COMPARISON OF CONTRACTILE RESPONSES TO 5-HYDROXYTRYPTAMINE AND SUMATRIPTAN IN HUMAN ISOLATED CORONARY-ARTERY - SYNERGY WITH THE THROMBOXANE A(2)-RECEPTOR AGONIST, U46619

1 The interaction between the thromboxane A2 receptor agonist, U46619 and two 5-hydroxytryptamine (5-HT) receptor agonists, the non-selective, naturally occurring agonist, 5-HT and the selective 5-HT1-like agonist, sumatriptan were studied in human epicardial coronary arteries in vitro. 2 Coronary artery rings (2-4 mm in diameter) were prepared from epicardial arteries from explant hearts of patients undergoing heart transplant (cardiomyopathy, n = 13; ischaemic heart disease, n = 10) and unused donor hearts (n = 5). Each ring of artery was set at optimal resting conditions to record changes in isometric force. 3 The majority of artery rings developed phasic, rhythmic contractions either spontaneously or in response to all vasoconstrictor agonists tested. Both the spontaneous and agonist-induced phasic contractions were abolished by nifedipine (0.1 muM). 4 Concentration-contraction curves to 5-HT-receptor agonists and noradrenaline (NA), were first constructed in artery rings that did not develop phasic activity. 5-HT and ergometrine were the most potent agonists with EC50 values of 6.8 +/- 0.2 and 7.7 +/- 0.2 (-log M) respectively. Potencies (EC50's) to sumatriptan, methysergide and noradrenaline could not be determined due to their poor ability to contract the coronary artery. Maximum contractions (E(max); normalized as a percentage of the contraction to a maximum-depolarizing concentration of K+ in physiological salt solution (KPSS)) for 5-HT, ergometrine, sumatriptan, methysergide and noradrenaline were 40 +/- 10, 9 +/- 3, < 5, < 5 and < 5% respectively. 5 In arteries without phasic activity, U46619 (1 nm) caused an increase in force of 3.8 +/- 1% KPSS. With U46619 present, the E(max) values for 5-HT, ergometrine, sumatriptan and methysergide were all markedly increased. For 5-HT and sumatriptan, E(max) values were 92 +/- 4% and 49 +/- 14% KPSS respectively. The presence of U46619 did not significantly change the sensitivity (EC50) to 5-HT. 6 In a separate series of arteries, nifedipine (0.1 mum) was used to block phasic, contractile activity. The synergy observed between U46619 and 5-HT or sumatriptan still occurred although the E(max) values for each agonist were depressed but the EC50 values were again unaffected. 7 In conclusion, these in vitro studies indicate that the normally poor contractions to sumatriptan, in human coronary arteries are significantly enhanced when active force is induced with a thromboxane A2-receptor agonist, U46619. The enhanced response is not specific for either sumatriptan or 5-HT1-like receptors since contractions to 5-HT, ergometrine and methysergide were also potentiated by U46619.