Acute deleterious effects of cocaine on cardiac conduction, hemodynamics, and ventricular fibrillation threshold: effects of interaction with a selective dopamine D1 antagonist SCH 39166.
Cocaine has demonstrated cardiotoxicity that has led to sudden death by unknown mechanisms. SCH 39166, a selective dopaminergic D1-receptor antagonist, suppresses the compulsive drug-intake actions of cocaine in primates. This study examined the cumulative toxic effects of cocaine after the long-term administration of SCH 39166. After pretreatment with oral placebo/SCH 39166 for 5 days, an i.v. infusion of 0.25 mg/kg/min of cocaine HCl was delivered to 14 anesthetized dogs, and cardiac conduction, arterial blood pressure, ventricular refractoriness, and arrhythmogenesis were examined. The cocaine infusion was stopped when QRS width increased by 20% from baseline (QRS20). In Coc + Placebo regimen, the QRS and His-Ventricular (HV) intervals showed a dose-dependent lengthening. Initially, the mean blood pressure (MBP) increased followed by a precipitate decrease at a mean dose of 2.03 +/- 0.5 mg/kg of cocaine. At QRS20, the ventricular effective refractory period (ERP) increased significantly, whereas the ventricular fibrillation threshold (VFT) showed a significant reduction from the baseline. In Coc + SCH, the QRS, HV intervals, and ERP increased similarly, but the decrease in MBP was attenuated, and the VFT was increased. A relatively small infusion of cocaine causes a hemodynamic compromise. The His-ventricular conduction delay and lengthened ERP suggest a predominant direct local anesthetic effect. Cocaine additionally decreased the VFT, suggesting an increased susceptibility to VF. SCH 39166 did not potentiate the cardiotoxic effects of cocaine. It displayed a protective trend by suppressing the arrhythmogenic effects and the hemodynamic compromise caused by cocaine.
Department of Psychiatry, Duke University Medical Center, Durham, North Carolina 27710, USA.
P M
PM
Kanani
P A
PA
Guse
W M
WM
Smith
A
A
Barnett
E H
EH
Ellinwood
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003042:Cocaine / Q000633:toxicity*; D004285:Dogs; D018492:Dopamine Antagonists / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity*; D004562:Electrocardiography / Q000187:drug effects; D004594:Electrophysiology; D006329:Heart Conduction System / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*; D014693:Ventricular Fibrillation / Q000503:physiopathology*
D001552:Benzazepines; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D017447:Receptors, Dopamine D1; C058081:ecopipam; D003042:Cocaine