Laboratory Investigation Myocardial Ischemia

The effects of two antianginal drugs, nicorandil and isosorbide dinitrate (ISDN), on metabolism and function of the ischemic myocardium were studied in a preparation of multiple coronary occlusions in barbital-anesthetized dogs. The preparation consisted of three 5 min occlusions of the left anterior descending coronary artery interspersed by 30 min of reperfusion. An equihypotensive dose of nicorandil (7.5 ,ug/kg/min) or ISDN (12.5 ,ug/kg/min) was infused 15 min before and during the second occlusion period. Hemodynamics, myocardial segment shortening (%SS), tissue blood flow, and myocardial oxygen consumption were determined throughout. Uptake of free fatty acids (FFA), glucose, and lactate were determined during control and ischemic periods. At the end of the final 30 min reperfusion period, biopsy samples of transmural tissue were taken for analysis of phosphocreatine, adenine nucleotides, and total tissue water content. No major hemodynamic changes were produced by either drug except for a 5 to 10 mm Hg decrease in mean aortic pressure. Compared with untreated and ISDN-treated hearts, hearts of dogs treated with nicorandil exhibited reversal of a significant increase in FFA uptake during recurrent ischemia. This was accompanied by an attenuation of the increase in oxygen extraction and CO2 production in the ischemic zone by nicorandil, but not by ISDN. Nicorandil, but not ISDN, improved %SS during reperfusion. Endocardial ATP and total adenine nucleotides were preserved in both nicorandiland ISDN-treated hearts. Tissue edema was also attenuated by both compounds. Thus, nicorandil improved both function and metabolism during recurrent myocardial ischemia independent of a hemodynamic effect, whereas ISDN only attenuated the loss of adenine nucleotides and increase in tissue water. Circulation 76, No. 4, 916-928, 1987. REPETITIVE, brief episodes of myocardial ischemia are common during angina pectoris in patients with coronary artery disease. Intermittent cross-clamping or repeated, brief periods of coronary artery occlusion are also used during cardiac surgery. However, it is not clear from experimental studies whether recurrent ischemic episodes of brief duration have a cumulative effect on the development of regional postischemic myocardial dysfunction. 1-4 Nicorandil [SG-75; 2-nicotinamidoethyl-nitrate (esFrom the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee. Supported by Chugai Pharmaceutical Company, Ltd., Tokyo, Japan, and USPHS grant HL 08311 from the National Institutes of Health. Address for correspondence: Dr. Galen M. Pieper, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. Received Nov. 1 1, 1986; revision accepted July 2. 1987. 916 ter)] has been developed as a new antianginal drug with potent vasodilating properties. It has recently been shown to improve postischemic segment dysfunction in anesthetized5 and conscious6 dogs after a single 10 or 15 min coronary artery occlusion. The improvement in postischemic myocardial function after nicorandil may be partially related to a reduction in afterload, but the improved functional recovery in the presence of nicorandil is significantly greater than that after an equihypotensive dose of nifedipine. Thus suggests that the beneficial effects of nicorandil on the ischemic myocardium may be independent of peripheral hemodynamics and that other mechanisms must be involved in its action. The purpose of this study was to determine whether there is a metabolic component of the action of nicorandil independent of its hemodynamic effect that CIRCULATION by gest on A ril 3, 2017 http://ciajournals.org/ D ow nladed from LABORATORY INVESTIGATION-MYOCARDIAL ISCHEMIA might explain its salient effect on postischemic myocardial function. Thus, we purposely chose a low dose of nicorandil that would not significantly alter the ratepressure product or myocardial oxygen consumption to determine whether the recovery of contractile function was enhanced after reperfusion. The experimental preparation of repeated, short periods of coronary artery occlusion was chosen for these studies to mimic the recurrent ischemia of anginal attacks observed clinically. Isosorbide dinitrate was chosen for purposes of comparison because this compound has a similar hemodynamic profile and plasma half-life to those of nicorandil.