L-arginin and tetrahydrobiopterin for PAH treatment

Background and hypothesis. Pulmonary arterial hypertension is a severe condition leading to right heart failure and death within 2 to 3 years after diagnosis. A decreased expression of endothelial nitric oxide synthase (eNOS) in pulmonary arteries has been identified as one of the underlying pathogenetic mechanisms. eNOS converts its substrate L-arginine zu L- citrulline and the vasoprotective nitric oxide (NO). eNOS activity depends on the availability of its co-factor tetrahydrobiopterin (BH4). The present study is based on the hypothesis that a combined oral supplementation of L- arginine and BH4 (the substrate and co-factor to eNOS) increases eNOS activity and NO release. Methods. An established animal model of pulmonary hypertension will be utilized. Rats with pulmonary hypertension and control animals will be randomized into four treatment arms, i.e. 1) vehicle, 2) BH4, 3) L-arginine or 4) BH4 in combination with L-arginine. Study endpoints will include 1) survival, 2) hemodynamic parameters, 3) exhaled NO, 4) ratio of right to left ventricular weight, 5) eNOS mRNA and protein levels in the lung as well as eNOS activity, and 6) pulmonary artery media thickness.

Background and hypothesis. Pulmonary arterial hypertension is a severe condition leading to right heart failure and death within 2 to 3 years after diagnosis. A decreased expression of endothelial nitric oxide synthase (eNOS) in pulmonary arteries has been identified as one of the underlying pathogenetic mechanisms. eNOS converts its substrate L-arginine zu L- citrulline and the vasoprotective nitric oxide (NO). eNOS activity depends on the availability of its co-factor tetrahydrobiopterin (BH4). The present study is based on the hypothesis that a combined oral supplementation of L- arginine and BH4 (the substrate and co-factor to eNOS) increases eNOS activity and NO release. Methods. An established animal model of pulmonary hypertension will be utilized. Rats with pulmonary hypertension and control animals will be randomized into four treatment arms, i.e. 1) vehicle, 2) BH4, 3) L-arginine or 4) BH4 in combination with L-arginine. Study endpoints will include 1) survival, 2) hemodynamic parameters, 3) exhaled NO, 4) ratio of right to left ventricular weight, 5) eNOS mRNA and protein levels in the lung as well as eNOS activity, and 6) pulmonary artery media thickness.