Fortnightly Review Biology and clinical relevance of nitric oxide

Abstract

Ten years ago the idea that nitric oxide might be a biological mediator would have seemed far fetched. Clinicians might have recalled from schooldays that nitric oxide is a clear, colourless gas which rapidly turns brown on contact with air, anaesthetists might have remembered the series of disasters related to inadvertent contamination of cylinders of nitrous oxide with nitric oxide, the environmentally aware would have been familiar with the gas as a product of car exhaust and cigarette smoke and as a pollutant, and for others it would have conjured up images of primordial swamps and electrochemical storms. However, in 1987 it was shown that mammalian cells synthesise nitric oxide, a year later it was suggested that cells communicate with each other by the synthesis of nitric oxide from the amino acid arginine,1 and in 1993 there were over 1000 publications on the biology of nitric oxide. This improbable biological mediator has been implicated in the pathogenesis of diseases ranging from hypertension to septic shock and dementia.1,2 Nitric oxide is synthesised from arginine by nitric oxide synthases. Despite the apparent simplicity of nitric oxide (a 1:1 combination of two abundant elements) nitric oxide synthases are large and complex proteins. They have common features with cytochrome P450 reductase and contain oxidative and reductive domains. Three isoforms of nitric oxide synthase have been identified: an endothelial type, a neuronal type, and a macrophage (inducible) type. The genes for these enzymes have been localised to chromosome 7 (endothelial type), chromosome 12 (neuronal type), and chromosome 17 (macrophage type).3 The neuronal isoform is found in some central and peripheral neurones and the endothelial isoform is in vascular endothelium, platelets, and the heart (endocardium and myocardium). These two isoforms are normal constituents of the cells but the macrophage enzyme is …