ADENOSINE A(1)-RECEPTOR MECHANISMS ANTAGONIZE BETA-ADRENERGIC PULMONARY VASODILATION IN HYPOXIA

Hypoxic pulmonary vasoconstriction is refractory to beta-adrenergic re ceptor (beta-AR)-mediated pulmonary vasodilation. We hypothesized that hypoxic pulmonary arteries release adenosine (Ado) that antagonizes b eta-AR-mediated pulmonary vasodilation. Using isolated rat pulmonary a rtery rings, we investigated 1) the effect of hypoxia and exogenous Ad o on beta-AR-mediated pulmonary vasodilation, 2) the intracellular sit e of dysfunctional beta-AR-mediated pulmonary vasodilation in hypoxia, and 3) the Ado receptor subtype responsible for dysfunction of beta-A R-mediated pulmonary vasodilation. Hypoxia attenuated normal beta-AR-m ediated pulmonary vasodilation to isoproterenol (97.5 +/- 0.8 vs. 71.5 +/- 2.3%, P < 0.01). In contrast, forskolin induced the same vasorela xation in hypoxic pulmonary rings as controls (P = 0.09). Incubation o f normoxic rings with Ado attenuated the vasorelaxation response induc ed by beta-AR stimulation (71.5 +/- 5.9%, P < 0.01), similar to the ef fect observed in hypoxia. Both nonspecific Ado receptor blockade (8-su lfophenyl-theophylline) and specific A(1)-receptor blockade (8-cyclope ntyl-1,3-dimethylxanthine) restored the vasorelaxation response of hyp oxic 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 sp ecific A(1) agonist (2-chloro-N-6-cyclopentyladenosine), demonstrating impaired vasorelaxation induced by beta-AR stimulation in normoxia (7 0.6 +/- 4.5%, P < 0.01). From these data, we conclude that hypoxia ant agonizes beta-AR-mediated pulmonary vasodilation via an Ado A(1)-recep tor mechanism.