European Journal of Pharmacology, 42 (1977) 339--346 339 © Elsevier/North-Holland Biomedical Press LACK OF PROTECTION OF ISCHEMIC MYOCARDIUM BY VERAPAMIL IN CONSCIOUS DOGS RONALD P. KARLSBERG, PHILIP D. HENRY, SYED A. AHMED, BURTON E. SOBEL and ROBERT ROBERTS Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri 6311 O, U.S.A. Received 18 August 1976, revised MS received 8 December 1976, accepted 14 December 1976 R.P. KARLSBERG, P.D, HENRY, S.A. AHMED, B.E. SOBEL and R. ROBERTS, Lack of protection of ischemic myocardium by verapamil in conscious dogs, European J. Pharmacol. 42 (1977) 339--346. To determine whether coronary dilatation and decreased myocardial oxygen requirements resulting from administration of verapamil, a calcium and slow current antagonist, protect ischemic myocardium in conscious dogs, we studied 15 treated and 15 control animals after coronary occlusion. Verapamil (0.2--0.7 mg/kg/h) was given by continuous infusion for 17 h beginning 5 h after the initial plasma creatine kinase (CK) elevation after coronary occlusion. Observed infarct size and infarct size predicted before verapamil were estimated from hourly plasma CK values and infarct size was estimated also from myocardial CK depletion measured directly, 24 h after occlusion. Changes in heart rate, blood pressure, and frequency of premature ventricular complexes (recorded every 30 min) after occlusion were similar in treated and control dogs. Coronary flow after verapamil, measured with radioactively labeled microspheres, did not increase in ischemic zones but increased by 90% in normal myocardium (p < 0.05). The differences between observed and predicted infarct size estimated from plasma CK changes in treated and controls were similar (3.0 + 2.2 (S.E.) and 2.0 + 1.4 CK-g-eq), and myocardial CK depletion was also comparable in the two groups (25 + 2% and 23 + 2%). Thus although verapamil, administered five hours after the initial plasma CK elevation, increased coronary flow in normal myocardium, it did not aug- ment flow in ischemic tissue or limit the extent of infarction. Myocardial creatine kinase Calcium antagonists Coronary perfusion Myocardial infarction Verapamil Ischemic injury 1. Introduction Since the extent of myocardial infarction is an important determinant of prognosis {Page et al., 1971; Sobel et al., 1972), attempts have been made to protect ischemic myocardium with interventions designed to reduce myocardial oxygen consumption or increase oxygen supply (Maroko et al., 1971). Verapamil, an inhibitor of calcium flux into vascular and myocardial cells, dilates periph- eral and coronary arteries (Haas and H~t- felder, 1962; Schlepper and Witzleg, 1962) and exerts negative inotropic effects on the heart (Magnussen and Kudsk, 1974). Ac- cordingly, it may be a useful agent for pro- tecting ischemic myocardium (Smith et al., 1975; Wende et al., 1975) by improving coronary collateral flow, enhancing oxygen supply in ischemic zones, and diminishing oxygen requirements by decreasing con- tractility and ventricular afterload. For these reasons, and also because of its antiarrhyth- mic properties (Singh and Vaughan Williams, 1972; Rosen et al., 1975), verapamil has been utilized for the treatment of angina pectoris. The present study was designed to evaluate the effects of verapamil on evolving experi- mental acute myocardial infarction in con- scious dogs by assessment of coronary flow, cardiac rhythm and hemodynamics, and enzyme release from ischemic myocardium.