Effects of coronary flow, pacing rate, isoprenaline and diltiazem on ischemic ventricular arrhythmias in guinea pig hearts

SC Dennis, WA Coetzee, JW de Jong, W Clusin and LH Opie

Ischemic Heart Disease Research Unit, University of Cape Town Medical School, Observatory, South Africa.

Although the Ca++ channel blockers can reduce early ischemic ventricular arrhythmias, the mechanisms are unclarified. The antiarrhythmic action of Ca++ antagonists may either be due to vasodilation and negative chronotropism or to trans-sarcolemmal Ca++ influx inhibition. In these studies we investigated the possible individual and additive effects of coronary flow, heart rate and Ca++ antagonism on ventricular arrythmia development in isolated, paced, globally underperfused guinea pig hearts. When the coronary flow during ischemia was raised from 5 to 7% of control and/or the stimulation frequency was decreased from 6 to 4 Hz, ATP and creatine phosphate levels were conserved and intraventricular conduction slowing leading to ventricular tachycardia (VT) was delayed. In contrast, when the coronary flow and pacing rates were fixed at 7% and 6 Hz and diltiazem (10(-6) M) was included in the perfusion medium, there was no effect on tissue high-energy phosphate depletion and development of VT. Even when the breakdown of ATP and the onset of VT were accelerated by isoprenaline (10(-6) M), diltiazem was not antiarrhythmic at this flow rate. Only when the coronary flow was reduced to 5% of control, in the absence and presence of isoprenaline, did diltiazem delay ventricular arrhythmias through a mechanism that was independent of changes in coronary flow and heart rate.

Volume 248, Issue 1, pp. 372-377, 01/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics