Diuretic response to adenosine A(1) receptor blockade in normotensive and spontaneously hypertensive rats: Role of pertussis toxin-sensitive G-proteins

Adenosine A(1) receptor antagonists are being developed for use as diuretic s in the treatment of hypertension, however, there is relatively little dat a in hypertensive animal models regarding the efficacy of these compounds. In addition, some controversy exists surrounding the role of pertussis toxi n (PT)-sensitive G-proteins in the signaling pathway for receptors acted on by A(1) antagonists. Our objectives for this study were 1) to compare the diuretic, natriuretic, and cardiovascular effects of acute A(1) receptor bl ockade in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto ra ts (WKY); and 2) to determine whether the diuretic effects are mediated thr ough a PT-sensitive mechanism. Acute administration of the selective A(1) a ntagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 10 mu g/kg/min) increa sed urine output (410 +/- 116 and 317 +/- 86 mu l/30 min/g kidney) and sodi um excretion (90.3 +/- 25.6 and 76.8 +/- 18.2 mu mol/30 min/g kidney) simil arly in WKY and SHR, respectively. DPCPX significantly decreased mean arter ial blood pressure in SHR (-11.4 +/- 2.7 mm Hg), but not WKY. Prior treatme nt with PT (30 mu g/kg i.v.) abolished the diuretic response to DPCPX in bo th SHR and WKY. In a subsequent experiment in PT-treated Sprague-Dawley rat s, DPCPX failed to evoke a diuretic response, whereas coinfusion of furosem ide with DPCPX induced marked diuresis. Our results indicate that acute DPC PX administration produces similar natriuretic/diuretic effects in SHR and WKY, with beneficial effects on blood pressure in SHR. PT abolishes the res ponse to DPCPX, indicating that the natriuretic/diuretic response to DPCPX is mediated via blockade of A(1) receptors linked to tubular sodium transpo rt through PT-sensitive G-proteins.