PHARMACOLOGICAL STUDIES ON A NEW ANTIHYPERTENSIVE AGENT, S-2150, A BENZOTHIAZEPINE DERIVATIVE .1. ANTINECROTIC AND ANTIARRHYTHMIC EFFECTS IN REPERFUSED RAT HEARTS

S-2150 is a new 1,5-benzothiazepine derivative that inhibits [H-3]dilt iazem and [H-3]WB4101 bindings to the membrane of rat tissue. The effe cts of S-2150 on ischemia/reperfusion injury were studied in anestheti zed rats. S-2150 reduced the myocardial infarct size (TS) induced by 2 0-min coronary artery occlusion followed by reperfusion. To evaluate r eperfusion-induced ventricular tachycardia and fibrillation (VT, VF), we occluded the coronary artery for 4 min and then reperfused it. The incidence of arrhythmia was blocked by S-2150, and this effect offered protection against cardiac death. Prazosin did not modify the IS or i ncidence of reperfusion arrhythmias, but combined treatment with a non effective dose of diltiazem showed significant cardioprotective effect s. We also compared the direct effects of S-2150 and diltiazem on card iac function and coronary perfusion flow using isolated rat hearts. Bo th drugs decreased mechanical function and increased coronary flow, wi th S-2150 being less cardiodepressive and more vasodilatory. S-2150 is cardioprotective at doses comparable to hypotensive doses even though its cardiodepressant effect is much weaker than that of diltiazem, Th is effectiveness may be partly explained by its dual characteristics: blocking the Ca channel and the alpha(1)-adrenoceptor.