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

Abstract

Summary 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.

β3 adrenergic receptor antagonist SR59230A exerts beneficial effects on right ventricular performance in monocrotaline‑induced pulmonary arterial hypertension

“…Increased ROS, an altered redox state and elevated oxidant stress have been indicated in the lung and RV of various PAH animal models, in addition to MCT toxicity (60). Furthermore, a more recent study revealed that a deficiency in tetrahydrobiopterin, an essential cofactor for eNOS coupling, may be associated with MCT-induced PAH rats (61). In addition, SR59230A may inhibit inflammatory infiltration in the perivascular and peribronchial regions, whereas inflammatory cell recruitment has been known to accelerate the accumulation of ROS and lung functional impairment (62).…”

Facilitating Nitrite-Derived S-Nitrosothiol Formation in the Upper Gastrointestinal Tract in the Therapy of Cardiovascular Diseases

“…While drugs that inhibit the degradation of cGMP are not usually used in patients with hypertension, they can be utilized in pulmonary arterial hypertension, such as the phosphodiesterase inhibitors sildenafil and tadalafil [ 50 ]. An impaired NO pathway is frequently associated with the development of this disease through different mechanisms, including pulmonary endothelial dysfunction, reduced NOS3 activity, decreased expression of the bone morphogenetic protein receptor II (BMPRII), increased symmetric and asymmetric dimethylarginine (ADMA) levels or arginase I, and tetrahydrobiopterin (BH4; a cofactor involved in NOS activity) or arginine deficiency [ 31 , 32 , 33 , 34 , 35 ].…”

“…The bioavailability of nitric oxide (NO) can be influenced by various factors that impact the activity of the standard NO synthesis pathway, carried out by nitric oxide synthases (NOSs). These factors include reduced levels of its substrate, arginine, or its cofactor tetrahydrobiopterin (BH4), and increased expression of arginase and levels of asymmetric dimethylarginine (ADMA), which competes with arginine for interaction with the enzyme [ 31 , 32 , 33 , 34 , 35 ]. Drugs that inhibit enzymes with nitrite reductase activity, such as xanthine oxidoreductase (XOR), can affect NO, as seen with febuxostat and allopurinol, which may inhibit nitrite-derived NO formation [ 36 ].…”

“…Similarly, other factors that diminish NO bioavailability may compromise physiological vasodilation and contribute to hypertension development. Bone morphogenetic protein receptor II (BMPRII) plays a role in endothelial cell survival and proliferation; reduced expression of this receptor has been linked to the development of endothelial dysfunction [ 31 , 32 , 33 , 34 , 35 ]. Factors that impair the enterosalivary nitrate cycle also decrease NO bioavailability, including ablation or dysfunction of salivary glands, which secrete nitrate into the oral cavity, and genetic disorders affecting the nitrate cotransporter in these glands (sialin) [ 38 ].…”

Endothelial Nitric Oxide Synthase (eNOS) and the Cardiovascular System: in Physiology and in Disease States

“…However, interdomain electron transfer from NADPH of the reductase domain to the oxygenase domain appears to be slow. Therefore, eNOS uses BH 4 cofactor as an electron donor to rapidly reduce the oxyferrous complex, which can dissociate to ferric heme and superoxide in BH 4 -depleted condition [32][33][34]. In addition, this BH 4 has been shown to play a role of "redox switch" which means that it can attenuate superoxide release and promote the formation of NO; and that an addition of 7,8-BH 2 or sepiapterin enhances superoxide release while inhibiting the production of NO [35,36].…”