Modulation of contractions to ergonovine and methylergonovine by nitric oxide and thromboxane A(2) in the human coronary artery

This study explored the modulatory effects of nitric oxide and thromboxane A(2) on contractions to ergonovine and methylergonovine in human coronary a rteries, To elucidate the different role of nitric oxide synthase in the re sponse to the ergot alkaloids, the serotonin (5-HT) receptors involved in n itric oxide synthase in the response to the ergot alkaloids, the 5-HT recep tors involved in nitric oxide release and the contraction of the Vascular s mooth muscle were characterized with more selective 5-HT-receptor agonists and antagonists. Rings of human coronary arteries from explanted hearts wer e suspended in organ chambers for isometric tension recording. After testin g for contractile (potassium chloride, 60 mM) and endothelial function (sub stance P, 10(-8) M), respectively, they were exposed to ergot alkaloids or other agonists in the absence or presence of U 46619 (10(-9) M), or nitro-L -arginine (10(-4) M), or both. Ergonovine and methylergonovine were compara ble, weak vasoconstrictors in untreated preparations. Contractions to ergon ovine were augmented by U 46619, but not by nitro-L-arginine. Contractions to methylergonovine were augmented only by combining U 46619 and nitro-L-ar ginine. Serotonin and methylergonovine, but not ergonovine, elicited endoth elium-dependent, nitric oxide-mediated relaxations. Nonselective 5-HT1B/1D- receptor stimulation caused both contractions and relaxations; selective 5- HT,, stimulation caused relaxations only. In the human coronary artery, con tractions to ergonovine are not dependent on NO release but are synergistic ally augmented by thromboxane. Methylergonovine causes similar effects on t he vascular smooth muscle, but contractions are inhibited by the release of NO from the endothelium. The 5-HT receptor on the endothelium appears to b e different from the receptor on the vascular smooth muscle, which mediates the contractile response to the ergot alkaloids.