Combination of Erythropoietin and Sildenafil Can Effectively Attenuate Hypoxia‐Induced Pulmonary Hypertension in Mice

Abstract

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.

Suppressed erythropoietin expression in a nitrofen‐induced congenital diaphragmatic hernia

“…At present, rhEPO is used to treat anemia, including early and late anemia due to premature birth, and the administration of rhEPO has proven to be both feasible and safe in neonates. In addition, co‐treatment of EPO and sildenafil (a phosphodiesterase type five inhibitor) showed a synergetic effect in a murine model of hypoxia‐induced PH . Taken together, these present and previous findings suggest that EPO treatment is safe and beneficial as a postnatal therapy for PH and lung injury for infants with CDH.…”

Association Between Serum Concentrations of Hypoxia Inducible Factor Responsive Proteins and Excessive Erythrocytosis in High Altitude Peru

“…Erythropoietin has also been associated with vascular remodeling and smooth muscle proliferation in the pulmonary vasculature (Karamanian et al, 2014). Higher serum erythropoietin has been correlated with pulmonary arterial hypertension in humans (Karamanian et al, 2014) and erythropoietin administration has been shown to blunt hypoxia-induced pulmonary hypertension in mice (Samillan et al, 2013). A correlation between higher EPO levels and higher PASP was also seen in this study.…”

Chronic pulmonary fibrosis alters the functioning of the respiratory neural network

“…As previously described ( Voituron et al, 2009 ; Niane et al, 2011 ; Samillan et al, 2013 ; Jeton et al, 2022 ), breathing variables were measured non-invasively in unanesthetized and unrestrained animals using whole-body flow barometric plethysmograph (Emka technologies, Paris, France). This method consists of measuring the pressure variations in a recording chamber during spontaneous ventilation.…”