RENAL EFFECTS OF FK453 - A POTENT NONXANTHINE ADENOSINE A(1) RECEPTORANTAGONIST

The renal effects of FK453, a potent and selective non-xanthine adenos ine A(1) receptor antagonist, were examined and compared with FR113452 (less active enantiomer of FK453), typical adenosine receptor antagon ists, 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 FR11345 2 nor CP66713 (an adenosine A(2) receptor antagonist) possessed diuret ic activity. Urinary uric acid excretion in rats increased with FK453, but other drugs had no effect. These diuretic and uricosuric activiti es of FK453 were also observed in dogs. In anesthetized dogs, FK453 in creased the renal blood flow (RBF), inulin clearance (Gin), and p-amin ohippuric acid clearance (C-PAH). However, hydrochlorothiazide had no effect on RBF, Cin, and C-PAH. Furthermore, osmolar clearance experime nts suggested that the renal site of action of FK453 was different fro m hydrochlorothiazide and furosemide. These results demonstrate that F K453 has diuretic activity and increases urinary uric acid excretion a nd 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 hydrochl orothiazide and furosemide. FK453 is a useful compound to clarify the physiological role of the adenosine A(1) receptor in the kidney. (C) 1 995 Wiley-Liss, Inc.