Long-lasting hypotensive and antihypertensive effects of a new 1,5-benzothiazepine calcium antagonist in hypertensive rats and renal hypertensive dogs.

Abstract

The hypotensive effect of a new 1,5-benzothiazepine derivative, TA-3090 ((+) (2S,3S)-3-acetoxy-8-chloro-5-(2-(dimethylamino)ethyl)-2, 3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)-one maleate), was studied in various models of experimental hypertension. In conscious spontaneously hypertensive rats (SHR), TA-3090 at a dose of 3 mg/kg p.o. or more caused significant hypotension. The effect was long-lasting, being observed for more than 8 h and 24 h at doses of 30 and 100 mg/kg p.o., respectively. Heart rate was not increased with doses up to 30 mg/kg p.o. TA-3090 like diltiazem, showed more potent hypotensive effect in SHR than in Wistar Kyoto rats (WKY). The enhancement of the hypotensive effect in SHR was more evident with TA-3090 and diltiazem than with 1,4-dihydropyridine calcium antagonists (1,4-DHPs). The enhanced hypotensive effect of TA-3090 was also observed in deoxycorticosterone acetate (DOCA)-salt hypertensive rats in which the minimum hypotensive dose of TA-3090 was 1 mg/kg p.o. In SHR, reflex tachycardia induced by TA-3090 was smaller than those induced by 1,4-DHPs, while diltiazem decreased the heart rate. In WKY, all calcium antagonists except diltiazem at a low dose (30 mg/kg p.o.) increased the heart rate. Development of hypertension in young SHR was significantly suppressed by chronic treatment with TA-3090 at a daily dose of 10 mg/kg p.o. or more. The antihypertensive effect of TA-3090 was also observed by administration in the diet in matured SHR. In addition, TA-3090 exhibited a dose-related natriuretic but not kaliuretic effect in SHR at doses slightly higher than the hypotensive ones.(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: H Narita, S Murata, H Yabana, K Kikkawa, Y Sugawara, Y Akimoto, T Nagao
• Journal: Arzneimittel-Forschung (Arzneimittelforschung) Vol. 38 Issue 4 Pg. 515-20 (Apr 1988) ISSN: 0004-4172 [Print] Germany
• PMID: 3041970 (Publication Type: Journal Article)

Chemical References

• Antihypertensive Agents
• Calcium Channel Blockers
• Electrolytes
• Thiazepines
• clentiazem
• Desoxycorticosterone
• Renin
• Diltiazem

Topics

• Animals
• Antihypertensive Agents
• Blood Pressure (drug effects)
• Calcium Channel Blockers (pharmacology)
• Desoxycorticosterone
• Diltiazem (analogs & derivatives)
• Dogs
• Electrocardiography
• Electrolytes (urine)
• Heart Rate (drug effects)
• Hypertension (chemically induced, drug therapy, physiopathology)
• Hypertension, Renal (drug therapy, physiopathology)
• Male
• Rats
• Rats, Inbred SHR
• Rats, Inbred WKY
• Renin (blood)
• Thiazepines (pharmacology)