Antihypertensive property of a novel uricosuric diuretic, S‐8666, in rats

Abstract

AbstractThe antihypertensive, diuretic, and toxicological effects of S‐8666 were studied in rats. At doses of more than 60 mg/kg/day, p.o., S‐8666 was antihypertensive in DOCA‐salt hypertensive rats with a potency corresponding to 1/20 of that of trichlormethiazide. The antihypertensive effect was dose‐dependent, and, at the higher doses, S‐8666 had a more potent depressor effect than trichlormethiazide. The antihypertensive activity of S‐8666 was shown predominantly by the S‐(−)‐enantiomer, with the R‐(+)‐enantiomer being only slightly active. A similar dose‐dependent antihypertensive effect was shown by furosemide, tienilic acid, or indacrinone, but the therapeutic index (LD50/minimum effective dose) of S‐8666 was the highest among them. The acute diuretic and natriuretic effects of S‐8666 after oral administration of 60–200 mg/kg to DOCA‐salt hypertensive rats correlated well with its antihypertensive effect, although such diuretic and natriuretic effects in normotensive rats had no effect on blood pressure. S‐8666, like trichlormethiazide, showed a prophylactic effect on the development of hypertension in DOCA‐salt hypertensive rats, salt‐loaded spontaneously hypertensive rats (SHR), and salt‐loaded Dahl‐S rats, though it was much less potent. Moreover, the combination of S‐8666 with captopril in SHR enhanced the depressor effect of captopril like hydrochlorothiazide. These results indicate that S‐8666 can be an effective nonthiazide diuretic for use as an antihypertensive agent.