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-PGF2β also evoked relaxations (albeit with lower potency), whereas the other F-ring isoprostanes (8-iso-PGF1α, 8-iso-PGF1β, and 8-iso-PGF2α) 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.
Footnotes
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These studies were supported by operating funds from the Canadian Institutes of Health Research and the Ontario Heart and Stroke Foundation, and salary support through a Scientist Award from the Canadian Institutes of Health Research.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.103.049353.
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ABBREVIATIONS: TP, thromboxane A2-selective prostanoid receptor; 8-iso-PG, 8-iso-prostaglandin; EDHF, endothelium-derived hyperpolarizing factor; EC50, half-maximally effective concentration; U46619, 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F2α; l-NNA, N-ω-nitro-l-arginine; ICI 192605, 4(Z)-6-[(2,4,5-cis)2-(2-chlorophenyl)-4-(2-hydroxyphenyl)1,3-dioxan-5-yl] hexenoic acid; EDCF, endothelium-derived contracting factor.
- Received January 23, 2003.
- Accepted February 27, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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