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.