1 This study was undertaken to compare the effects of 8-epi prostaglandin F2l ) to those of prostaglandin F2a (PGF2a) 4 PGF2a constricted porcine 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. Concentration-dependent constriction to U46619 in porcine coronary arteries was competitively inhibited by SQ29548 (10-8 M to l0-7 M) and BM13505 (10-8 M to 10-6 M) with no decrease in maximal responses. 6 Concentration-dependent constriction to 8-epi PGF2a 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 gM) and 8-epi PGF2a (30 jgM) 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 PGF2a, pre-incubation of these vessels with 8-epi PGF2a caused a rightward shift of the U46619 response curve in a concentration-dependent manner.9 Pre-incubation of porcine coronary arteries with 8-epi PGF2a competitively inhibited responses to U46619 with a Schild slope of 0.99 and a pA2 of 6.13. 10 We conclude that 8-epi PGF2a is a vasoconstrictor within porcine and bovine coronary arteries, with a potency approximately twice that of PGF2a but 5-20 times lower than U46619. The data suggest that 8-epi PGF2a is acting as a partial agonist on the TP-receptor in the coronary vasculature.
1 8-epi prostaglandin (PG) F 2a , a vasoconstrictor isoprostane, is synthesized under conditions of oxidative stress. This study was undertaken to investigate the vasoconstrictor e ect of 8-epi PGF 2a in the coronary circulation before and after a period of oxidative stress.2 The e ects of the isoprostane 8-epi PGF 2a and the thromboxane mimetic U46619 were compared in the isolated rat heart perfused in the Langendor mode at a constant pressure of 80 mmHg. 3 In normal hearts U46619 caused a dose-related reduction in coronary¯ow (ED 50 4.7+2.2 nmol). In contrast, 8-epi PGF 2a had no e ect. 4 After reducing perfusion pressure to 20 mmHg for 30 min and reperfusing at 80 mmHg, the dose-response curve to U46619 was una ected. In contrast, 8-epi PGF 2a caused a dose-dependent drop in coronary¯ow (ED 50 52.6+12.7 nmol), producing a similar maximal reduction to U46619. 5 Similarly, after perfusion with xanthine and xanthine oxidase for either 15 or 30 min there was little change in the response to U46619 in comparison to control hearts. In contrast, 8-epi PGF 2a caused a reduction in coronary¯ow similar to that produced by U46619, the magnitude of the response being related to the length of xanthine/xanthine oxidase perfusion. 6 Responses to both U46619 and 8-epi PGF 2a after xanthine/xanthine oxidase perfusion were blocked by the selective thromboxane receptor antagonist SQ29548 10 77 M. 7 These results show that oxidative stress in the isolated perfused rat heart reveals a potent vasoconstrictor e ect of the isoprostane 8-epi PGF 2a by an action on the thromboxane receptor. 8 The data also suggest that, since 8-epi PGF 2a is a partial agonist at the thromboxane receptor, thromboxane receptor reserve is increased by oxidative stress.
8-epi prostaglandin F2alpha(8-epi PGF2alpha) contracted rat thoracic aorta rings in a concentration-dependent manner in the presence or absence of functional endothelium [median effective concentration (EC50) values, 455+/-52 and 268+/-34 nM, respectively; Student's t test; p=0.006]. U46619 was a more potent agonist with or without functional endothelium (EC50 values, 6.8+/-1.6 and 4.5+/-1.0 nM, respectively). SQ29548 [a thromboxane (TP)-receptor antagonist] inhibited contractions to both 8-epi PGF2alpha and U46619 in a competitive manner, with mean pA2 values of 8.3 and 7.9, respectively. 8-Epi PGF2alpha had a further contractile effect in vessels that had been contracted with noradrenaline and had been shown to possess a functional endothelium. Inhibition of thromboxane synthesis with OKY-046 or blockade of endothelin receptors with bosentan had no effect on responses to 8-epi PGF2alpha or U46619. Preincubation with 8-epi PGF2alpha or noradrenaline shifted the concentration-response curves to U46619 upward at low concentrations of U46619 with no significant change in EC50 values or maximal responses. Reduction of TP-receptor number in rat aorta with dithiothreitol caused a concentration-dependent inhibition of responses to both U46619 and 8-epi PGF2alpha, with no effect on maximal responses and or on the responses to U46619 after the preincubation with 8-epi PGF2alpha. These results indicate that 8-epi PGF2alpha is a potent vasoconstrictor in the rat aorta and are suggestive of an action of 8-epi PGF2alpha at the TP receptor.
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