title: Endothelial 5-HT receptors mediate relaxation of porcine pulmonary arteries in response to ergotamine and dihydroergotamine.
abstract: 1. The aim of the present study was to investigate whether antimigraine ergot compounds may act at endothelial 5-hydroxytryptamine (5-HT) receptors which trigger the release of endothelium-derived relaxing factor (EDRF). Changes in tone of porcine isolated pulmonary arteries were measured isometrically. The integrity of the endothelium was assessed by the bradykinin-induced relaxation of prostaglandin F2 alpha (PGF2 alpha, 3 microM)-precontracted vessels. 2. The ergot derivatives ergotamine, dihydroergotamine (DHE) and dihydroergocristine, as well as 5-HT and (+/-)-alpha-methyl-5-HT, elicited a reversible endothelium-dependent relaxation of PGF2 alpha-precontracted arterial ring segments. The relaxation to both ergotamine and 5-HT was associated with an increase in cyclic GMP. After pretreatment of the vessels with NG-nitro-L-arginine methyl ester (200 microM), or removal of endothelium by mechanical rubbing, the relaxant responses were abolished. 3. The mean pEC50 values for relaxant responses followed the order: (+/-)-alpha-methyl-5-HT (8.80) > 5-HT (8.75) > ergotamine (8.17) > DHE (7.70) > 5-carboxamidotryptamine (7.62) > dihydroergocristine (7.17). 4. The relaxant effects of both ergotamine and dihydroergotamine were resistant to block by indomethacin (3 microM), prazosin (1 microM) and ketanserin (1 microM). However, the ergotamine-induced relaxation was highly susceptible to block by pizotifen (pA2 = 8.23), norclozapine (pA2 = 8.20), methiothepin (-log IC50 = 7.26), rauwolscine (pA2 = 7.24) and mesulergine (pA2 = 6.64). Each antagonist inhibited the relaxant responses to (+/-)-alpha-methyl-5-HT in the same manner with similar potency as that determined against ergotamine. 5. Recently, mRNA transcripts for 5-HT1D beta and 5-HT2B receptors have been demonstrated in porcine pulmonary arteries. The rank order of potencies of agonists and antagonists in the present study suggests that the relaxant responses to 5-HT and ergot derivatives are mediated through activation of endothelial 5-HT receptors which are similar to the 5-HT2B receptor subtypes.
authors.affiliation: University Jena, Medical Faculty, Center for Vascular Biology and Medicine, Erfurt, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Glusa
authors.forename: A
authors.initials: A
authors.lastname: Roos
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D004087:Dihydroergotamine / Q000494:pharmacology*; D015237:Dinoprost / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure*; D004878:Ergotamine / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D009126:Muscle Relaxation / Q000187:drug effects* / Q000502:physiology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure*; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013552:Swine; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D014662:Vasoconstrictor Agents; D015016:Yohimbine; D012701:Serotonin; D004087:Dihydroergotamine; D015237:Dinoprost; D004878:Ergotamine