S-2150 is a new 1,5-benzothiazepine derivative that inhibits [3H]diltiazem and [3H]WB4101 bindings to the membrane of rat tissue. The effects of S-2150 on ischemia/ reperfusion injury were studied in anesthetized rats. S-2150 reduced the myocardial infarct size (IS) induced by 20-min coronary artery occlusion followed by reperfusion. To evaluate reperfusion-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 incidence of reperfusion arrhythmias, but combined treatment with a noneffective dose of diltiazem showed significant cardioprotective effects. We also compared the direct effects of S-2150 and diltiazem on cardiac function and coronary perfusion flow using isolated rat hearts. Both drugs decreased mechanical function and increased coronary flow, with 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. This effectiveness may be partly explained by its dual characteristics: blocking the Ca channel and the alpha 1-adrenoceptor.
The hypotensive and antimyocardial-stunning effects of a new 1,5-benzothiazepine antihypertensive agent, S-2150, were investigated in dogs. S-2150 (30 mg/kg, p.o.) decreased the blood pressure in conscious renal hypertensive dogs. Although the maximal hypotensive effect of S-2150 was observed at 5-9 h after administration, the effect of diltiazem was seen at 2.0 h. Arrhythmia was not observed as a hypotensive effects of S-2150 but was markedly induced by diltiazem. In anesthetized open-chest dogs, S-2150 (20 micrograms/kg/min, i.v.) caused by hypotensive effect similar to that of diltiazem but decreased myocardial work (double product) by much less than did diltiazem. S-2150 more promptly improved the local myocardial stunning caused by occlusion of the left anterior descending coronary artery and its reperfusion. This effect did not accompany the energy-sparing action in ischemic/reperfused myocardium, which was different from the case of diltiazem. In isolated dog mesenteric arteries, S-2150 relaxed KCl and phenylephrine contracture. These results suggest that S-2150 is a favorable hypotensive agent for hypertensive patients with ischemic heart disease. Blockage of both Ca2+ channels and alpha 1-adrenoceptors by S-2150 seems to lead to cardiovascular effects different from those of diltiazem.
A series of 4-aryl-4,7-dihydropyrazolo[3,4-b]pyridine-5-carboxylate derivatives (72-149) was prepared and the compounds were tested for Ca-blocking activity in isolated guinea pig portal vein, antihypertensive activity in spontaneously hypertensive rats, and coronary vasodilating effect in isolated guinea pig heart. A number of derivatives had potent antihypertensive and coronary vasodilating activities. The structure-activity relationships of the series indicated that a 3cyclopentyl or 3-cyclohexyl substituent and a hydrophobic 5-ester moiety with moderate bulkiness were effective for increasing the pharmacological potencies.
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