Reduction of Myocardial Ischemia-Reperfusion Injury by KT-362, a New Intracellular Calcium Antagonist in Anesthetized Dogs

Abstract

Summary: The effects of a new intracellular calcium antagonist, KT-362 (5-[3-[[2-(3,4-dimethoxyphenyl)-ethyl]amino]-1-oxopropyl]-2,3,4,5,-tetrahydro-1,5-ben-zothiazepine fumarate) on myocardial infarct size following a 90-min occlusion and 3-h reperfusion of the left anterior descending coronary artery (LAD) were determined in anesthetized dogs. Regional myocardial blood flow was measured by radioactive microsphere technique, and infarct size was determined using triphenyltetrazolium chloride histochemical stain. Vehicle or KT-362 (300 μg/kg/min for 20 min followed by 150 μg/kg/min for 80 min) was administered intravenously (i.v.) 10 min prior to coronary occlusion and continued throughout the occlusion period in separate experimental groups. KT-362 produced a reduction in heart rate (HR) and the HR-systolic pressure product. Mean arterial pressure (MAP) was reduced during occlusion and early reperfusion in the KT-362-treated group, and segment function (% segment shortening) was improved during the first hour of reperfusion. There were no differences in collateral blood flow between the two groups. However, at 3 h postreperfusion, ischemic zone subendocardial blood flow in the KT-362-treated group was significantly greater than in the vehicle-treated group, resulting in an increase in endo/epi. There were no differences in ventricular mass, mass of the area at risk, or percentage of the left ventricle at risk. As compared with the control group, KT-362 produced a marked reduction in myocardial infarct size expressed as a percentage of the area at risk infarcted, percentage of the left ventricle infarcted, and absolute weight of infarcted tissue. This beneficial effect was most likely due to a decrease in myocardial energy requirements during occlusion as a result of inhibition of intracellular calcium release.