Nitric Oxide

Nitric oxide (NO) is produced by the enzyme nitric oxide synthase (NOS), which converts L-arginine to citrulline and NO [113]. Three known isoforms of NOS exist: endothelial NOS (eNOS), neuronal NOS (nNOS) and inducible NOS (iNOS). The terms "eNOS" and "nNOS" reflect the original tissues from which these isoforms were cloned; however, both isoforms are widely distributed beyond the endothelium and central nervous system, respectively. Generally speaking, both eNOS and nNOS are constitutively active, dependent on intracellular calcium for activity, and produce relatively small amounts of NO. iNOS derives its name from the observation that it requires de novo gene expression for maximal activity. In addition, iNOS is calcium independent and is responsible for high level production of NO following proinflammatory and other forms of stimuli. Although historically these isoforms have been classified as being "constitutive" and "inducible," it is now recognized that the eNOS and nNOS genes can undergo regulation (i.e., induction) under certain conditions, and that iNOS can also be constitutively active [113,114]. Finally, the human genes for the NOS isoforms are now categorized based on the order in which they were cloned; thus human nNOS, iNOS, and eNOS are termed NOS1, NOS2, and NOS3, respectively [115],

One of the primary mechanisms by which NO affects cellular function is through the activation of soluble guanylate cyclase leading to increased intracellular levels of cGMP. Since NO is a free radical gas, other important NO mechanisms that affect cellular function include reactions with metal complexes, nitrosation, nitration, and oxidation reactions [116]. The degree to which any one of these mechanisms is operative in a given biological process is, in turn, highly dependent on the amount of NO produced and the biological milieu.

An abundance of quality data indicate that NO can function as a cytoprotective molecule. Assigning biological significance to these data, however, is difficult given that the literature suggests that a very broad spectrum of biological processes are affected by NO and that equally abundant and quality data indicate that NO can be either directly cytotoxic or mediate cytotoxic/ pathologic processes. Thus, NO appears to have dual properties as both a cytoprotective and a cytotoxic molecule. Unscrambling this controversy is not feasible within the context of this chapter. Examples of NO-dependent cytoprotection will be provided below, but the reader is reminded that for virtually each example of cytoprotection, there is an example of NO functioning in an opposite manner (i.e., cytotoxicity).

Apoptosis, or programmed cell death, can be modulated by NO and is perhaps the most prominent and well studied example of NO-mediated cytoprotection [117,118]. Various examples exist demonstrating that NO can either inhibit apoptosis or promote apoptosis. The anti-apoptotic effects of NO have been demonstrated in various cultured cells such as human B lymphocytes [119], endothelial cells [120], splenocytes [121], and hepatocytes [122,123], and in whole animal models [124,125], In addition, NO has been demonstrated to prevent apoptosis secondary to diverse signals such as tumour necrosis factor, growth factor withdrawal, and Fas [117,118], The mechanisms by which NO inhibits apoptosis are also quite diverse. For example, NO can induce expression of the aforementioned cytoprotective proteins, haem oxygenase-1 and heat shock protein 70, and thereby prevent apoptosis [122,126], Since cGMP can also prevent apoptosis, NO-mediated activation of cGMP is another mechanism by which NO can prevent apoptosis, possibly by lowering intracellular calcium levels [121], NO has also been shown to inhibit caspase activity [123] and inhibit cytochrome C release [127], two key events in the pro-apoptotic pathway. Finally, NO has been demonstrated to maintain or preserve intracellular levels of Bcl-2, a key anti-apoptotic protein [ 121,127],

NO can also be protective to whole organs. Examples include the liver [128], kidney [129], brain [130], heart [131], and intestine [132]. The mechanisms by which NO protects these organs involve many of the known physiologic and biologic functions of NO, such as vascular dilation, prevention of platelet and neutrophil adherence, antioxidant effects by reactions with reactive oxygen species, anti-apoptotic effects, and induction of other cytoprotective mechanisms (e.g., heat shock protein 70 and haem oxygenase-1). Thus, NO can protect organs during various forms of injury or stress by maintaining blood flow, preventing thrombosis, limiting inflammation, decreasing oxidant stress, and/or preventing apoptosis [128-132]. Again, the degree to which any one of these mechanisms is operative, or predominant, is dependent on the type of injury/stress, the amount of NO produced, and the biological context in which the NO is produced.

The cytoprotective properties of NO are indisputable and many biologically plausible mechanisms account for the observed cytoprotective effects. The availability of commonly used NO-

donors (e.g., sodium nitroprusside and nitroglycerin) and novel NO-donors allows for the direct application of these principles in the clinical setting as a means of affording organ and tissue protection during a variety of disease states [125,131]. Enthusiasm for this approach must be tempered, however, by the known dual nature of NO as both a cytoprotective and cytotoxic molecule.

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