Contribution of prostaglandins in hypoxia-induced vasodilatation in isolated rabbit hearts. Relation to adenosine and KATP channels

The mechanism of hypoxia-induced coronary vasodilatation was studied in isolated, saline-perfused rabbit hearts under constant flow conditions. Reduction in the perfusion solution PO₂ (from 520±6 to 103±9 mm Hg) under control conditions halved the coronary resistance and was accompanied by a significant release of the prostaglandin (PG) 6-keto-PGF₁ (from 1.8±0.3 to a maximum of 4.4±0.9 pmol min^–1 g^–1). The cyclooxygenase inhibitor, diclofenac (1 M), blocked the release of PGI₂ and reduced hypoxia-induced vasodilatation (from 47±8% to 25±5%, P<0.05). The relative contribution of adenosine, prostaglandins, and adenosine triphosphate (ATP)-sensitive K⁺ channel (K_ATP channel) activation in hypoxia-induced vasodilatation was assessed by comparing the differential change (control response minus response after treatment) in coronary perfusion pressure (CPP) during infusion of 8-phenyltheophylline (8-PT), diclofenac, and glibenclamide, respectively. The differential change in CPP with 8-PT and diclofenac given together (–48 ±7%) was found to be equivalent to the sum of their respective effects (–24±7 and –19±4%, respectively). Glibenclamide (0.3 M) reduced significantly hypoxia-induced vasodilatation (differential change in CPP of –27±6%) as well as the dilator response to 10 M adenosine and to the stable PGI₂-analogue, iloprost. Forskolin-induced coronary vasodilatation in arrested hearts was slightly, but significantly, reduced by glibenclamide. Our results suggest that both cyclooxygenase products and adenosine, acting independently and concomitantly, contribute to the dilator response of coronary resistance vessels to hypoxia, in part through the activation of K_ATP channels. K_ATP channel activation by prostacyclin and adenosine may involve both cyclic adenosine monophosphate-dependent and independent pathways.