Two genetically selected strains of rats exhibit hypersensitivity or resistance to cocaine-induced fatal arrhythmias

We identified for the first time two genetically selected strains of rats t hat differ markedly in sensitivity to cocaine-induced life-threatening card iac arrhythmias and arrest. The two strains of rats, designated as Fast and Slow, were bred for sensitivity (Fast) or resistance (Slow) to electricall y kindled seizures. Studies were performed on halothane-anesthetized, mecha nically ventilated rats. Animals were given cocaine (3 or 4 mg/kg/min i.v.) until they died. Arrhythmias (atrioventricular conduction block) developed at much lower cumulative cocaine doses in Slow-kindling rats than in Fast- kindling rats (15 +/- 1 versus 42 +/- 3 mg/kg, p < .01). The lethal cocaine dose (the dose that caused cardiac arrest) was also markedly lower in Slow than in Fast strains (32 +/- 2 versus 62 +/- 6 mg/kg, p < .01). These diff erences between the two strains were not significantly altered by pretreatm ent of animals with either ganglionic blockers, hexamethonium (20 mg/kg i.v .) or chlorisondamine (5 mg/kg i.v.), or a nonselective beta adrenergic rec eptor blocker, propranolol (1 mg/kg i.v.). A nonselective alpha adrenergic receptor blocker, phentolamine (10 mg/kg i.v.), however, abolished the diff erences between the Fast and Slow strains in the doses of cocaine required to produced atrioventricular conduction block and cardiac arrest. The resul ts provide the first evidence of genetically determined susceptibility or r esistance to cocaine-induced cardiotoxicity. There appears to be a genetica lly determined difference in the alpha adrenergic receptor system between t he two strains that is responsible for the differential sensitivity to coca ine-induced arrhythmias and cardiac arrest.