Eur Heart J 33(7): 829-837

Nitric oxide synthases: regulation and function

^{Department of Pharmacology, Johannes Gutenberg University Medical Center, 55101 Mainz, Germany}

^{Department of Pharmacology and Vascular Biology, and Therapeutics Program, Yale University School of Medicine, New Haven CT 06520, USA}

^{Corresponding author: Department of Pharmacology, Johannes Gutenberg University Medical Center, Obere Zahlbacher Strasse 67, 55131 Mainz, Germany. Tel: +49 6131 17 9150, Fax: +49 6131 17 9043, Email:}ed.zniam-inu@nnamretsrof.hcirlu

Received 2011 Jan 7; Revised 2011 Jul 14; Accepted 2011 Jul 28.

Abstract

Nitric oxide (NO), the smallest signalling molecule known, is produced by three isoforms of NO synthase (NOS; EC 1.14.13.39). They all utilize l-arginine and molecular oxygen as substrates and require the cofactors reduced nicotinamide-adenine-dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and (6R-)5,6,7,8-tetrahydrobiopterin (BH₄). All NOS bind calmodulin and contain haem. Neuronal NOS (nNOS, NOS I) is constitutively expressed in central and peripheral neurons and some other cell types. Its functions include synaptic plasticity in the central nervous system (CNS), central regulation of blood pressure, smooth muscle relaxation, and vasodilatation via peripheral nitrergic nerves. Nitrergic nerves are of particular importance in the relaxation of corpus cavernosum and penile erection. Phosphodiesterase 5 inhibitors (sildenafil, vardenafil, and tadalafil) require at least a residual nNOS activity for their action. Inducible NOS (NOS II) can be expressed in many cell types in response to lipopolysaccharide, cytokines, or other agents. Inducible NOS generates large amounts of NO that have cytostatic effects on parasitic target cells. Inducible NOS contributes to the pathophysiology of inflammatory diseases and septic shock. Endothelial NOS (eNOS, NOS III) is mostly expressed in endothelial cells. It keeps blood vessels dilated, controls blood pressure, and has numerous other vasoprotective and anti-atherosclerotic effects. Many cardiovascular risk factors lead to oxidative stress, eNOS uncoupling, and endothelial dysfunction in the vasculature. Pharmacologically, vascular oxidative stress can be reduced and eNOS functionality restored with renin- and angiotensin-converting enzyme-inhibitors, with angiotensin receptor blockers, and with statins.

Keywords: (6R-)5,6,7,8-Tetrahydrobiopterin; l-Arginine; Asymmetric dimethyl-l-arginine; NADPH oxidase; Peroxynitrite

Abstract

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