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CARDIOVASCULAR

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

Firestone Institute for Respiratory Health, Father Sean O'Sullivan Research Centre, and Department of Medicine, McMaster University, St. Joseph's Hospital, Hamilton, Ontario, Canada

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 also evoked relaxations (albeit with lower potency), whereas the other F-ring isoprostanes (8-iso-PGF₁, 8-iso-PGF₁, and 8-iso-PGF₂) 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.

Address correspondence to: Dr. L. J. Janssen, Department of Medicine, McMaster University St. Joseph's Healthcare, 50 Charlton Avenue, East Hamilton, Ontario, L8N 4A6, Canada. E-mail: janssenl{at}mcmaster.ca

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