ENDOTHELIAL 5-HT RECEPTORS MEDIATE RELAXATION OF PORCINE PULMONARY-ARTERIES IN RESPONSE TO ERGOTAMINE AND DIHYDROERGOTAMINE

1 The aim of the present study was to investigate whether antimigraine ergot compounds may act at endothelial 5-hydroxytryptamine (5-HT) rec eptors which trigger the release of endothelium-derived relaxing facto r (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 F-2 alpha (PGF(2 alpha), 3 mu M)-precantracted vessels. 2 The ergot derivatives ergota mine, dihydroergotamine (DHE) and dihydroergocristine, as well as 5-HT and (+/-)-alpha-methyl-5-HT, elicited a reversible endothelium-depend ent relaxation of PGF(2 alpha)-precontracted arterial ring segments. T he relaxation to both ergotamine and 5-HT was associated with an incre ase in cyclic GMP. After pretreatment of the vessels with N-G-nitro-L- arginine methyl ester (200 mu M), or removal of endothelium by mechani cal rubbing, the relaxant responses were abolished. 3 The mean pEC(50) values for relaxant responses followed the order: (+/-)-alpha-methyl- 5-HT (8.80)> 5-HT (8.75)> ergotamine (8.17)> DHE (7.70)> 5-carboxamido tryptamine (7.62)> dihydroergocristine (7.17). 4 The relaxant effects of both ergotamine and dihydroergotamine were resistant to block by in domethacin (3 mu M), prazosin (1 mu M) and ketanserin (1 mu M). Howeve r, the ergotamine-induced relaxation was highly susceptible to block b y pizotifen (pA(2)=8.23), norclozapine (pA(2)=8.20), methiothepin (-lo g IC50=7.26), rauwolscine (pA(2)=7.24) and mesulergine (pA(2)=6.64). E ach antagonist inhibited the relaxant responses to (+/-)-alpha-methyl- 5-HT in the same manner with similar potency as that determined agains t ergotamine. 5 Recently, mRNA transcripts for 5-HT1D beta and 5-HT2B receptors have been demonstrated in porcine pulmonary arteries. The ra nk order of potencies of agonists and antagonists in the present study suggests that the relaxant responses to 5-HT and ergot derivatives ar e mediated through activation of endothelial 5-HT receptors which are similar to the 5-HT2B receptor subtypes.