PHARMACOLOGICAL STUDIES ON A NEW ANTIHYPERTENSIVE AGENT, S-2150, A BENZOTHIAZEPINE DERIVATIVE .2. HYPOTENSIVE EFFECTS IN NORMOTENSIVE AND HYPERTENSIVE RATS

S-2150 is a new 1,5-benzothiazepine derivative possessing both calcium channel-blocking and alpha(1)-adrenoceptor-blocking effects. In isola ted rat thoracic aorta precontracted with KCl (18 mM), the 50% inhibit ory concentration (IC50) value was 190 nM for S-2150, which was simila r to that of diltiazem. In aorta precontracted with phenylephrine (0.3 mu M), IC50 values of S-2150 and diltiazem were 29 nM and >10 mu M, r espectively. The relative contribution of calcium channel-blocking and alpha(1)-adrenoceptor-blocking activities to hypotension was determin ed by using anesthetized rats before and after masking of the alpha(1) -receptors with prazosin. The hypotensive effect of S-2150 [0.3 and 1 mg/kg intravenously (i.v.)] was attenuated by 40% after prazosin treat ment, whereas that of diltiazem was not. In conscious spontaneously hy pertensive rats (SHRs), renal hypertensive rats, and normotensive rats , S-2150 [10, 30, and 60 mg/kg orally (p.o.)] caused dose-dependent hy potensive effects. The effect of S-2150 was 4-7 times more potent than that of diltiazem. There were no changes in the hypotensive effects w ith consecutive administration of S-2150 during 6-8 weeks in SHRs and stroke-prone SHRs (SHRSPs). In SHRSPs, S-2150 reduced the mortality by stroke and snail arterial hyperplasia in abdominal organs and also am eliorated renal excretory function. These results suggest that S-2150 may be a useful antihypertensive agent possessing both calcium-antagon istic and alpha(1)-adrenoceptor-blocking effects.