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: M Kawakami, S Matsumura, T Shimamura, T Iwasaki, H Furukawa, K Matsunaga, Y Yonetani, K Iwaki
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 28 Issue 5 Pg. 695-702 (Nov 1996) ISSN: 0160-2446 [Print] United States
• PMID: 8945684 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Adrenergic alpha-1 Receptor Antagonists
• Antihypertensive Agents
• Calcium Channels
• S 2150
• Diltiazem

Topics

• Adrenergic alpha-1 Receptor Antagonists
• Animals
• Antihypertensive Agents (therapeutic use)
• Aorta (drug effects)
• Blood Pressure (drug effects)
• Calcium Channels (drug effects)
• Cardiovascular Diseases (prevention & control)
• Diltiazem (analogs & derivatives, pharmacology, therapeutic use)
• Heart Rate (drug effects)
• Hypertension (drug therapy)
• Hypotension (chemically induced, physiopathology)
• Kidney Diseases (prevention & control)
• Male
• Muscle, Smooth, Vascular (drug effects, physiology)
• Rats
• Rats, Inbred SHR
• Rats, Wistar