Comparison of contractile responses to 5-hydroxytryptamine and sumatriptan in human isolated coronary artery: synergy with the thromboxane A2-receptor agonist, U46619

Abstract

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 microM). 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 (Emax; 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 Emax values for 5-HT, ergometrine, sumatriptan and methysergide were all markedly increased. For 5-HT and sumatriptan, E., values were 92+/- 4% and 49 +/- 14% KPSSrespectively. The presence of U46619 did not significantly change the sensitivity (EC50) to 5-HT.6. In a separate series of arteries, nifedipine (0.1 microM) was used to block phasic, contractile activity. The synergy observed between U46619 and 5-HT or sumatriptan still occurred although the Emax 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, inhuman 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-HT,-like receptors since contractions to 5-HT, ergometrine and methysergide were also potentiated by U46619.