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Vol. 292, Issue 2, 752-760, February 2000

Diuretic Response to Adenosine A1 Receptor Blockade in Normotensive and Spontaneously Hypertensive Rats: Role of Pertussis Toxin-Sensitive G-Proteins

Curtis K. Kost, Jr., William A. Herzer, Barbara R. Rominski, Zaichuan Mi and Edwin K. Jackson

Center for Clinical Pharmacology, Departments of Medicine and Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Adenosine A1 receptor antagonists are being developed for use as diuretics in the treatment of hypertension, however, there is relatively little data in hypertensive animal models regarding the efficacy of these compounds. In addition, some controversy exists surrounding the role of pertussis toxin (PT)-sensitive G-proteins in the signaling pathway for receptors acted on by A1 antagonists. Our objectives for this study were 1) to compare the diuretic, natriuretic, and cardiovascular effects of acute A1 receptor blockade in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto rats (WKY); and 2) to determine whether the diuretic effects are mediated through a PT-sensitive mechanism. Acute administration of the selective A1 antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 10 µg/kg/min) increased urine output (410 ± 116 and 317 ± 86 µl/30 min/g kidney) and sodium excretion (90.3 ± 25.6 and 76.8 ± 18.2 µmol/30 min/g kidney) similarly in WKY and SHR, respectively. DPCPX significantly decreased mean arterial blood pressure in SHR (-11.4 ± 2.7 mm Hg), but not WKY. Prior treatment with PT (30 µg/kg i.v.) abolished the diuretic response to DPCPX in both SHR and WKY. In a subsequent experiment in PT-treated Sprague-Dawley rats, DPCPX failed to evoke a diuretic response, whereas coinfusion of furosemide with DPCPX induced marked diuresis. Our results indicate that acute DPCPX administration produces similar natriuretic/diuretic effects in SHR and WKY, with beneficial effects on blood pressure in SHR. PT abolishes the response to DPCPX, indicating that the natriuretic/diuretic response to DPCPX is mediated via blockade of A1 receptors linked to tubular sodium transport through PT-sensitive G-proteins.

0022-3565/00/2922-0752$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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