Endothelin receptor blockade combined with phosphodiesterase-5 inhibition increases right ventricular mitochondrial capacity in pulmonary arterial hypertension

Abstract

We determined the effects of single and combination treatment with Bosentan [an ET type A (ET A)/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 PULMONARY ARTERIAL HYPERTENSION (PAH) is a severe progressive disease of the small lung vasculature leading to increased pulmonary vascular resistance (PVR). The right ventricle (RV) hypertrophies to withstand the rise in PVR and maintain cardiac output (CO) (16,48). Subsequently, RV contractile dysfunction occurs, and failure may develop (8, 51). Many factors influence the capacity of the RV to adapt to PAH, such as the degree of RV wall stress, myocardial ischemia, or microvascular endothelial dysfunction. However, the exact sequence of events leading the RV toward failure, and the effects of treatments to counteract this process remain uncertain (51).Various treatments for PAH have been developed over time, which primarily act as vasodilators of the pulmonary vasculature. These treatments include anticoagulant therapy, prostacyclin infusion, endothelin (ET) receptor blockade, and phosphodiesterase-5 (PDE5) inhibition (9, 25). ET receptor blockade by Bosentan and PDE5 inhibition by Sildenafil are both common strategies in PAH treatment (9,25,43). The ET system is highly active in PAH and causes sustained vasoconstriction of pulmonary arteries. It increases the mitogenic activity of smooth muscle cells and fibroblasts in the pulmonary vessel wall, thereby decreasing the lumen of pulmonary vessels, also contributing to increased pulmonary vascular resistance (PVR) ...

Clinical and histopathological relationship of sildenafil and bosentan treatments in rats with monocrotaline induced pulmonary hypertension

“…In rats, in which PH is developed, right ventricular dilatation occurs whereas LVDD decreases. Mouchers et al has reported that in rats which PAH is formed LVDD was decreased; whereas the values have increased in sildenafi l group, but no increase in bosentan group (17). Moreover, similarly, our study also revealed smaller LVDD in the treatment groups when compared to SF group in PH developed rats.…”

“…In addition to PAH development, treatment in PAH developed rats was studied in experimental models. Mouchers et al reported that RVDD has had a statistically signifi cant decrease in combined treatment group (17). RVDD was also decreased in sildenafi l group without a statistical signifi cance, whereas no decrease at all in bosentan group (17).…”

“…Mouchers et al reported that RVDD has had a statistically signifi cant decrease in combined treatment group (17). RVDD was also decreased in sildenafi l group without a statistical signifi cance, whereas no decrease at all in bosentan group (17). Clozel et al reported a decrease in right ventricular wall thickness in bosentan, sildenafi l and combined therapy groups in PAH formed rats (13).…”

Pulmonary artery pressure limits exercise capacity at high altitude

“…This could have affected the distribution of systemic perfusion, which has been reported to be altered in hypoxia [2]. Selective endothelin antagonist-mediated increases in nitric oxide availability [9] could improve mitochondrial capacity by a protein kinase Gmediated pathway, thereby improving myocardial and skeletal O 2 uptake [29,30]. Thus, sitaxsentan could also have affected the matching of convectional and diffusional oxygen transport systems, which have been modelled to occur at a lower Q in hypoxia [3].…”

Rapid Quantification of Myocardial Fibrosis: A New Macro-Based Automated Analysis

“…Moreover, as observed earlier, collagen fibers are expected to change as function of age or as wound healing progresses. It is also known that monocrotaline induced PH activates neurohumoral factors, which can also influence structural remodeling of the LV, in the absence of mechanical overload [1,23,27]. In addition, vice versa, the RV also shows severe fibrosis in the setting of systemic hypertension [4,39,47].…”