Cardiovascular and Renal Effects of Blocking A1 Adenosine Receptors

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Abstract
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 FK.453) 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 μg/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 hind-quarter 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 μl/30 min for DPCPX, and from 386 ± 76 to 814 ± 156 μl/30 min for FK453) and natriuresis (from 0.88 ± 0.30 to 5.09 ± 1.28 μmol/min for DPCPX, and from 1.58 ± 0.56 to 5.95 ± 1.02 μmol/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 cause diuresis without disturbing potassium homeostasis.

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