CHARACTERIZATION OF 5-HT RECEPTORS ON HUMAN PULMONARY-ARTERY AND VEIN- FUNCTIONAL AND BINDING-STUDIES

1 This study aimed to investigate the 5-hydroxytryptamine (5-HT) recep tors mediating contraction of ring preparations isolated from human pu lmonary arteries and veins. In functional studies, the responses to 5- HT, sumatriptan, ergotamine, serotonin-O-carboxymethyl-glycyl-tyrosina mide (SCMGT), alpha-methyl 5-HT (alpha-Me) and 2-methyl 5-HT (2-Me) we re studied with WAY100635, GR127935, ritanserin, zacopride and SB20407 0 as antagonists. 2 All agonists produced concentration-dependent cont ractions of human pulmonary artery and vein preparations. The order of potency (-log EC50 values) was ergotamine (6.88) > 5-HT (6.41) greate r than or equal to SCMGT (6.20) = sumatriptan (6.19) greater than or e qual to alpha-Me (6.04) in the artery, and ergotamine (7.84) > 5-HT (6 .96) > sumatriptan (6.60) = alpha-Me (6.56) > SCMGT (6.09) in the vein . The potency of each agonist, except for SCMGT, was greater in vein t han in artery preparations. Contractile responses to 5-HT were similar in intact and endothelium-denuded preparations but responses to sumat riptan were enhanced in artery rings without endothelium. 3 GR127935 ( 1 nM to 0.5 mu M) produced an unsurmountable antagonism of the respons e to 5-HT, sumatriptan, ergotamine and SCMGT. Ritanserin (1 nM to 1 mu M) also reduced the maximum contractile responses to 5-HT, ergotamine and alpha-Me in artery and vein preparations without affecting those to sumatriptan and SCMGT. In endothelium-denuded preparations, surmoun table antagonism of sumatriptan by GR127935 (in the presence of ritans erin) and of alpha-Me by ritanserin (in the presence of GR127935) allo wed for the calculation of the apparent pK(B) values of GR127935 (9.17 +/- 0.11 in artery and 9.11 +/- 0.05 in vein) and ritanserin (8.82 +/ - 0.09 in artery and 8.98 +/- 0.12 in vein). 4 WAY100635 (1 nM to 1 mu M), zacopride (1 nM to 1 mu M), or SB204070 (1 nM) did not significan tly alter the concentration-response curves for 5-HT, sumatriptan, erg otamine, SCMGT or 2-Me in human pulmonary artery or vein thus indicati ng that 5-HT1A, 5-HT3 and 5-HT4 receptors are presumably not involved in the contractile response to these agonists. 5 Binding studies using selective radioligands for different 5-HT receptors could not detect the presence of 5-HT1A receptor binding in human pulmonary blood vesse ls whereas the 5-HT1B/1D radioligand [H-3]-5-CT significantly labelled a population of specific binding sites in both vessel types. The pres ence of 5-HT2A receptors could also be inferred from the level of bind ing of [H-3]-ketanserin to membranes obtained from human pulmonary ves sels, although significance could not be reached for arteries. 5-HT4 s pecific receptor binding was scarce in veins and absent in the case of arteries. 6 These findings indicate that the human pulmonary artery a nd vein have a mixed functional population of 5-HT1B/1D and 5-HT2A rec eptors mediating the contractile response to 5-HT which is consistent with results of the binding studies.