A selective adenosine A1 receptor antagonist attenuates renal dysfunction during controlled hypotension with adenosine in rats.
Adenosine infusion produces sustained, reversible, controlled hypotension in humans, but markedly compromises renal function. Since adenosine inhibits renal perfusion and filtration via stimulation of intrarenal A1 receptors, we hypothesized that antagonism of A1-subtype receptors with the selective adenosine A1-receptor antagonist (+-)N6-endonorbornan-2-yl-9-methyladenine (N-0861) would attenuate adenosine-induced renal dysfunction while still allowing induction and maintenance of hypotension. Systemic and renal hemodynamic and excretory responses were measured in clearance studies conducted in six groups of anesthetized rats treated with: vehicle+saline, vehicle+adenosine, N-0861 (10 or 30 mumol/kg intravenously [i.v.])+saline, or N-0861 (10 or 30 mumol/kg i.v.),+adenosine. The A1-receptor antagonist had little effect on the magnitude, maintenance, or reversibility of controlled hypotension produced by adenosine infusion. Oliguria, hypofiltration, and electrolyte retention induced by adenosine infusion were attenuated in rats pretreated with N-0861. Adenosine A1-receptor antagonism also reduced the rebound hyperfiltration and hyperperfusion associated with cessation of adenosine infusion. N-0861 alone had only a modest effect on renal or systemic hemodynamics, but produced significant dose-related diuresis/natriuresis. These results suggest that coadministration of, or pretreatment with, a selective adenosine A1-receptor antagonist may attenuate the undesirable renal effects of adenosine while allowing maintenance of controlled hypotension.
Barrett
R J
RJ
Department of Pharmacology, Whitby Research, Inc., Richmond, Virginia.
Wright
K F
KF
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D007023:Hypotension, Controlled; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009636:Norbornanes / Q000494:pharmacology*; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley
D009636:Norbornanes; D058915:Purinergic P1 Receptor Antagonists; C073387:N 0861; D000225:Adenine; D000241:Adenosine