Tetrahydrobiopterin and Nitric Oxide Synthase Recouplers
Generation of nitric oxide (NO) by the nitric oxide synthase (NOS) enzymes plays multiple signalling roles in every organ system, with crucial roles in the cardiovascular system, mediated by endothelial nitric oxide synthase (eNOS, encoded by NOS3) and ne
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Contents 1 Importance of Nitric Oxide and Nitroso-Redox Signalling 1.1 Nitric Oxide Synthase Coupling and Uncoupling 1.2 Availability of L-Arginine Substrate and Presence of Methylarginine Inhibitors 1.3 NOS Post-translational Modification 2 BH4-Dependent eNOS Uncoupling as a Therapeutic Target 2.1 Clinical Trials of Oral BH4 in Cardiovascular Disease 2.2 Augmenting BH4 Bioavailability by Co-administration of Antioxidants and Folates 2.3 Activation of BH4 Synthesis by Targeting GTPCH Activity 2.4 Recycling BH4 from BH2 by Dihydrofolate Reductase (DHFR) References
K. M. Channon (*) BHF Field Marshal Earl Alexander Professor of Cardiovascular Medicine, University of Oxford and Oxford University Hospitals, Oxford, UK e-mail: [email protected] # Springer Nature Switzerland AG 2020 Handbook of Experimental Pharmacology, https://doi.org/10.1007/164_2020_390
K. M. Channon
Graphical Abstract
THF
BH 4
DHFR
Cit
Arg ADMA
BH 2 uc -NOS3
NOSr
BH 4 NOS3
ROS ROS
NO
Generation of nitric oxide (NO) by the nitric oxide synthase (NOS) enzymes plays multiple signalling roles in every organ system, with crucial roles in the cardiovascular system, mediated by endothelial nitric oxide synthase (eNOS, encoded by NOS3) and neuronal nitric oxide synthase (nNOS, encoded by NOS1) in regulation of blood pressure, flow, oxygen delivery and cardiac function. Loss of normal NO-mediated functions in cardiovascular disease state is associated with changes in nitroso-redox signalling that are not dependent solely upon altered NO generation, but increased generation of reactive oxygen species (ROS). The NOS enzymes can also generate ROS, in a catalytic mode whereby the generation of NO from L-arginine is ‘uncoupled’ from the reduction of molecular oxygen. NOS uncoupling is determined by several factors, including the availability and oxidation state of the required NOS cofactor, tetrahydrobiopterin (BH4). The duality of NOS functions as enzymes that generate both NO and ROS under different regulatory states has emerged as an important pathophysiologic mechanism, and is a potential therapeutic target, via agents that can maintain or restore NOS coupling, for example via effects on BH4 availability. Keywords
Cardiovascular disease · Endothelium · Nitric oxide · Reactive oxygen species · Tetrahydrobiopterin
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Importance of Nitric Oxide and Nitroso-Redox Signalling
Generation of nitric oxide (NO) by the nitric oxide synthase (NOS) enzymes plays multiple signalling roles in every organ system, with crucial roles in neurotransmission, immune function, cardiovascular regulation and energy metabolism. In the
Tetrahydrobiopterin and Nitric Oxide Synthase Recouplers
cardiovascular system, endothelial nitric oxide synthase (eNOS, encoded by NOS3) and neuronal nitric oxide synthase (nNOS, encoded by NOS1) regulate blood pressure, blood flow, oxygen delivery by haemoglobin, cardiac contractility and relaxation (Forstermann and Sessa 2012). Cardiovascular disease states, particularly those associated with deranged endothelial functio
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