Abstract
BackgroundEndothelin-1 signalling plays an important role in pathogenesis of pulmonary hypertension. Although different endothelin-A receptor antagonists are developed, a novel therapeutic option to cure the disease is still needed. This study aims to investigate the therapeutic efficacy of the selective endothelin-A receptor antagonist TBC3711 in monocrotaline-induced pulmonary hypertension in rats.MethodsMonocrotaline-injected male Sprague-Dawley rats were randomized and treated orally from day 21 to 35 either with TBC3711 (Dose: 30 mg/kg body weight/day) or placebo. Echocardiographic measurements of different hemodynamic and right-heart hypertrophy parameters were performed. After day 35, rats were sacrificed for invasive hemodynamic and right-heart hypertrophy measurements. Additionally, histologic assessment of pulmonary vascular and right-heart remodelling was performed.ResultsThe novel endothelin-A receptor antagonist TBC3711 significantly attenuated monocrotaline-induced pulmonary hypertension, as evident from improved hemodynamics and right-heart hypertrophy in comparison with placebo group. In addition, muscularization and medial wall thickness of distal pulmonary vessels were ameliorated. The histologic evaluation of the right ventricle showed a significant reduction in fibrosis and cardiomyocyte size, suggesting an improvement in right-heart remodelling.ConclusionThe results of this study suggest that the selective endothelin-A receptor antagonist TBC3711 demonstrates therapeutic benefit in rats with established pulmonary hypertension, thus representing a useful therapeutic approach for treatment of pulmonary hypertension.
Highlights
Endothelin-1 signalling plays an important role in pathogenesis of pulmonary hypertension
The ET-A receptors are mostly expressed on pulmonary artery smooth muscle cells (PASMCs), cardiomyocytes and fibroblasts, whereas the ET-B receptors are presented on endothelial cells and, to a lesser extent, on PASMCs [8]
Nishida et al suggest that ET-A receptor mediated action is exclusively involved in the pathogenesis of MCT-induced Pulmonary hypertension (PH), they could not rule out a protective role of ET-B receptor mediated actions [13]
Summary
Endothelin-1 signalling plays an important role in pathogenesis of pulmonary hypertension. ET-1 is primarily produced by endothelial cells and manifests effects through 2 G-protein-coupled receptors ET-A and ET-B These receptors have a different localization and cause the different biological responses. Nishida et al suggest that ET-A receptor mediated action is exclusively involved in the pathogenesis of MCT-induced PH, they could not rule out a protective role of ET-B receptor mediated actions [13]. These facts created a novel paradigm that selective ET-A receptor antagonism is more favorable than a nonselective ET-A/ET-B approach
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