01 March 2017

Parallels between endothelin-1 receptor antagonists in pulmonary arterial hypertension and foetal development

To prevent drug-induced developmental malformations, drugs with that feature adverse teratogenic effects are regulated via the Pregnancy Prevention Program (PPP). Remarkably, among the ten PPP-enlisted drugs are three endothelin-1 (ET-1) receptor antagonists (ERAs). ERAs are approved for the treatment of pulmonary arterial hypertension (PAH). While ERAs hamper pathological remodelling of the pulmonary vasculature and, as such, exert beneficial effects in PAH, they disturb foetal development of cardiopulmonary tissues. However, the effects of ERAs in PAH pathobiology and cardiopulmonary foetal development show also remarkable parallels in non-pregnant PAH patients. An important physiologic response of the right ventricle is to induce compensative hypertrophy as adaptation to the increased pulmonary vascular resistance. To facilitate this process, the right ventricle re-activates a foetal gene programme; specific developmental genes. Therefore, inhibition of the ET-1-mediated positive inotropic effects and myocardial foetal gene induction by ERAs may affect right ventricular adaptation to the increased pulmonary vascular resistance in both the foetus but also in the adult –and non-pregnant- PAH patient.

A part of the submitted abstract has been published in Reproductive Toxicology, PMID: 26111581

Key Contributors

Michiel Alexander de Raafa,b, Manon Beekhuijzenc, Christophe Guignabertd,e,Anton Vonk Noordegraafa, Harm Jan Bogaarda aPulmonary Hypertension Knowledge Center, Department of Pulmonology, VU University Medical Center/Institute for Cardiovascular Research,Amsterdam, The Netherlands bErasmus MC – Sophia children hospital, Dept. Neonatology & Pharmacology, Rotterdam, The Netherlands cCharles River, ‘s-Hertogenbosch, The Netherlands dINSERM UMR S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France eUniversity of Paris-Sud, School of Medicine, Kremlin-Bicêtre, France

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