Further evidence that 5-HT-induced relaxation of pig pulmonary artery is mediated by endothelial 5-HT2B receptors

1 The endothelial 5-HT receptor mediating relaxation of pig pulmonary arter y has been characterized using the selective 5-HT2B receptor agonist BW 723 C86 and a variety of structurally diverse 5-HT receptor antagonists. 2 If arterial rings with intact endothelium were precontracted with prostag landin F-2 alpha (3 mu M). BW 723C86 caused concentration-dependent relaxat ion with a pEC(50) = 8.21 +/- 0.03 and E-max = 89 +/- 4% relative to 5-HT. The relaxant responses to BW 723C86 were inhibited by the 5-HT2B receptor a ntagonist SB 204741, the 5-HT2B/2C receptor antagonist SB 206553 and the an timigraine drug pizotifen, yielding pA(2) values of 6.68, 7.20 and 8.32, re spectively. The pA(2) values against BW 723C86 were similar to those determ ined against 5-HT. 3 The relaxant effect of 5-HT was antagonized by a variety of 22 compounds of diverse chemical structures. Based on the calculated mean pA(2) values t he order of the most potent antagonists was ritanserin (9.38) > methysergid e (8.86) > pizotifen (8.47) greater than or equal to methiothepin (8.32) > LY 53857 (7.84) greater than or equal to amoxapine (7.80) greater than or e qual to loxapine (7.73) greater than or equal to metergoline (7.64) greater than or equal to mianserin (7.51) greater than or equal to rauwolscine (7. 39). Compounds with weak blocking potency were yohimbine (6.37), spiperone (5.88) and ketanserin (5.85). Correlation analysis between the affinities o f the antagonists in pig pulmonary artery and those from radioligand bindin g studies at human and rat 5-HT2B, receptors showed a highly significant co rrelation (r = 0.95 and 0.84, P < 0.002 and < 0.005). Correlation with 5-HT 2C receptors was much lower (r = 0.57, P = 0.035), and no correlations were obtained with 5-ht(6) and 5-HT7 receptors. 4 It is concluded that the 5-HT receptor mediating endothelium-dependent re laxation of pig pulmonary artery is of the 5-HT2B subtype.