Contractile responses to sumatriptan and ergotamine in the rabbit saphenous vein:: effect of selective 5-HT1F receptor agonists and PGF2α

1 Contractile responses to ergotamine. sumatriptan and the novel 5-HT1F receptor agonists LY334370 and LY334864 were examined using the rabbit saphenous vein. 2 Ergotamine (pEC(50) = 8.7 +/- 0.06) was 30 fold more potent than 5-hydroxytryptamine (5-HT) (pEC(50) = 7.2 +/- 0.13) and 300 fold more potent than sumatriptan (pEC(50) = 6.0 +/- 0.08) in contracting the rabbit saphenous vein in vitro. The selective 5-HT1F receptor agonists, LY334370 or LY344864 (up to 10(-4) M). did not contract the rabbit saphenous vein. 3 The contractile response to ergotamine in this tissue resulted from activation of both alpha, and 5-HT1B1D receptors based on the observation that prazosin (10(-6) M), an alpha-adrenoceptor antagonist, and GR127935 (10(-8) M) a 5-HT1B1D receptor antagonist, dextrally shifted the contractile response to ergotamine. In contrast, prazosin (10(-6) M) did not alter contraction to sumatriptan whereas GR127935 (10(-8) M) was a potent antagonist (-log K-B = 10.0) suggesting that sumatriptan-induced contraction of the rabbit saphenous vein was mediated only by activation of receptors similar or identical to 5-HT1B1D receptors. 4 PGF(2 alpha) (3 x 10(-7) M) produced a modest increase (approximately 5.0-10.0% maximum PGF(2 alpha) contraction! In saphenous vein force. Precontraction with PGF(2 alpha) (3 x 10(-7) M) dramatically augmented the potency and maximal contractile response to sumatriptan (pEC(50) = 7.1) and modestly enhanced the contractile potency of ergotamine (pEC(50) = 9.0) in the rabbit saphenous vein. However. PGF(2 alpha) (3 x 10(-7) M) only unmasked a contraction to the 5-HT1F receptor agonists when concentrations exceeded 10(-5) M. concentrations considerably higher than their 5-HT1F receptor affinities. 5 LY334370(10(-6) M) pretreatment did not alter contraction to either sumatriptan or ergotamine aod a higher concentration (10(-5) M) of LY334370 or LY344864 inhibited contraction to sumatriptan. 6 Thus, activation of 5-HT1F receptors will not induce vascular contraction (either alone or following modest tone with PGF(2 alpha)) or augment contraction to other contractile agonists in the rabbit saphenous vein.