Renal action of a novel uricosuric diuretic, S-8666. I. Clearance and tubular microinjection studies in rats

T Shimuizu, M Nakamura and M Imai

Department of Pharmacology, National Cardiovascular Center Research Institute, Osaka, Japan.

Clearance and tubular microinjection techniques were used to evaluate the effects of a novel uricosuric diuretic, S-8666, on renal function and tubular absorption of urate by the rat kidney. Tubular sites of diuretic action of S-8666 were determined indirectly using osmolar clearance techniques. The i.v. injection of S-8666 at a dose ranging from 0.3 to 3.0 mg caused a dose-dependent increase in urine flow and sodium excretion. Potassium excretion was increased significantly but the increase was not marked as compared with sodium excretion. Glomerular filtration rate was not changed by S-8666. The diuretic response reached a maximum within 5 min and was retained for 45 min with 1 mg of S-8666. The comparison with the effect of furosemide revealed that furosemide was 13 times more potent than S-8666. Both the free water reabsorption on hydropenia and free water clearance in hydrated animals decreased with administration of S-8666. The urinary excretion of urate increased significantly after the administration of S-8666. By contrast, furosemide did not increase urinary excretion of urate. Total urinary urate recovery after S-8666 administration was higher after the microinjection of [14C]urate into early proximal tubule sites. We conclude that S-8666 acts as a uricosuric diuretic agent with the major site of altered urate absorption being in the proximal convoluted tubule and the major site of diuretic action being in the cortical and medullary diluting segments.

Volume 245, Issue 2, pp. 644-650, 05/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics

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