Abstract

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-PGF_2β also evoked relaxations (albeit with lower potency), whereas the other F-ring isoprostanes (8-iso-PGF_1α, 8-iso-PGF_1β, and 8-iso-PGF_2α) 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.