Salutary action of nicorandil, a new antianginal drug, on myocardial metabolism during ischemia and on postischemic function in a canine preparation of brief, repetitive coronary artery occlusions: comparison with isosorbide dinitrate.

Abstract

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 micrograms/kg/min) or ISDN (12.5 micrograms/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 nicorandil- and 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.