Renal effects of FK453: A potent non-xanthine adenosine A1 receptor antagonist

The renal effects of FK453, a potent and selective non-xanthine adenosine A 1 receptor antagonist, were examined and compared with FR113452 (less active enantiomer of FK453), typical adenosine receptor antagonists, and diuretics. In rats FK453 possessed diuretic activity similar to 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, adenosine A 1 receptor antagonist), hydrochlorothiazide, and furosemide, but neither FR113452 nor CP66713 (an adenosine A 2 receptor antagonist) possessed diuretic activity. Urinary uric acid excretion in rats increased with FK453, but other drugs had no effect. These diuretic and uricosuric activities of FK453 were also observed in dogs. In anesthetized dogs, FK453 increased the renal blood flow (RBF), inulin clearance (Cin), and p-aminohippuric acid clearance (C PAH ). However, hydrochlorothiazide had no effect on RBF, Cin, and C PAH . Furthermore, osmolar clearance experiments suggested that the renal site of action of FK453 was different from hydrochlorothiazide and furosemide. These results demonstrate that FK453 has diuretic activity and increases urinary uric acid excretion and suggest that the diuretic activity of FK453 is related to adenosine A 1 receptor antagonism; also, the diuretic mechanism of action and the renal site of action of FK453 are different from those of hydrochlorothiazide and furosemide. FK453 is a useful compound to clarify the physiological role of the adenosine A 1 receptor in the kidney. © 1995 Wiley-Liss, Inc.