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 r eactivity to 5-hydroxytryptamine (5-HT) and sumatriptan previously obs erved in human isolated coronary arteries when active force was raised with the thromboxane A(2)-mimetic, U46619. 2 Ring segments of dog iso lated 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 c oncentrations 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 max imum contraction or sensitivity (PEC(50)) to 5-HT, sumatriptan and met hysergide. 4 Ketanserin (1 mu M) had no effect on contractions to suma triptan and methysergide in endothelium-denuded coronary artery rings, but reduced the maximum contraction to 5-HT by approximate to 90% to a value (5% F-max) similar to that for sumatriptan and methysergide. U nder these conditions, U46619 precontraction had no effect on either P EC(50) or maximum for 5-HT, sumatriptan or methysergide. 5 In rings of saphenous vein with endothelium and treated with ketanserin (1 mu M), 5-HT and sumatriptan caused equal maximum responses of 65% F-max whic h were approximately double that of methysergide (32% F-max). The maxi mum responses and sensitivity to 5-HT, sumatriptan, methysergide and n oradrenaline were unaffected by precontraction with U46619. 6 Pretreat ment of the saphenous vein with sodium nitroprusside (SNP; 10 mu M) ca used a small sustained relaxation and significantly depressed the maxi mal contraction to 5-HT without affecting sensitivity and abolished th e contraction curve to sumatriptan and methysergide. When the relaxati on response to SNP was reversed with U46619 (1-4 nM), the contraction curves to 5-HT, sumatriptan and methysergide were similar to those obt ained prior to relaxation with SNP. In contrast, the same treatment wi th SNP had little affect on the contraction curve to noradrenaline. 7 In conclusion, the pattern of U46619-enhanced reactivity of 5-HT, suma triptan and methysergide in SNP-treated dog saphenous vein, highlights the importance of functional antagonism when assessing reactivity to contractile agonists in isolated blood vessels.