Reduction of the serotonin 5-HT 1B and 5-HT 2A receptor-mediated contraction of human pulmonary artery by the combined 5-HT 1B receptor antagonist and serotonin transporter inhibitor LY393558.

Background: LY393558 is a combined antagonist of serotonin (5-HT) 5-HT _1B receptors and inhibitor of serotonin transporter (SERT). LY393558 reduces 5-HT-induced vasoconstriction and remodelling of rat and/or mouse pulmonary arteries. The aim of our study was to examine the effect of LY393558 on the 5-HT-stimulated vasoconstriction of human pulmonary arteries (hPAs) and to determine the underlying mechanism(s).
Methods: Vascular effects of 5-HT receptor agonists, antagonists and a SERT inhibitor were examined in organ bath studies on intralobar hPAs obtained from patients during resection of lung carcinoma.
Results: Serotonin and agonists of the 5-HT _1B receptor (5-carboxamidotryptamine, 5-CT) and 5-HT _2A receptor (α-methyl-5-HT) contracted endothelium-intact hPAs in a concentration-dependent fashion. The 5-HT _1B antagonists SB224289 and GR55562 reduced responses induced by 5-HT and 5-CT and the 5-HT _2A antagonist ketanserin inhibited the effects of 5-HT and α-methyl-5-HT. Administration of the SERT inhibitor citalopram (at a concentration that failed to modify the 5-HT-induced vasoconstriction) in combination with SB224289 or GR55562 was more effective in inhibiting the response to 5-HT than the 5-HT _1B antagonists alone. LY393558 showed the greatest antagonistic effect against the vasoconstriction elicited by 5-HT, 5-CT and α-methyl-5-HT.
Conclusions: LY393558 reduces the 5-HT-induced contraction antagonizing 5-HT _1B and 5-HT _2A receptors probably due to synergic interaction between SERT inhibition and 5-HT _1B receptor antagonism. Thus, it might represent a valuable future option in the pulmonary arterial hypertension therapy.