title: Endothelin receptor blockade combined with phosphodiesterase-5 inhibition increases right ventricular mitochondrial capacity in pulmonary arterial hypertension.
abstract: 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 (ET(A))/type B (ET(B)) 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.
authors.affiliation: Department of Pulmonary Diseases, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands.
authors.forename: Koen T B
authors.initials: KT
authors.lastname: Mouchaers
authors.forename: Ingrid
authors.initials: I
authors.lastname: Schalij
authors.forename: Amanda M G
authors.initials: AM
authors.lastname: Versteilen
authors.forename: Awal M
authors.initials: AM
authors.lastname: Hadi
authors.forename: Geerten P
authors.initials: GP
authors.lastname: van Nieuw Amerongen
authors.forename: Victor W M
authors.initials: VW
authors.lastname: van Hinsbergh
authors.forename: Pieter E
authors.initials: PE
authors.lastname: Postmus
authors.forename: Willem J
authors.initials: WJ
authors.lastname: van der Laarse
authors.forename: Anton
authors.initials: A
authors.lastname: Vonk-Noordegraaf
mesh_terms: D000818:Animals; D001835:Body Weight / Q000502:physiology; D000077300:Bosentan; D002196:Capillaries / Q000502:physiology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004058:Diffusion; D065128:Endothelin Receptor Antagonists; D005355:Fibrosis; D006439:Hemodynamics / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000000981:diagnostic imaging / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects; D009211:Myoglobin / Q000378:metabolism; D009929:Organ Size / Q000502:physiology; D010101:Oxygen Consumption; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011651:Pulmonary Artery / Q000503:physiopathology*; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D014463:Ultrasonography
chemical_list: D065128:Endothelin Receptor Antagonists; D009211:Myoglobin; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D013450:Sulfones; D000068677:Sildenafil Citrate; D017869:Cyclic GMP-Dependent Protein Kinases; D000077300:Bosentan