Effects of KB-944, a novel calcium antagonist, in several models of canine myocardial ischemia.

The actions of KB-944 ([4-(2-benzothiazolyl)-phenylmethyl]phosphonic acid diethylester) on hemodynamics and regional myocardial blood flow during partial or total coronary artery occlusion were studied in anesthetized dogs. In one series of experiments a severe stenosis, that reduced distal diastolic coronary perfusion pressure to 40 mm Hg, was applied to the left anterior descending coronary artery whereas in another series of experiments the left anterior descending was ligated to produce a total occlusion. Intravenous infusion of KB-944 (100 and 200 micrograms/kg/min) decreased heart rate and left ventricular systolic and aortic blood pressure. Total coronary artery blood flow and regional perfusion of normal myocardium were increased by KB-944 in both models. KB-944 increased regional segment function in normal and ischemic regions and maintained distal coronary artery perfusion pressure, coronary flow and transmural regional myocardial blood flow during partial coronary artery occlusion despite a reduction in aortic pressure. In a model of total coronary artery occlusion, KB-944 had no effect on the indirect indices of collateral function, retrograde flow and retrograde pressure. However, when diastolic aortic pressure was maintained, KB-944 produced transmural increases in myocardial blood flow to normal and collateral dependent zones. Thus, KB-944 maintains ischemic zone blood flow despite decreases in coronary perfusion pressure and increases in tissue flow in the collateral dependent region when aortic pressure is prevented from decreasing.