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

Purpose: Pulmonary 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. Methods: Monocrotaline-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. Results: In 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 100 mg/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 100 mg/kg) ameliorated pulmonary vascular muscularization in a dose-dependent manner. RVSP was reduced in RVH and pulmonary vascular muscularization was attenuated. BH₄ at 10 mg/kg reduced RV myocyte diameter while BH₄ at 100 mg/kg reversed it to control level. BH₄ restored normal levels of eNOS protein and in a dose of 100 mg/kg enhanced lung tissue levels of BH₄, cGMP, and NO compared to placebo. Conclusion: The current study provides scientific evidence for a therapeutic potential of BH₄ in PH and invites further investigation.