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Am J Physiol Heart Circ Physiol 297: H200-H207, 2009. First published April 24, 2009; doi:10.1152/ajpheart.00893.2008
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Endothelin receptor blockade combined with phosphodiesterase-5 inhibition increases right ventricular mitochondrial capacity in pulmonary arterial hypertension

Koen T. B. Mouchaers,1 Ingrid Schalij,1 Amanda M. G. Versteilen,2 Awal M. Hadi,1 Geerten P. van Nieuw Amerongen,2 Victor W. M. van Hinsbergh,2 Pieter E. Postmus,1 Willem J. van der Laarse,2 and Anton Vonk-Noordegraaf1

Departments of 1Pulmonary Diseases and 2Physiology, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands

Submitted 14 August 2008 ; accepted in final form 13 April 2009

Pulmonary arterial hypertension (PAH) is often treated with endothelin (ET) receptor blockade or phosphodiesterase-5 (PDE5) inhibition. Little is known about the specific effects on right ventricular (RV) function and metabolism. We determined the effects of single and combination treatment with Bosentan [an ET type A (ETA)/type B (ETB) receptor blocker] and Sildenafil (a PDE5 inhibitor) on RV function and oxidative metabolism in monocrotaline (MCT)-induced PAH. Fourteen days after MCT injection, male Wistar rats were orally treated for 10 days with Bosentan, Sildenafil, or both. RV catheterization and echocardiography showed that MCT clearly induced PAH. This was evidenced by increased RV systolic pressure, reduced cardiac output, increased pulmonary vascular resistance (PVR), and reduced RV fractional shortening. Quantitative histochemistry showed marked RV hypertrophy and fibrosis. Monotreatment with Bosentan or Sildenafil had no effect on RV systolic pressure or cardiac function, but RV fibrosis was reduced and RV capillarization increased. Combination treatment did not reduce RV systolic pressure, but significantly lowered PVR, and normalized cardiac output, RV fractional shortening, and fibrosis. Only combination treatment increased the mitochondrial capacity of the RV, as reflected by increased succinate dehydrogenase and cytochrome c oxidase activities, associated with an activation of PKG, as indicated by increased VASP phosphorylation. Moreover, significant interactions were found between Bosentan and Sildenafil on PVR, cardiac output, RV contractility, PKG activity, and mitochondrial capacity. These data indicate that the combination of Bosentan and Sildenafil may beneficially contribute to RV adaptation in PAH, not only by reducing PVR but also by acting on the mitochondria in the heart.

Bosentan; Sildenafil; mitochondria; oxidative capacity; chronic heart failure


Address for reprint requests and other correspondence: A. Vonk-Noordegraaf, Dept. of Pulmonology, C5-P, Vrije Universiteit Univ. Medical Center, PO Box 7057, Amsterdam 1007 MB, The Netherlands (e-mail: a.vonk{at}vumc.nl)






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