Effects of U46619 on contractions to 5-HT, sumatriptan and meethysergide in canine coronary artery and saphenous vein in vitro

摘要

1 The aim of this study was to investigate the mechanism of enhanced reactivity to 5-hydroxytryptamine (5-HT) and sumatriptan previously observed in human isolated coronary arteries when active force was raised with the thromboxane A_2-mimetic, U46619. 2 Ring segments of dog isolated coronary artery and saphenous vein were suspended in organ baths and cumulative concentration-contraction curves to 5-HT, sumatriptan and methysergide were constructed in the absence and presence of low concentrations of U46619. 3 In both endothelium-intact and endothelium-denuded rings of coronary artery, precontraction with U46619 to low (< 10% F_(max); the contraction to a maximum depolarizing 125 mM KCl Krebs solution; KPSS) levels of active force had no effect on either the maximum contraction or sensitivity (pEC_(50)) to 5-HT, sumatriptan and methysergide. 4 Ketanserin (1 μM) had no effect on contractions to sumatriptan and methysergide in endothelium-denuded coronary artery rings, but reduced the maximum contraction to 5-HT by ≈ 90% to a value (5% F(max)) similar to that for sumatriptan and methysergide. Under these conditions, U46619 precontraction had no effect on either pEC_(50) or maximum for 5-HT, sumatriptan or methysergide. 5 In rings of saphenous vein with endothelium and treated with ketanserin (1 μM), 5-HT and sumatriptan caused equal maximum responses of 65% F_(max) which were approximately double that of methysergide (32% F_(max)). The maximum responses and sensitivity to 5-HT, sumatriptan, methysergide and noradrenaline were unaffected by precontraction with U46619. 6 Pretreatment of the saphenous vein with sodium nitroprusside (SNP; 10 μM) caused a small sustained relaxation and significantly depressed the maximal contraction to 5-HT without affecting sensitivity and abolished the contraction curve to sumatriptan and methysergide. When the relaxation response to SNP was reversed with U46619 (1-4 nM), the contraction curves to 5-HT, sumatriptan and methysergide were similar to those obtained prior to relaxation with SNP. In contrast, the same treatment with SNP had little affect on the contraction curve to noradrenaline. 7 In conclusion, the pattern of U46619-enhanced reactivity of 5-HT, sumatriptan and methysergide in SNP-treated dog saphenous vein, highlights the importance of functional antagonism when assessing reactivity to contractile agonists in isolated blood vessels.