title: Pharmacological studies on a new antihypertensive agent, S-2150, a benzothiazepine derivative: 2. Hypotensive effects in normotensive and hypertensive rats.
abstract: S-2150 is a new 1,5-benzothiazepine derivative possessing both calcium channel-blocking and alpha 1-adrenoceptor-blocking effects. In isolated rat thoracic aorta precontracted with KCl (18 mM), the 50% inhibitory concentration (IC50) value was 190 nM for S-2150, which was similar to that of diltiazem. In aorta precontracted with phenylephrine (0.3 microM), IC50 values of S-2150 and diltiazem were 29 nM and > 10 microM, respectively. The relative contribution of calcium channel-blocking and alpha 1-adrenoceptor-blocking activities to hypotension was determined 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 treatment, whereas that of diltiazem was not. In conscious spontaneously hypertensive rats (SHRs), renal hypertensive rats, and normotensive rats, S-2150 [10, 30, and 60 mg/kg orally (p.o.)] caused dose-dependent hypotensive effects. The effect of S-2150 was 4-7 times more potent than that of diltiazem. There were no changes in the hypotensive effects with 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 small arterial hyperplasia in abdominal organs and also ameliorated renal excretory function. These results suggest that S-2150 may be a useful antihypertensive agent possessing both calcium-antagonistic and alpha 1-adrenoceptor-blocking effects.
authors.affiliation: Discovery Research Laboratories II, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kawakami
authors.forename: S
authors.initials: S
authors.lastname: Matsumura
authors.forename: T
authors.initials: T
authors.lastname: Shimamura
authors.forename: T
authors.initials: T
authors.lastname: Iwasaki
authors.forename: H
authors.initials: H
authors.lastname: Furukawa
authors.forename: K
authors.initials: K
authors.lastname: Matsunaga
authors.forename: Y
authors.initials: Y
authors.lastname: Yonetani
authors.forename: K
authors.initials: K
authors.lastname: Iwaki
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001011:Aorta / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D015220:Calcium Channels / Q000187:drug effects*; D002318:Cardiovascular Diseases / Q000517:prevention & control; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy*; D007022:Hypotension / Q000139:chemically induced* / Q000503:physiopathology; D007674:Kidney Diseases / Q000517:prevention & control; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000959:Antihypertensive Agents; D015220:Calcium Channels; C104615:S 2150; D004110:Diltiazem