Tetrahydrobiopterin (BH4): Targeting endothelial nitric oxide synthase as a potential therapy for pulmonary hypertension

PurposePulmonary Hypertension (PH) is complex disease which is associated with endothelial and cardiac dysfunction. Tetrahydrobiopterin (BH4) regulates endothelial nitric oxide synthase (eNOS) to produce nitric oxide rather than superoxide which maintains normal endothelial and cardiac function. This study explores the therapeutic potential of BH4 in experimental PH. MethodsMonocrotaline-induced PH in rats and Hph-1 deficiency in mice were used for animal experiments. Hemodynamic measurements using pressure transducers were conducted for pulmonary and cardiac pressures, and Langendorff apparatus was used for isolated heart experiments; preventive as well as rescue treatment protocols were conducted; tissues were collected for histological and biochemical studies. ResultsIn vivo acute BH4 administration reduced pulmonary artery pressure (PAP) only in the MCT rat. In a Langendorff preparation, BH4 increased right ventricular systolic pressure (RVSP) in right ventricular hypertrophy (RVH) but not in control. In prevention therapy, BH4 (10 and 100mg/kg) attenuated the development of PH in rat MCT model. eNOS protein levels in lung homogenates were maintained and cGMP levels were increased. In rescue therapy, BH4 (10 and 100mg/kg) ameliorated pulmonary vascular muscularization in a dose-dependent manner. RVSP was reduced in RVH and pulmonary vascular muscularization was attenuated. BH4 at 10mg/kg reduced RV myocyte diameter while BH4 at 100mg/kg reversed it to control level. BH4 restored normal levels of eNOS protein and in a dose of 100mg/kg enhanced lung tissue levels of BH4, cGMP, and NO compared to placebo. ConclusionThe current study provides scientific evidence for a therapeutic potential of BH4 in PH and invites further investigation.