Cardiovascular and renal effects of blocking A1 adenosine receptors.
The primary objective of this study was to test the hypothesis that endogenous adenosine/A1 receptor interactions participate in the normal regulation of the cardiovascular system and kidneys. In anesthetized rats, we examined the effects of pharmacologically equivalent doses of DPCPX and FK453 (two structurally dissimilar A1 receptor antagonists) and the effects of FR113452 (the less active enantiomer of FK453) on 20 hemodynamic and renal function parameters. After baseline measurements, animals were randomized to an intravenous infusion of either vehicle or DPCPX, FK453, or FR113452 (10, 30, and 30 micrograms/kg/min, respectively), and all measurements were repeated. Neither DPCPX, FK453, nor FR113452 affected significantly the heart rate; cardiac output; stroke volume; arterial blood pressure; total vascular resistance; regional blood flows to and regional vascular resistances of the carotid, mesenteric, renal, and hindquarter vascular beds; glomerular filtration rate; filtration fraction; or potassium excretion. However, DPCPX and FK453, but not FR113452, caused a pronounced diuresis (from 194 +/- 30 to 696 +/- 144 microliters/30 min for DPCPX, and from 386 +/- 76 to 814 +/- 156 microliters/30 min for FK453) and natriuresis (from 0.88 +/- 0.30 to 5.09 +/- 1.28 mumol/min for DPCPX, and from 1.58 +/- 0.56 to 5.09 +/- 1.02 mumol/min for FK453). These results firmly establish that (a) endogenous adenosine/A1 receptor interactions regulate renal excretory function, (b) this regulation is via a renal tubular, rather than hemodynamic, mechanism, and (c) A1 receptor antagonists caused diuresis without disturbing potassium homeostasis.
Kuan
C J
CJ
Center for Clinical Pharmacology, University of Pittsburgh Medical Center, Pennsylvania 15261.
Herzer
W A
WA
Jackson
E K
EK
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D004231:Diuresis / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006461:Hemolysis / Q000187:drug effects; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D058914:Purinergic Antagonists; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects*; D014970:Xanthines / Q000494:pharmacology
D000959:Antihypertensive Agents; D058914:Purinergic Antagonists; D011720:Pyrazoles; D011725:Pyridines; D014970:Xanthines; C077100:FK 453; C051360:1,3-dipropyl-8-cyclopentylxanthine