Review of evidence for a novel model of cocaine-induced cardiovascular toxicity.
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.
Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, MO 63104, USA.
M M
MM
Knuepfer
P J
PJ
Mueller
D000818:Animals; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000503:physiopathology; D003042:Cocaine / Q000633:toxicity*; D004285:Dogs; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity*; D006439:Hemodynamics / Q000187:drug effects; D008954:Models, Biological; D051381:Rats
D018765:Dopamine Uptake Inhibitors; D003042:Cocaine