Vasodilatory and Electrophysiological Actions of 8-iso-Prostaglandin E2 in Porcine Coronary Artery

We examined the effects of several E-ring and F-ring isoprostanes on mechanical and electrophysiological activity in porcine coronary artery. Several isoprostanes evoked concentration-dependent contractions, with 8-iso-PGE2 being the most potent (-log EC50 of 6.9 +/- 0.1); this excitatory effect has been described in detail elsewhere and was not examined further here. 8-iso-PGE2 evoked dose-dependent relaxations in tissues preconstricted with the thromboxane A2-agonist U46619 (10(-6) M), with a negative log EC50 of 6.0 +/- 0.1 (n = 5). 8-iso-PGE1 and 8-iso-PGF2 beta also evoked relaxations (albeit with lower potency), whereas the other F-ring isoprostanes (8-iso-PGF1 alpha, 8-iso-PGF1 beta, and 8-iso-PGF2 alpha) were largely ineffective in this respect. The potency and efficacy of 8-iso-PGE2 in reversing tone were not dependent upon the concentration of U46619 used to preconstrict the tissues (10(-8) to 10(-6) M), indicating a lack of U46619-induced functional antagonism of these responses. 8-iso-PGE2 was able to completely relax tissues that had been denuded of endothelium (as indicated by loss of responsiveness to bradykinin). 8-iso-PGE2-evoked relaxations were markedly reduced by elevating the K+ equilibrium potential using 30 mM KCl and abolished by 60 mM KCl; they were also sensitive to charybdotoxin (10(-7) M) but not to 4-aminopyridine (1 mM). 8-iso-PGE2 also caused membrane hyperpolarization and augmentation of outward K+ current. We conclude that 8-iso-prostaglandin E2 acts directly on the smooth muscle to increase K+ conductance, leading to membrane hyperpolarization and vasodilation.