PURPOSE: The term pulmonary arterial hypertension (PAH) describes a group of diseases characterized by elevated pulmonary arterial pressure. The cause can be due to vascular changes, including remodeling in the pre-capillary resistance arterioles. If left untreated, patients might die from right heart failure within an average of three years. Current available treatments may have some clinical benefits but no single therapy can reverse the disease process. The present study was designed to investigate single and combination therapy with erythropoietin (epo) and sildenafil on hypoxia-induced PAH.
METHODS: Mice were randomized, first in a normoxic and a hypoxic group and second to receive saline (control, n=6), epo (n=6), sildenafil (n=6) or epo and sildenafil (n=6). Epo was injected three times per weekly (500 IU/kg) and sildenafil daily (10 mg/kg). The animals were exposed to three weeks of either hypoxia (10 % oxygen) or normoxia, after which they underwent the different treatments for an additional two weeks under the same conditions. Immunohistochemistry was performed to elucidate changes in morphology of pulmonary arterioles and of right heart hypertrophy. Plasma levels of cardiotrophin-1 and atrial natriuretic peptide (ANP) were measured as well as 32 cytokines involved in inflammation and remodeling. Ventilatory parameters were measured using whole body plethysmography.
RESULTS: On average the hypoxic mice lost approximately 20 % of their body weight. This was reduced to 5 % for the group receiving the combination treatment whereas the single treatments showed no effect. The hypoxia-induced increase in right ventricular hypertrophy and medial wall thickness of pulmonary arterioles was significantly attenuated with the combination therapy compared both to the control and to the single treatment groups. Similar results were also observed for cardiotrophin-1 and ANP levels. Animals in the hypoxic group exhibited a deteriorated lung function that could be improved upon treatment. Furthermore, the hypoxia-induced elevated cytokines expression was also attenuated in response to the treatments.
CONCLUSIONS: The combination treatment with epo and sildenafil demonstrated an improvement in the clinical outcome in hypoxia-induced PAH in mice.
CLINICAL IMPLICATIONS: This can provide the basis for future treatment modalities favoring combined epo and sildenafil treatment to potentially improve treatment efficacy.
DISCLOSURE: Gassmann Max: Grant monies (from industry related sources): grant
Louise Ostergaard: Grant monies (from industry related sources): Grant
The following authors have nothing to disclose: Victor Samillan soto, Colin Schwarzwald, Thomas Haider, Johannes Vogel
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