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.
Zhang
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Y
Firestone Institute for Respiratory Health, Father Sean O'Sullivan Research Centre, and Department of Medicine, McMaster University, St. Joseph's Healthcare, Hamilton, Ontario, L8N 4A6, Canada.
Tazzeo
T
T
Hirota
S
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Janssen
L J
LJ
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004594:Electrophysiology; D004730:Endothelium, Vascular / Q000187:drug effects; D005071:Evoked Potentials / Q000187:drug effects; D028421:Isoprostanes / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D011460:Prostaglandins F / Q000494:pharmacology; D013552:Swine; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
D028421:Isoprostanes; D011460:Prostaglandins F; D014662:Vasoconstrictor Agents; C033761:prostaglandin F1beta; C037027:prostaglandin F2beta; D015232:Dinoprostone; D011188:Potassium; C011987:8-isoprostaglandin E2; C100006:prostaglandin F1