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

Abstract

The renal effects of FK453, a potent and selective non-xanthine adenosine A, receptor antagonist, were examined and compared with FR113452 (less active enantiomer o i FK453), typical adenosine receptor antagonists, and diuretics. In rats FK453 possessed diuretic activity similar to 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, adenosine A , receptor antagonist), hydrochlorothiazide, and furosemide, but neither FR113452 nor CP66713 (an adenosine AL 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 (CPAH). However, hydrochlorothiazide had no effect on RBF, Cin, and CpAH. 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, 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 i s a useful compound to clarify the physiological role of the adenosine A, receptor in the kidney. Q 1995 Wiley-Liss, Inc.

FK453: A Novel Non‐Xanthine Adenosine A1 Receptor Antagonist as Diuretic

“…On the other hand, FK453 and hydrochlorothiazide increased C,,, and free water reabsorption during antidiuresis, whereas furosemide increased C, , , but had little effect on free water reabsorption. These results suggest that FK453 produced potent diuretic and natriuretic effects by suppressing water and sodium transport in the proximal part of the nephron (42).…”

“…We feel, therefore, that FK453 differs from hydrochlorothiazide and furosemide in its hemodynamic effects as well as its tubular site of action. Our previous study in pentobarbital anesthetized dogs demonstrated that FK453 significantly increased renal blood flow and GFR, but hydrochlorothiazide had little effect on either parameter (42).…”

“…The site of diuretic action of FK453 within the nephron was assessed from the pattern of water excretion in the hydrated and hydropenic states according to the principle of water clearance (38,42). During water diuresis, FK453 increased osmolar clearance (COsm) and free water clearance (CHZ,), whereas furosemide and hydrochlorothiazide increased C,,, and decreased the CH,,.…”

“…4), and that DPCPX tended to increase these effects (42). On the other hand, FR113452 and CP667 13 (4-amino-8-chloro-1 -phenyl [ 1,2,4] triazolo [4, 3-a] quinoxaline; adenosine A, receptor antagonist) (36) had no uricosuric action (42).…”

“…During a search for diuretics, FK453 was found to possess a potent diuretic activity with renal vasodilatory and uricosuric effects (40). In addition.…”