Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats

R. Dumitrascu, C. Kulcke, M. Königshoff, F. Kouri, X. Yang, N. Morrell, H. A. Ghofrani, N. Weissmann, R. Reiter, W. Seeger, F. Grimminger, O. Eickelberg, R. T. Schermuly, S. S. Pullamsetti

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterised by vasoconstriction and remodelling of the pulmonary vasculature. The serotonin (5- hydroxytryptamine (5-HT)) pathway has been shown to play a major role in the pathogenesis of PAH, but pharmacological modulation of this pathway for treatment of PAH is, to date, at a preclinical level. Terguride is a 5-HT receptor (5-HTR) antagonist that is well tolerated and clinically approved for ovulation disorders. Immunohistochemistry against 5-HTR2A/B on human lungs revealed their localisation to the vascular smooth muscle layer and quantitative RT-PCR showed 5-HTR2B upregulation in pulmonary artery smooth muscle cells (PASMC) isolated from PAH patients. Proliferation and migration of cultured primary human PASMC were dose-dependently blocked by terguride. Therapeutic 5-HT signalling inhibition was 1) demonstrated in isolated, ventilated and perfused rat lungs and 2) by chronic terguride treatment of rats with monocrotaline (MCT)-induced pulmonary hypertension in a preventive or curative approach. Terguride inhibited proliferation of PASMCs and abolished 5-HT-induced pulmonary vasoconstriction. Chronic terguride treatment prevented dose-dependently the development and progression of MCT-induced PAH in rats. Thus, terguride represents a valuable novel therapeutic approach in PAH. Copyright

Original languageEnglish (US)
Pages (from-to)1104-1118
Number of pages15
JournalEuropean Respiratory Journal
Volume37
Issue number5
DOIs
StatePublished - May 1 2011

Keywords

  • Collagen
  • Experimental therapeutics
  • Inflammation
  • Pulmonary hypertension
  • Smooth muscle cells
  • Vascular remodelling

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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    Dumitrascu, R., Kulcke, C., Königshoff, M., Kouri, F., Yang, X., Morrell, N., Ghofrani, H. A., Weissmann, N., Reiter, R., Seeger, W., Grimminger, F., Eickelberg, O., Schermuly, R. T., & Pullamsetti, S. S. (2011). Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats. European Respiratory Journal, 37(5), 1104-1118. https://doi.org/10.1183/09031936.00126010