Long-lasting hypotensive and antihypertensive effects of a new 1,5-benzothiazepine calcium antagonist in hypertensive rats and renal hypertensive dogs.
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)
D000818:Animals; D000959:Antihypertensive Agents; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003900:Desoxycorticosterone; D004110:Diltiazem / Q000031:analogs & derivatives*; D004285:Dogs; D004562:Electrocardiography; D004573:Electrolytes / Q000652:urine; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012083:Renin / Q000097:blood; D013841:Thiazepines / Q000494:pharmacology*
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004573:Electrolytes; D013841:Thiazepines; C056595:clentiazem; D003900:Desoxycorticosterone; D012083:Renin; D004110:Diltiazem