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Endothelin receptor blockade combined with phosphodiesterase-5 inhibition increases right ventricular mitochondrial capacity in pulmonary arterial hypertension.
- Source :
-
American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2009 Jul; Vol. 297 (1), pp. H200-7. Date of Electronic Publication: 2009 Apr 24. - Publication Year :
- 2009
-
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.
- Subjects :
- Animals
Body Weight physiology
Bosentan
Capillaries physiology
Cyclic GMP-Dependent Protein Kinases metabolism
Diffusion
Fibrosis
Hemodynamics physiology
Hypertension, Pulmonary diagnostic imaging
In Vitro Techniques
Male
Mitochondria, Heart enzymology
Myocardial Contraction drug effects
Myocardium pathology
Myocytes, Cardiac drug effects
Myoglobin metabolism
Organ Size physiology
Oxygen Consumption
Piperazines pharmacology
Purines pharmacology
Rats
Rats, Wistar
Sildenafil Citrate
Sulfonamides pharmacology
Sulfones pharmacology
Ultrasonography
Endothelin Receptor Antagonists
Hypertension, Pulmonary physiopathology
Mitochondria, Heart drug effects
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors pharmacology
Pulmonary Artery physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1539
- Volume :
- 297
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Heart and circulatory physiology
- Publication Type :
- Academic Journal
- Accession number :
- 19395550
- Full Text :
- https://doi.org/10.1152/ajpheart.00893.2008