Vol. 288, Issue 2, 685-692, February 1999

Two Genetically Selected Strains of Rats Exhibit Hypersensitivity or Resistance to Cocaine-Induced Fatal Arrhythmias¹

Bing Shi, James E. Heavner , Jian Liu, Martin J. Wang, Lorenz O. Lutherer, Dan C. McIntyre and Charles E. Reigel

Departments of Anesthesiology (B.S., J.E.H., J.L.), Physiology (J.E.H., L.O.L.), and Pharmacology (C.E.R.), Texas Tech University Health Sciences Center, Lubbock, Texas; BioMedical Consulting, Foster City, California (M.J.W.); and Department of Psychology, Carleton University, Ottawa, Canada (D.C.M.)

We identified for the first time two genetically selected strains of rats that differ markedly in sensitivity to cocaine-induced life-threatening cardiac arrhythmias and arrest. The two strains of rats, designated as Fast and Slow, were bred for sensitivity (Fast) or resistance (Slow) to electrically kindled seizures. Studies were performed on halothane-anesthetized, mechanically 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 differences between the two strains were not significantly altered by pretreatment of animals with either ganglionic blockers, hexamethonium (20 mg/kg i.v.) or chlorisondamine (5 mg/kg i.v.), or a nonselective beta adrenergic receptor blocker, propranolol (1 mg/kg i.v.). A nonselective alpha adrenergic receptor blocker, phentolamine (10 mg/kg i.v.), however, abolished the differences between the Fast and Slow strains in the doses of cocaine required to produced atrioventricular conduction block and cardiac arrest. The results provide the first evidence of genetically determined susceptibility or resistance to cocaine-induced cardiotoxicity. There appears to be a genetically determined difference in the alpha adrenergic receptor system between the two strains that is responsible for the differential sensitivity to cocaine-induced arrhythmias and cardiac arrest.