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PubMed | University of Zürich, Cayetano Heredia Peruvian University, ETH Zurich, Alas Peruanas University and Institute for Veterinary Physiology
Type: Journal Article | Journal: Pulmonary circulation | Year: 2014

Pulmonary hypertension (PH) is an incurable disease that often leads to right ventricular hypertrophy and right heart failure. This study investigated single versus combined therapy with sildenafil and erythropoietin on hypoxia-induced pulmonary hypertension in mice. Mice were randomized into 5 groups and exposed to either hypoxia (10% oxygen) or normoxia for a total of 5 weeks. Hypoxic mice were treated with saline solution, erythropoietin (500 IU/kg 3 times weekly), sildenafil (10 mg/kg daily), or a combination of the two drugs for the last 2 weeks of hypoxic exposure. We measured right ventricular pressures using right heart catheterization, and the ventilatory response to hypoxia was recorded via whole-body plethysmography. Histological analyses were performed to elucidate changes in pulmonary morphology and appearance of right heart hypertrophy. Plasma levels of cardiotrophin-1 and atrial natriuretic peptide were quantified. Treatment with either erythropoietin or sildenafil alone lowered the hypoxia-induced increase of pulmonary pressure and reduced pulmonary edema formation, pulmonary vascular remodeling, and right ventricular hypertrophy. Notably, the combination of the two drugs had the most prominent effect. Changes in cardiotrophin-1 and atrial natriuretic protein levels confirmed these observations. The combination treatment with erythropoietin and sildenafil demonstrated an attenuation of the development of hypoxia-induced PH in mice that was superior to that observed for either drug when given alone.


Gammella E.,University of Milan | Gammella E.,Institute for Veterinary Physiology | Leuenberger C.,Institute for Veterinary Physiology | Leuenberger C.,ETH Zurich | And 4 more authors.
American Journal of Physiology - Lung Cellular and Molecular Physiology | Year: 2013

Endothelial cell dysfunction is a common event to several pathologies including pulmonary hypertension, which is often associated with hypoxia. As the endothelium plays an essential role in regulating the dynamic interaction between pulmonary vasodilatation and vasoconstriction, this cell type is fundamental in the development of vascular remodeling and increased vascular resistance. We investigated the protective effects of sildenafil, a phosphodiesterase type 5 inhibitor, given in combination with erythropoietin (Epo), as it has been demonstrated that both drugs have antiapoptotic effects on several cell types. Specifically, we examined the viability and angiogenic properties of rat pulmonary artery endothelial cells upon exposure to either 21% or 1% oxygen, in presence of sildenafil (1 and 100 nM) and Epo (5 and 20 U/ml) alone or in combination (1 nM and 20 U/ml). Cell proliferation and viability were analyzed by Trypan blue staining, MTT assay, and Annexin V/propidium iodide stainings. In all assays, the ability of the combination treatment in improving cell viability was superior to that of either drug alone. The angiogenic properties were studied using a migration and a 3D collagen assay, and the results revealed increases in the migration potential of endothelial cells as well as the ability to form tube-like structures in response to sildenafil and the combination treatment. We therefore conclude that both drugs exert protective effects on endothelial cells on hypoxia and that sildenafil enhances the migratory and angiogenic properties, especially in hypoxic conditions. Furthermore, we present evidence of possible additive or synergistic effects of both drugs. © 2013 the American Physiological Society.

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