Characterization of 5-HT receptors on human pulmonary artery and vein: functional and binding studies

Abstract

1. This study aimed to investigate the 5-hydroxytryptamine (5-HT) receptors mediating contraction of ring preparations isolated from human pulmonary arteries and veins. In functional studies, the responses to 5-HT, sumatriptan, ergotamine, serotonin-O-carboxymethyl-glycyl-tyrosinamide (SCMGT), α-methyl 5-HT (α-Me) and 2-methyl 5-HT (2-Me) were studied with WAY100635, GR127935, ritanserin, zacopride and SB204070 as antagonists.

2. All agonists produced concentration-dependent contractions of human pulmonary artery and vein preparations. The order of potency (−log EC₅₀ values) was ergotamine (6.88)>5-HT (6.41)⩾SCMGT (6.20)=sumatriptan (6.19) ⩾α-Me (6.04) in the artery, and ergotamine (7.84)>5-HT (6.96)>sumatriptan (6.60)=α-Me (6.56)>SCMGT (6.09) in the vein. The potency of each agonist, except for SCMGT, was greater in vein than in artery preparations. Contractile responses to 5-HT were similar in intact and endothelium-denuded preparations but responses to sumatriptan were enhanced in artery rings without endothelium.

3. GR127935 (1 nM to 0.5 μM) produced an unsurmountable antagonism of the response to 5-HT, sumatriptan, ergotamine and SCMGT. Ritanserin (1 nM to 1 μM) also reduced the maximum contractile responses to 5-HT, ergotamine and α-Me in artery and vein preparations without affecting those to sumatriptan and SCMGT. In endothelium-denuded preparations, surmountable antagonism of sumatriptan by GR127935 (in the presence of ritanserin) and of α-Me by ritanserin (in the presence of GR127935) allowed 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 μM), zacopride (1 nM to 1 μM), or SB204070 (1 nM) did not significantly alter the concentration-response curves for 5-HT, sumatriptan, ergotamine, SCMGT or 2-Me in human pulmonary artery or vein thus indicating that 5-HT_1A, 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-HT_1A receptor binding in human pulmonary blood vessels whereas the 5-HT_1B/1D radioligand [³H]-5-CT significantly labelled a population of specific binding sites in both vessel types. The presence of 5-HT_2A receptors could also be inferred from the level of binding of [³H]-ketanserin to membranes obtained from human pulmonary vessels, although significance could not be reached for arteries. 5-HT₄ specific receptor binding was scarce in veins and absent in the case of arteries.

6. These findings indicate that the human pulmonary artery and vein have a mixed functional population of 5-HT_1B/1D and 5-HT_2A receptors mediating the contractile response to 5-HT which is consistent with results of the binding studies.

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