LABORATORY INVESTIGATION CORONARY ARTERY DISEASE Protective effect of early and late treatment with nifedipine during myocardial infarction in the conscious dog

The effect of early and late nifedipine treatment on collateral blood flow and myocardial infarct size was investigated in 24 previously instrumented conscious dogs. Nifedipine was infused intravenously for 5 hr beginning 15 min (n = 9) and 3 hr (n = 6) after permanent occlusion of the midcircumflex coronary artery and compared with early and delayed vehicle treatment (controls; n = 9). Doses of nifedipine (90 to 168 ,gg/hr) were titrated to reduce mean arterial pressure by 5% to 10%. After animals died or were killed 2 to 7 days later, the anatomic risk region, or occluded coronary bed, was defined by postmortem coronary arteriography. The masses of infarct and risk region were measured by planimetry of weighed transverse sections of the left ventricle. Infarct size was smaller (p < .05) with early and late nifedipine treatment compared with control, both as percent of left ventricle (15.6% and 14.6% vs 21.6%) and as percent of risk region (46.7% and 41.6% vs 65.7%). Collateral blood flow, measured with radioactive microspheres, increased 31% to 50% during 5 hr of nifedipine treatment, but the mean increase was not statistically greater than that seen in controls. Myocardial protection by nifedipine occurred consistently when epicardial collateral flow exceeded 0.40 ml/min/g and the increase after the drug was at least 0.1 ml/min/g. When flows were less than these amounts, however, only about half of the animals demonstrated reduced infarct size. The results suggest that an increase in collateral flow accounts for part of the beneficial effect of nifedipine but that direct mechanisms not mediated by flow may also contribute. Circulation 69, No. 1, 131-141, 1984. NIFEDIPINE, a drug that inhibits the intracellular movement of calcium through specific membrane channels, has been studied as a means of protecting ischemic myocardium from irreversible injury. By blocking calcium entry into vascular smooth muscle and myocardial cells, nifedipine causes vasodilation in coronary and systemic vascular beds and depression of myocardial contractility. These actions would be expected to cause an amelioration of myocardial ischemia by increasing coronary flow and reducing myocardial oxygen demands. In addition, inhibition of calcium uptake by ischemic or reperfused myocardial From the Department of Medicine, Cardiology Division, and the Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore. Supported by the National Heart, Lung and Blood Institute Ischemic Heart Disease SCOR grant 2 P 50 HL 17655, National Institutes of Health, Bethesda. Dr. Melin was a recipient of a Fogarty International Fellowship. Address for correspondence: Lewis C. Becker, M.D., Division of Cardiology, Johns Hopkins Hospital, 600 North Wolfe St., Baltimore, MD 21205. Received April 7, 1983; revision accepted Sept. 29, 1983. *Present address: Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium. Vol. 69, No. 1, January 1984 cells might afford direct myocardial protection, since calcium overload appears to be important in the pathogenesis of irreversible damage.'-' Experimentally, nifedipine has been shown in the anesthetized and conscious dog to increase collateral flow regionally under ischemic conditions,4 although this finding has not been universal.7 Nifedipine has been associated with improved short-term indexes of myocardial damage, including better regional and global ventricular function,"-" less electrocardiographic R wave loss,6 less depletion of myocardial adenosine triphosphate,'2 and delayed release of creatine kinase. Henry et al.4 found that treatment with nifedipine in conscious dogs resulted in less marked depletion of creatine kinase at myocardial sites matched for the initial degree of ischemia. However, Geary et al.'3 found no myocardial protection in the anesthetized baboon, an animal known to have sparse native intercoronary collateral channels. 14, 1' This study was designed to assess the relative importance of collateral flow changes and direct actions of nifedipine not mediated by flow in protecting regional131 by gest on A ril 2, 2017 http://ciajournals.org/ D ow nladed from