LONG-LASTING HYPOTENSIVE AND ANTIHYPERTENSIVE EFFECTS OF A NEW 1,5-BENZOTHIAZEPINE CALCIUM-ANTAGONIST IN HYPERTENSIVE RATS AND RENAL HYPERTENSIVE DOGS

  • 1 April 1988
    • journal article
    • research article
    • Vol. 38-1  (4) , 515-520
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 hypotensive 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. In renal hypertensive dogs, TA-3090 at doses of 1 and 2 mg/kg p.o. decreased the blood pressure for more than 5 h. At 2 mg/kg it increased the PQ-interval of electrocardiogram and plasma renin activity but not plasma aldosterone concentration. The time course of hypotensive effect of TA-3090 was not in parallel with the plasma levels time course. Diltiazem showed effects similar to those of TA-3090, but its hypotensive potency was approximately one-half that of TA-3090. Thus, TA-3090 was demonstrate to produce more potent and longer lasting hypotensive effects than diltiazem in various models of hypertension. Furthermore, TA-3090 showed natriuretic effect in SHR at comparable doses to the hypotensive ones.