Hemodynamic response profile predicts susceptibility to cocaine-induced toxicity

Cocaine evokes pressor responses due either to a large increase in systemic vascular resistance despite a decrease (>8%) in cardiac output (vascular responders) or to small increases in both cardiac output and vascular resistance (mixed responders) in conscious rats. These studies were designed to determine (1) if the hemodynamic response pattern to cocaine correlates with relative sensitivity to toxicity and (2) if altering the hemodynamic response pattern to cocaine using propranolol enhances toxicity. Rats were instrumented for determination of cardiac output and arterial pressure. After recovery, rats were classified as vascular or mixed responders to cocaine (5 mg/kg, i.v., four to six trials). Two weeks later, cocaine was infused (1.5 mg/kg/min) until death after pretreatment with saline or propranolol (1 mg/kg). Saline-pretreated mixed responders (n=6) had greater tolerance to cocaine toxicity compared to vascular responders (n=11). Furthermore, saline-pretreated vascular responders were less sensitive than propranolol-pretreated vascular responders (n=9) to cocaine toxicity. Therefore, we propose that the initial hemodynamic response pattern to cocaine predicts sensitivity to cocaine toxicity. In addition, propranolol, a drug that enhances the increase in vascular resistance to cocaine, also increases toxicity to cocaine in vascular responders.