EVIDENCE THAT PROSTAGLANDINS I-2, E(2), AND D-2 MAY ACTIVATE ATP-SENSITIVE POTASSIUM CHANNELS IN THE ISOLATED RAT-HEART

Objective: The aim was to study the contribution of ATP sensitive potassium channels (K-ATP channels) in the coronary vasodilatation produced by prostaglandins I-2, E(2), and D-2 in rats. Methods: Isolated Langendorff rat hearts, perfused under constant flow conditions, and rat aortic rings were used. Dose-response curves to PGE(2), PGD(2), and iloprost, a PGI(2) analogue, were performed before and during K-ATP channel blockade with glibenclamide. Arachidonic acid was used to increase the formation of endogenous PGI(2). Results: Infusions of PGE(2), PGD(2), and iloprost in isolated hearts induced marked vasodilatation, as reflected by the reduction in coronary perfusion pressure of 27(SEM 7), 30(6), and 43(6)%, for 0.1 mu M PGE(2), PGD(2), and iloprost, respectively. Infusion of glibenclamide (0.3 mu M) was accompanied by a 23(3)% increase in coronary perfusion pressure. The vasodilatation induced by levcromakalim (0.1 mu M) was completely inhibited in the presence of glibenclamide, whereas that of papaverine (30 mu M) was unaffected. Glibenclamide significantly reduced the vasodilatation induced by iloprost (at 3 to 100 nM), PGE(2) (30 and 100 nM), and PGD(2) (30 and 100 nM), at all concentrations studied. In contrast, glibenclamide (1 mu M) had no effect on iloprost induced relaxation of aortic rings. Arachidonic acid infusion (from 0.1 to 3 mu M) in isolated hearts induced a pronounced vasodilatation and a significant release of 6-keto-PGF(1 alpha) into the coronary effluent in a dose dependent fashion. Both responses to arachidonic acid were significantly reduced in the presence of the cyclo-oxygenase inhibitor diclofenac (1 mu M). In an additional experimental series, the vasodilatation induced by arachidonic acid infusions was found to be significantly reduced in the presence of glibenclamide. Conclusions: Glibenclamide is a potent inhibitor of the coronary dilator action of prostaglandins I-2, E(2), and D-2. This observation suggests that these prostaglandins may cause vasodilatation by opening K-ATP channels.