Coronary artery constriction by the isoprostane 8-epi prostaglandin F2 alpha.
1. This study was undertaken to compare the effects of 8-epi prostaglandin F2 alpha (8-epi PGF2 alpha) to those of prostaglandin F2 alpha (PGF2 alpha) and U46619, a thromboxane mimetic, on ovine, bovine and porcine coronary arteries. 2. 8-epi PGF2 alpha constricted porcine and bovine coronary arteries in a concentration-dependent manner with EC50 values of 689.0 +/- 229.3 and 1361.0 +/- 272.3 nM, respectively, but had no effect on ovine coronary arteries. 3. U46619 was a potent vasoconstrictor of porcine, ovine and bovine coronary arteries with EC50 values of 33.0 +/- 23.5, 373.3 +/- 69.7 and 254.1 +/- 134.3 nM, respectively. Emax values were significantly greater than those obtained with 8-epi PGF2 alpha. 4. PGF2 alpha constricted procine and bovine coronary arteries in a concentration-dependent manner with EC50 values of 1631.0 +/- 207.6 and 3644.0 +/- 344.8 nM, respectively, but had no effect on ovine coronary arteries. 5. Concentration-dependent constriction to U46619 in porcine coronary arteries was competitively inhibited by SQ29548 (10(-8) M to 10(-7) M) and BM13505 (10(-8) M to 10(-6) M) with no decrease in maximal responses. 6. Concentration-dependent constriction to 8-epi PGF2 alpha in porcine coronary arteries was inhibited in a concentration-dependent manner by SQ29548 (10(-8) M to 10(-7) M) and BM13505 (10(-8) M to 10(-6) M). However, the inhibition was associated with a decrease in maximal response. 7. Maximal responses of porcine coronary artery to U46619 (1 microM) and 8-epi PGF2 alpha (30 microM) were inhibited in a concentration-dependent manner by SQ29548 with IC50 values 99 +/- 12.36 nM and 46.5 +/- 18.67 nM, respectively. 8. Although ovine coronary arteries did not constrict to 8-epi PGF2 alpha pre-incubation of these vessels with 8-epi PGF2 alpha caused a rightward shift of the U46619 response curve in a concentration-dependent manner. 9. Pre-incubation of porcine coronary arteries with 8-epi PGF2 alpha competitively inhibited responses to U46619 with a Schild slope of 0.99 and a pA2 of 6.13. 10. We conclude that 8-epi PGF2 alpha is a vasoconstrictor within porcine and bovine coronary arteries, with a potency approximately twice that of PGF2 alpha but 5-20 times lower than U46619. The data suggest that 8-epi PGF2 alpha is acting as a partial agonist on the TP-receptor in the coronary vasculature.
Kromer
B M
BM
Department of Biochemistry, Imperial College of Science, Technology and Medicine, London.
Tippins
J R
JR
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D002417:Cattle; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D010648:Phenylacetates / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D012756:Sheep; D013449:Sulfonamides / Q000494:pharmacology; D013552:Swine; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D010648:Phenylacetates; D011450:Prostaglandin Endoperoxides, Synthetic; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; C075750:8-epi-prostaglandin F2alpha; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015237:Dinoprost; C051762:daltroban