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

• Published in: The Journal of pharmacology and experimental therapeutics 2003-06, Vol.305 (3), p.1054-1060
• Main Authors: Zhang, Y, Tazzeo, T, Hirota, S, Janssen, L J
• Format: Article
• Language: English
• Subjects: Animals; Aorta - drug effects; Aorta - physiology; Coronary Vessels - drug effects; Coronary Vessels - physiology; Dinoprostone - analogs & derivatives; Dinoprostone - pharmacology; Electrophysiology; Endothelium, Vascular - drug effects; Evoked Potentials - drug effects; Isoprostanes - pharmacology; Potassium - metabolism; Prostaglandins F - pharmacology; Swine; Vasoconstrictor Agents - pharmacology; Vasodilation - drug effects
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.049353

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-PGE 2 being the most potent (-log EC 50 of 6.9 ± 0.1); this excitatory effect has been described in detail elsewhere and was not examined further here. 8-iso-PGE 2 evoked dose-dependent relaxations in tissues preconstricted with the thromboxane A 2 -agonist U46619 (10 - 6 M), with a negative log EC 50 of 6.0 ± 0.1 ( n = 5). 8-iso-PGE 1 and 8-iso-PGF 2 β also evoked relaxations (albeit with lower potency), whereas the other F-ring isoprostanes (8-iso-PGF 1 α , 8-iso-PGF 1 β , and 8-iso-PGF 2 α ) were largely ineffective in this respect. The potency and efficacy of 8-iso-PGE 2 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-PGE 2 was able to completely relax tissues that had been denuded of endothelium (as indicated by loss of responsiveness to bradykinin). 8-iso-PGE 2 -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-PGE 2 also caused membrane hyperpolarization and augmentation of outward K + current. We conclude that 8-iso-prostaglandin E 2 acts directly on the smooth muscle to increase K + conductance, leading to membrane hyperpolarization and vasodilation.