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

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 A2-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% Fmax; 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 (pEC50) to 5-HT, sumatriptan and methysergide. 4. Ketanserin (1 microM) had no effect on contractions to sumatriptan and methysergide in endothelium-denuded coronary artery rings, but reduced the maximum contraction to 5-HT by approximately 90% to a value (5% Fmax) similar to that for sumatriptan and methylsergide. Under these conditions, U46619 precontraction had no effect on either pEC50 or maximum for 5-HT, sumatriptan or methysergide. 5. In rings of saphenous vein with endothelium and treated with ketanserin (1 microM), 5-HT and sumatriptan caused equal maximum responses of 65% Fmax which were approximately double that of methysergide (32% Fmax). 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 microM) 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.