Effect of calcium channel antagonists on cocaine-induced malignant arrhythmias: protection against ventricular fibrillation.
It is increasingly apparent that cocaine can provoke lethal cardiac events, including ventricular fibrillation (VF). Cocaine-induced accumulation of intracellular calcium could contribute significantly to the development of these lethal arrhythmias. In order to test this hypothesis, a 2-min coronary occlusion was initiated during the last minute of exercise in instrumented mongrel dogs. Twenty-eight animals were selected in which this test failed to induce ventricular arrhythmias. The test was repeated after cocaine HCl (1.0 mg/kg). Cocaine significantly (P < .01) increased heart rate, left ventricular pressure and d(left ventricular pressure)/dt maximum, and elicited VF in 21 animals. The cocaine exercise+ischemia test was repeated in the animals that developed VF after the pretreatment with the following calcium channel antagonists: diltiazem (n = 8, 1.0 mg/kg), flunarizine (n = 7, 2.5 mg/kg), magnesium sulfate (n = 7, 100 mg/kg), nifedipine (n = 7 100 micrograms/kg), Ro 40-5967 (n = 7, 1.0 mg/kg) and verapamil (n = 6, 250 micrograms/kg). Diltiazem, flunarizine, nifedipine, Ro 40-5967 and verapamil completely suppressed cocaine-induced VF, whereas magnesium prevented VF in five of seven animals. Many of the calcium channel antagonists attenuated the heart rate and systolic pressure increases provoked by cocaine, as well as the heart rate increase induced by the ischemia. Heart rate was therefore matched to the cocaine values by ventricular pacing (verapamil+pace, n = 5), whereas the pressure increases were prevented by nitroprusside (n = 4). Even with heart rate held constant, verapamil prevented VF, whereas nitroprusside failed to protect any animal. Thus, myocardial calcium entry may play a critical role in cocaine-induced VF, whereas calcium antagonists can prevent these malignant arrhythmias independently of their vascular action.
Billman
G E
GE
Department of Physiology, Ohio State University, Columbus.
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003042:Cocaine / Q000633:toxicity*; D004285:Dogs; D006321:Heart / Q000187:drug effects; D008274:Magnesium / Q000627:therapeutic use; D009206:Myocardium / Q000378:metabolism; D014693:Ventricular Fibrillation / Q000139:chemically induced / Q000517:prevention & control*
D002121:Calcium Channel Blockers; D008274:Magnesium; D003042:Cocaine; D002118:Calcium