The Effect of Verapamil on Experimental Myocardial Ischaemia with a Particular Reference to Regional Myocardial Blood Flow and Metabolism*

Abstract

The effects of verapamil on epicardial ST segment elevation, regional myocardial metabolism and collateral blood flow were studied in open-chest anesthetized dogs following left anterior descending coronary artery occlusion. Collateral blood flow was measured by radioactive microspheres (15 +/- 5 micron diameter) and regional metabolism was studied by measuring lactate concentration in venous blood draining the infarcting myocardium. Verapamil (0-2 mg/kg intravenously) produced a significant reduction (50-60%) in the epicardial ST elevation when it was given before coronary occlusion; when administered 15 minutes after coronary occlusion and infusion continued for two hours, it minimized (30-40%) ST segment elevation, and prevented the fall in cardiac index and rise in systemic resistance found in the untreated animals in which the ST segment remained persistently elevated. Changes in epicardial ST segment occurred without alterations in the QRS duration. Verapamil had no effect on either the total collateral blood flow or the relative distribution of flow to the endocardial and epicardial halves of the ischemic ventricular myocardium. No significant differences were found between the levels of lactate in blood sampled from small epicardial veins at the center of the infarct when the control animals were compared with those treated with verapamil.

Effects of verapamil on ischemia-induced changes in extracellular K+, pH, and local activation in the pig.

“…'9 Verapamil dilates the coronary vasculature,38 but no consistent effect on blood supply to an ischemic area has been demonstrated. 21 38 Diltiazem has been shown to improve blood flow to partially perfused areas in the pig,39 but no effects on blood flow to severely ischemic areas were seen. In view of these findings and the minimal collateral circulation in the swine heart,40 it seems unlikely that the coronary vasodilating effects of 842 verapamil account for the effects on [K']e and pH, at least in the center of the ischemic zone.…”

The effects of verapamil, quiescence, and cardioplegia on calcium exchange and mechanical function in ischemic rabbit myocardium.

“…The observation that verapamil and cardioplegia do not directly inhibit calcium entry on reperfusion is in contrast to many studies (Wende et al, 1975;Reimer et al, 1977;Smith et al, 1977;Lefer et al, 1979) which have shown that, when given prior to a period of ischemia, calcium antagonists delay or prevent tissue damage, and also reduce calcium accumulation Witts et al, 1979;Lefer et al, 1979;Nayler et al, 1980). There are fewer reports of the effects of calcium antagonists given after the onset of ischemia.…”

“…Verapamil and other calcium antagonists block the slow calcium current of the action potential (Kohlhardt et al, 1972a(Kohlhardt et al, , 1972bCranefield et al, 1974;Kohlhardt and Mnich, 1978;Henry, 1980). When these drugs are given prior to or at the onset of a period of ischemia, they have been shown to preserve tissue ultrastructure (Reimer et al, 1977), to reduce enzyme release (Wende et al, 1975;Smith et al, 1977;Lefer et al, 1979), to diminish S-T elevation (Lefer et al, 1979;Selwyn et al, 1979), to improve hemodynamic function (Magee et al, 1979;Clark et al, 1979), to maintain tissue ATP (Lefer et al, 1979;Watts et al, 1979;Nayler et al, 1980;Weishaar and Bing, 1980), and to prevent calcium accumulation in whole tissue and isolated mitochondria Watts et al, 1979;Lefer et al, 1979;Nayler et al, 1980). The uniformly beneficial results obtained in such experiments are in sharp contrast to the results of experiments in which calcium antagonists have been administered, not prior to ischemia, but either after the ischemic myocardium has ceased to contract or at the time of reperfusion.…”

Protection of hypoxic myocardium by intracoronary administration of verapamil in open-chest dogs.

“…In an experimental preparation of isolated hearts, inhibition of Ca2+ influx across the sarcolemma was indicated as the principal mechanism of the myocardial protection observed. ' 10-13 In contrast, in studies of open-chest dogs receiving the drug systemically, the importance of direct effects on the ischemic myocardium remained unclear.3`6 The effects of the drug on the collateral circulation and on peripheral hemodynamics have also been shown to influence the balance of oxygen demand and supply, 5 1 obscuring the direct effects on the jeopardized myocardium.…”