Chapter 21 Nitric oxide as a bioregulator

Abstract

Summary Nitric oxide (NO) is a free radical synthesized from the semi-essential amino acid, L-arginine, in a wide variety of different cell types and tissues throughout the mammalian body. The biological effects of NO are mediated by activation of soluble guanylyl cyclase to increase intracellular concentrations of cGMP. The enzyme, nitric oxide synthase (NOS), responsible for converting L-arginine into NO and citrulline exists as at least two different isoforms. Constitutive NOS (cNOS) occurs in vascular endothelial cells and neurones and is both calmodulin and calcium dependent. Inducible NOS (iNOS) is synthesised de novo in inflammatory leucocytes, vascular smooth muscles, hepatocytes and endothelial cells following exposure to bacterial endotoxins or cytokines. A wide range of physiological roles of NO have been suggested. These include the control of blood vessel caliber (and hence, blood pressure), platelet aggregation and adhesion, pain perception, neurodegeneration, memory, and in the defensive response of the body by destroying invading microorganisms including bacteria, fungi, and some viruses, NO, NO secretogogues or stable NO donor drugs, as well as NOS inhibitors such as L-NAME, L-NMMA and 7-nitro indazole have potential therapeutic uses in the cardiovascular system (hypotension due to endotoxic or septic shock), central nervous system (analgesia, protection against neuronal cell death in cerebral stroke), peripheral nervous system (impotence), airways (adult respiratory distress syndrome, ARDS) and perhaps as protection against infections of various types. Further research is required to evaluate the physiological significance of NO in these and other body systems as is the development of isoform-selective inhibitors of both cNOS and iNOS. Nevertheless, the clinical potential of drugs which interact with the L-arginine: NO system is indicated at least from studies in experimental animals. The importance of NO in man is only beginning to be determined. Only time will tell whether NO, novel NO donor drugs or, more likely, NOS inhibitors prove to be of value in therapeutics.