanol (E, 1.5 g ⁄ kg followed by placebo), cocaine (C, placebo followed by cocaine, 7.5 mg ⁄ kg IV), or cocaine plus ethanol (C + E). All measurements were made at control, after placebo or ethanol, and then at fixed time intervals after cocaine or placebo bolus over 3 hours. Results: In both the C + E and the C groups, circumflex blood flow (CBF) decreased by 71% (95% confidence interval [CI] = 56% to 85%) and 57% (95% CI = 43% to 72%, both p < 0.04 vs. baseline) immediately after cocaine bolus. This was associated with transient depression of cardiac output, myocardial contractile function, and rate-pressure product (RPP), all indices of myocardial oxygen demand. A subsequent rebound increase of coronary sinus blood flow (CSBF) of 56% (95% CI = 26% to 137%, p < 0.03) compared to baseline occurred only in the C group and was associated with increases of myocardial contractile function and RPP. In the C + E group, 2 hours after drug administration, there was a decrease in CSBF of 49% (95% CI = 32% to 67%; p < 0.01) compared to baseline, which was associated with concomitant numerical decreases of the indices of myocardial oxygen demand and accumulation of cocaethylene. Conclusions: Acute decreases in myocardial flow secondary to cocaine, and cocaine and ethanol in combination, were similar and temporally associated with cocaine's direct myocardial-depressant effects. Rebound increases in myocardial function and blood flow due to cocaine were attenuated by ethanol. Delayed myocardial depression and decreases in myocardial blood flow were observed only with coadministration of cocaine and ethanol.

Immediate Effects of Intravenous Cocaine on the Thoracic Aorta and Coronary Arteries

Chest, 1996

Cocaine use has been associated with a number of life-threatening cardiovascular complications, including dissection and rupture ofthe thoracic aorta and myocardial ischemia and infarction.' 5 Arterial vasoconstriction is thought to play a role in the etiology of these life-threatening cardiovascular complications, and this theory is supported by a number of studies documenting cocaine-induced vasoconstriction of the thoracic aorta6 and coronary arteries.7-10 Cocaine has been shown to cause vasoconstriction of *From the Cardiovascular Research Institute (Dr. Eisenber), the Cardiology Division of the Department of Medicine (Drs. risenber Redberg, and Foster),

Dichotomous cardiac and systemic vascular responses to cocaine in conscious rats

Life Sciences, 1993

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.

Pharmacological mechanisms in cocaine's cardiovascular effects

Drug and Alcohol Dependence, 1995

The squirrel monkey is a reliable model for the cardiovascular effects of cocaine in that it mimics the human response to cocaine; low to moderate doses of cocaine produce a sustained pressor effect and tachycardia. Pretreatment experiments have indicated the importance of o-1 and o-1 adrenoceptor mechanisms in mediating the pressor and tachycardiac effects of cocaine, respectively. Little support for a role of dopaminergic mechanisms in the hemodynamic effects of cocaine has been found. Toxicity to cocaine is often observed hours after its administration, pointing to a potential role of the cocaine metabolites. Studies on the direct effects of a variety of cocaine metabolites indicate that their cardiovascular effects do not necessarily mimic those produced by cocaine, and therefore these differing effects of the metabolites should be considered when evaluating the cardiovascular toxicity of cocaine. Further, as these metabolites are present in the body for long periods of time, these results suggest a role of the metabolites in producing toxicity long after cocaine administration. Finally, studies using both dopaminergic and calcium channel antagonists indicate that the pharmacological mechanisms involved in the cardiovascular effects of cocaine are not the same as those involved in its behavioral effects.

Cocaine and Cardiotoxicity: A Literature Review

Cureus

Long-term cocaine use, as well as acute cocaine use, is associated with adverse cardiovascular consequences, including arrhythmias, angina, myocardial infarction, heart failure, and other conditions. Over the long term, cocaine can result in structural changes to the heart such as increased left-ventricular mass and decreased left-ventricular end-diastolic volume. Patients arriving with cocaine-associated cardiovascular complaints may not be forthcoming about their cocaine or polysubstance abuse or may be unresponsive. The role of beta-blockers, a first-line treatment for many forms of heart disease, is controversial in this population. Cocaine is a powerful sympathomimetic agent, and it was thought that beta-blockade would result in unopposed alpha-adrenergic stimulation and adverse consequences. A number of small, singlecenter, retrospective and observational studies suggest that beta-blockers may be safe, effective, and beneficial in this population. Further study is needed to clarify the role of beta-blockers in this population.

Review of Evidence for a Novel Model of Cocaine-Induced Cardiovascular Toxicity

Pharmacology Biochemistry and Behavior, 1999

KNUEPFER, M. M. AND P. J. MUELLER. Review of evidence for a novel model of cocaine-induced cardiovascular toxicity. PHARMACOL BIOCHEM BEHAV 63 (3) 489-500, 1999.-Cocaine is known to produce life-threatening cardiovascular complications in some but not all individuals. This review considers the premise that an appropriate animal model for cocaine-induced cardiotoxicity should be characterized by varying sensitivity in the population to the deleterious effects of cocaine. We have studied such a model in which physiological, biochemical, and pathological sensitivity to cocaine varies in rats. Our studies have identified a subset of rats that respond to cocaine with a decrease in cardiac output and a substantial increase in systemic vascular resistance (named vascular responders). In contrast, another group, designated mixed responders, is characterized by a smaller increase in systemic vascular resistance and a small increase in cardiac output. We reported that vascular responders are more likely to develop hypertension and cardiomyopathies with repeated cocaine administration. Under chloralose anesthesia, vascular responders have more profound pressor responses to cocaine and an initial brief spike in renal sympathetic nerve activity not usually noted in mixed responders. Vascular responders have higher resting and cocaine-induced dopamine turnover in the striatum. In addition, vascular responders have higher alpha-adrenergic vasoconstrictor tone, whereas mixed responders have higher adrenergic cardiac tone. The difference in cardiac output and systemic vascular resistance responses to cocaine in these two subsets of the population can be prevented by L-type calcium channel, muscarinic, or alpha-adrenergic blockade. Similar hemodynamic response variability is noted with other psychoactive agents and with acute stress, suggesting that the response patterns are not unique to cocaine. We propose that individual hemodynamic response variability is dependent on differences in CNS responsiveness and correlated with the incidence of cardiovascular disease.