1 We investigated the potent 5-hydroxytryptamine (5-HT)-mediated vasorelaxation of the sheep pulmonary vein. Here we present evidence that this response is due to activation of 5-HT4 receptors.2 5-HT (1-1000 nM) caused concentration-dependent, maintained relaxations (pEC50 = 8.4 ± 0.1) of isolated rings of sheep pulmonary vein pre-contracted with endothelin-l (3 nM). 3 The relaxation response to 5-HT was unaffected by either removal of the endothelium or by inhibition of NO-synthase by N0-nitro-L-arginine (1001M). 4 Ketanserin, methiothepin, methysergide and MDL 72222 at concentrations that selectively block 5-HT2, 5-HTI-like and 5-HT3 receptors respectively, had no effect on the concentration-relaxation curve to 5-HT. (estimated pKB values of 6.4 and 6.9 respectively). Relaxation curves to both 5-HT and BIMU 8 were unaffected by cocaine (6 jM). 8 In conclusion, these results indicate that the sheep pulmonary vein possesses 5-HT4 receptors that mediate potent endothelium-independent relaxation. 5-HT,-like relaxant receptors are also present in this tissue but 5-HT has a lower affinity at these receptors. This preparation may thus provide a robust and sensitive bioassay for future development of selective 5-HT4 receptor agonists and antagonists.
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