Objective-6R-5,6,7,8-tetrahydro-L-biopterin (6R-BH4) is a cofactor for endothelial nitric oxide synthase but also has antioxidant properties. Its stereo-isomer 6,7, and structurally similar pterin 6R, 6,7, are also antioxidants but have no cofactor function. When endothelial nitric oxide synthase is 6R-BH4 -deplete, it synthesizes superoxide rather than nitric oxide. Reduced nitric oxide bioavailability by interaction with reactive oxygen species is implicated in endothelial dysfunction (ED). 6R-BH4 corrects ED in animal models of ischemia reperfusion injury (IRI) and in patients with cardiovascular risks. It is uncertain whether the effect of exogenous 6R-BH4 on ED is through its cofactor or antioxidant action. Methods and Results-In healthy volunteers, forearm blood flow was measured by venous occlusion plethysmography during intra-arterial infusion of the endothelium-dependent vasodilator acetylcholine, or the endothelium-independent vasodilator glyceryl trinitrate, before and after IRI. IRI reduced plasma total antioxidant status (Pϭ0.03) and impaired vasodilatation to acetylcholine (Pϭ0.01), but not to glyceryl trinitrate (Pϭ0.3). Intra-arterial infusion of 6R-BH4, 6S-BH4 and NH4 at approximately equimolar concentrations prevented IRI. Conclusion-IRI causes ED associated with increased oxidative stress that is prevented by 6R-BH4, 6S-BH4, and NH4, an effect mediated perhaps by an antioxidant rather than cofactor function. R-5,6,7,8-terahydro-L-biopterin (6R-BH4) is an essential cofactor for endothelial nitric oxide synthase (NOS) that catalyzes production of the vasodilator and atheroprotective mediator NO. 1,2 Biosynthesis of 6R-BH4 occurs in the endothelium, promoting NO synthesis by facilitating electron transfer from the reductase domain of NOS to arginine. 6R-BH4 also stabilizes the NOS dimer and exerts an allosteric effect, enhancing substrate binding. 3 Changes in 6R-BH4 availability influence NO production. A reduction in 6R-BH4 leads not only to a diminished NO synthesis but also to the generation of NOS-derived superoxide (O 2 ⅐Ϫ ) that has been implicated in the development of endothelial dysfunction. 4 Ischemia reperfusion injury (IRI), such as occurs after thrombolysis or balloon angioplasty, is associated with endothelial dysfunction, which may contribute to cellular damage. The mechanism underlying endothelial dysfunction in IRI is incompletely understood but adhesion of activated neutrophils to endothelial cells, 5 an increase in oxygen radical generation, 6,7 the elaboration of inflammatory cytokines, and a reduction in NO production 8,9 are all believed to play a role.In humans, local delivery of 6R-BH4 by intra-arterial infusion improves endothelium dependent vasodilation in patients with coronary artery disease, 10 type II diabetes mellitus, 11 elevated cholesterol, 12 raised blood pressure, 13 and in smokers, 14 leading to the proposal that an acquired deficiency in 6R-BH4 and defective NOS catalysis underlies endothelial dysfunction in these states. Supplementation with 6R-BH4 also red...
Background-(6R)-5,6,7,8-Tetrahydro-L-biopterin (BH4) is a cofactor for enzymes involved in catecholamine and nitric oxide generation whose synthesis is initiated by GTP cyclohydrolase I (GTPCH-1), encoded by GCH1. In the absence of a potent, specific GTPCH-1 inhibitor, natural BH4 deficiency caused by mutations in GCH1 in the rare movement disorder, DOPA-responsive dystonia (OMIM DYT5), offers the opportunity to study the role of endogenous BH4 in humans. Methods and Results-In 16 DOPA-responsive dystonia patients with mutations predicted to affect GTPCH-1 expression or function and in age-and sex-matched control subjects, we measured plasma biopterin and nitrogen oxides by highperformance liquid chromatography and the Griess reaction, respectively, endothelial function by brachial artery flowmediated dilation (FMD), sympathetic function by measurement of plasma norepinephrine, epinephrine, and heart rate and blood pressure in response. Cardiac function and structure were assessed by echocardiography. 9%, Pϭ0.91). In patients but not control subjects, FMD was insensitive to nitric oxide synthase inhibition (FMD at baseline, 6.7Ϯ2.1%; FMD during L-NMMA infusion, 6.2Ϯ2.5, Pϭ0.68). The heart rate at rest was higher in patients, but the heart rate and blood pressure response to sympathetic stimulation did not differ in patients and control subjects despite lower concentrations of norepinepherine (264Ϯ8 pg/mL versus 226Ϯ9 pg/mL, Pϭ0.006) and epinephrine (33.8Ϯ5.2 pg/mL versus 17.8Ϯ4.6 pg/mL, Pϭ0.03) in patients. There was also no difference in cardiac function and structure. Conclusions-Sympathetic, cardiac, and endothelial functions are preserved in patients with GCH1 mutations despite a neurological phenotype, reduced plasma biopterin, and norepinepherine and epinephrine concentrations. Lifelong endogenous BH4 deficiency may elicit developmental adaptation through mechanisms that are inaccessible during acquired BH4 deficiency in adulthood. (Circ Cardiovasc Genet. 2010;3:513-522.)Key Words: endothelium Ⅲ sympathetic function Ⅲ tetrahydrobiopterin Ⅲ DOPA-responsive dystonia T etrahydrobiopterin (BH4), synthesized from GTP by the rate-limiting enzyme GTP cyclohydrolase I (GTPCH-1) and encoded by the GCH1 gene, is an essential cofactor for the aromatic amino acid hydroxylases (phenylalanine, tyrosine, and tryptophan hydroxylase), which are responsible for the synthesis of the central and sympathetic neurotransmitters dopamine (DA), norepinephrine (NE), epinephrine, and 5-hydroxytryptamine (5HT), as well as the nitric oxide synthases (eNOS, iNOS, and nNOS). The Michaelis constant (K m ) for BH4 of the aromatic amino acid hydroxylases (100 mol/L) 1 is higher than that for the NOSs (100 nmol/ L), 2 suggesting that they may be more sensitive to the effect of inherited or acquired BH4 deficiency. Clinical Perspective on p 522In the absence of a specific, potent inhibitor of GTPCH-1 for use in humans, it has been difficult to evaluate the precise physiological role of BH4 in sympathetic, endothelial, and cardiac functions....
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.