The endothelial 5-HT receptor mediating relaxation of pig pulmonary artery has been characterized using the selective 5-HT2B receptor agonist BW 723C86 and a variety of structurally diverse 5-HT receptor antagonists.
If arterial rings with intact endothelium were precontracted with prostaglandin F2α (3 μM), BW 723C86 caused concentration-dependent relaxation with a pEC50=8.21±0.03 and Emax=89±4% relative to 5-HT. The relaxant responses to BW 723C86 were inhibited by the 5-HT2B receptor antagonist SB 204741, the 5-HT2B/2C receptor antagonist SB 206553 and the antimigraine drug pizotifen, yielding pA2 values of 6.68, 7.20 and 8.32, respectively. The pA2 values against BW 723C86 were similar to those determined against 5-HT.
The relaxant effect of 5-HT was antagonized by a variety of 22 compounds of diverse chemical structures. Based on the calculated mean pA2 values the order of the most potent antagonists was ritanserin (9.38) > methysergide (8.86) > pizotifen (8.47) methiothepin (8.32) > LY 53857 (7.84) amoxapine (7.80) loxapine (7.73) metergoline (7.64) mianserin (7.51) rauwolscine (7.39). Compounds with weak blocking potency were yohimbine (6.37), spiperone (5.88) and ketanserin (5.85). Correlation analysis between the affinities of the antagonists in pig pulmonary artery and those from radioligand binding studies at human and rat 5-HT2B receptors showed a highly significant correlation (r=0.95 and 0.84, P<0.002 and <0.005). Correlation with 5-HT2C receptors was much lower (r=0.57, P=0.035), and no correlations were obtained with 5-ht6 and 5-HT7 receptors.
It is concluded that the 5-HT receptor mediating endothelium-dependent relaxation of pig pulmonary artery is of the 5-HT2B subtype.
British Journal of Pharmacology (2000) 130, 692–698; doi:10.1038/sj.bjp.0703341