Endothelin receptor blockade combined with phosphodiesterase-5 inhibition increases right ventricular mitochondrial capacity in pulmonary arterial hypertension.
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.
Mouchaers
Koen T B
KT
Department of Pulmonary Diseases, Institute for Cardiovascular Research, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands.
Schalij
Ingrid
I
Versteilen
Amanda M G
AM
Hadi
Awal M
AM
van Nieuw Amerongen
Geerten P
GP
van Hinsbergh
Victor W M
VW
Postmus
Pieter E
PE
van der Laarse
Willem J
WJ
Vonk-Noordegraaf
Anton
A
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
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