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 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 A(1) antagonists. Our objectives for this study were 1) to compare the diuretic, natriuretic, and cardiovascular effects of acute A(1) 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 A(1) antagonist 1, 3-dipropyl-8-cyclopentylxanthine (DPCPX; 10 microgram/kg/min) increased urine output (410 +/- 116 and 317 +/- 86 microliter/30 min/g kidney) and sodium excretion (90.3 +/- 25.6 and 76.8 +/- 18.2 micromol/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 microgram/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 A(1) receptors linked to tubular sodium transport through PT-sensitive G-proteins.
Kost
C K
CK
Center for Clinical Pharmacology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. Kost@med1.dept-med.pitt.edu
Herzer
W A
WA
Rominski
B R
BR
Mi
Z
Z
Jackson
E K
EK
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004231:Diuresis / Q000187:drug effects*; D004347:Drug Interactions; D005665:Furosemide / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000187:drug effects; D006973:Hypertension / Q000503:physiopathology; D008297:Male; D009318:Natriuresis / Q000187:drug effects*; D037342:Pertussis Toxin; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000145:classification; D010566:Virulence Factors, Bordetella / Q000633:toxicity; D014970:Xanthines / Q000494:pharmacology*
D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D010566:Virulence Factors, Bordetella; D014970:Xanthines; D005665:Furosemide; C051360:1,3-dipropyl-8-cyclopentylxanthine; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins