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.