Adenosine A1-receptor mechanisms antagonize beta-adrenergic pulmonary vasodilation in hypoxia.
Hypoxic pulmonary vasoconstriction is refractory to beta-adrenergic receptor (beta-AR)-mediated pulmonary vasodilation. We hypothesized that hypoxic pulmonary arteries release adenosine (Ado) that antagonizes beta-AR-mediated pulmonary vasodilation. Using isolated rat pulmonary artery rings, we investigated 1) the effect of hypoxia and exogenous Ado on beta-AR-mediated pulmonary vasodilation, 2) the intracellular site of dysfunctional beta-AR-mediated pulmonary vasodilation in hypoxia, and 3) the Ado receptor subtype responsible for dysfunction of beta-AR-mediated pulmonary vasodilation. Hypoxia attenuated normal beta-AR-mediated pulmonary vasodilation to isoproterenol (97.5 +/- 0.8 vs. 71.5 +/- 2.3%, P < 0.01). In contrast, forskolin induced the same vasorelaxation in hypoxic pulmonary rings as controls (P = 0.09). Incubation of normoxic rings with Ado attenuated the vasorelaxation response induced by beta-AR stimulation (71.5 +/- 5.9%, P < 0.01), similar to the effect observed in hypoxia. Both nonspecific Ado receptor blockade (8-sulfophenyl-theophylline) and specific A1-receptor blockade (8-cyclopentyl-1,3-dimethylxanthine) restored the vasorelaxation response of hypoxic rings induced by beta-AR stimulation (93.3 +/- 2.3 and 92.2 +/- 2.8%, P < 0.01). The effects of hypoxia and Ado were reproduced by a specific A1 agonist (2-chloro-N6-cyclopentyladenosine), demonstrating impaired vasorelaxation induced by beta-AR stimulation in normoxia (70.6 +/- 4.5%, P < 0.01). From these data, we conclude that hypoxia antagonizes beta-AR-mediated pulmonary vasodilation via an Ado A1-receptor mechanism.
McIntyre
R C
RC
Department of Surgery, University of Colorado Health Sciences Center, Denver 80262.
Banerjee
A
A
Bensard
D D
DD
Brew
E C
EC
Hahn
A R
AR
Fullerton
D A
DA
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D010100:Oxygen / Q000008:administration & dosage*; D011651:Pulmonary Artery / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects
D011943:Receptors, Adrenergic, beta; D018047:Receptors, Purinergic P1; D005576:Colforsin; C058394:2-chloro-N(6)cyclopentyladenosine; D000241:Adenosine; D007545:Isoproterenol; D010100:Oxygen