Effect of chronic cocaine administration and cocaine withdrawal on coronary flow rate and heart rate responses to epinephrine and cocaine in isolated perfused rat hearts.
The acute dose-dependent effects of epinephrine and cocaine on heart rate and coronary flow rate (CFR) were examined in isolated, perfused (Langendorff) rat hearts from animals: i) pretreated with daily cocaine injections (20 mg/kg/day) for 8 weeks; ii) after 2-day withdrawal from 8-week cocaine pretreatment; iii) vehicle-treated controls. Chronic cocaine (CC) hearts were significantly less sensitive to the chronotropic effects of epinephrine than control (C) or withdrawal (CW) hearts. CW hearts exhibited significantly higher heart rates in response to epinephrine than C and CC hearts. Epinephrine alone (2.5 x 10(-7) M) decreased CFR 11% (C), 9%(CC), 14%(CW) from respective baseline levels. Cocaine alone had no significant effect on CFR in C hearts but produced slight dose-dependent decrements in CFR in CC and particularly CW hearts at higher doses. Cocaine plus epinephrine markedly decreased CFR in all groups, particularly in CW hearts. The results indicate that chronic daily cocaine administration produces a functional tolerance of the heart to the chronotropic actions of epinephrine but a 2-day withdrawal from chronic cocaine results in a rebound supersensitivity to adrenergic stimulation and cocaine's sympathomimetic effects. In addition, cocaine produces only minor decrements in coronary flow in the rat heart, while cocaine acts synergisticallly with epinephrine to produce a marked decrease in CFR.
Avakian
E V
EV
Department of Physiology and Pharmacology, School of Pharmacy, University of the Pacific, Stockton, California 95211.
LeRoy
M
M
St John-Allan
K
K
Sayre
F W
FW
Malone
M H
MH
D000818:Animals; D003042:Cocaine / Q000633:toxicity*; D003326:Coronary Circulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004837:Epinephrine / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D009924:Organ Culture Techniques; D010477:Perfusion; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains
D003042:Cocaine; D004837:Epinephrine