B. Shi et al., Two genetically selected strains of rats exhibit hypersensitivity or resistance to cocaine-induced fatal arrhythmias, J PHARM EXP, 288(2), 1999, pp. 685-692
Citations number
32
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
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.