Reduction of the serotonin 5-HT1B and 5-HT2A receptor-mediated contraction of human pulmonary artery by the combined 5-HT1B receptor antagonist and serotonin transporter inhibitor LY393558

Marta Baranowska-Kuczko, Hanna Kozłowska, Eberhard Schlicker, Manfred Göthert, Margaret R. MacLean, Mirosław Kozłowski, Monika Kloza, Olga Sadowska, Barbara Malinowska

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Abstract

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.

Original languageEnglish
Pages (from-to)756-762
Number of pages7
JournalPharmacological Reports
Volume72
Issue number3
Early online date24 Apr 2020
DOIs
Publication statusPublished - 30 Jun 2020

Keywords

  • serotonin
  • LY393558
  • serotonin transporter

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