Inducible nitric oxide synthase and cardiovascular disease.

Abstract

The simple gas nitric oxide (NO) has a diverse array of actions in numerous physiological and pathophysiological processes in the cardiovascular system. Three distinct NO synthase (NOS) isoforms, each encoded for by separate genes, have now been identified [1–4]. nNOS (or ‘neuronal’ NOS, NOS1) and eNOS (or ‘endothelial’ NOS, NOS3) are constitutive, Ca2+-regulated isoforms expressed not only in nervous tissue and endothelium respectively, but also in several other cell types. iNOS (or NOS2) can be expressed in almost any cell type upon appropriate stimulation. All NOS isoforms can be transcriptionally and post-transcriptionally regulated [5]. The generation of NO requires l-arginine, O2, NADPH, and tetrahydrobiopterin (BH4). In situations where there is l-arginine and/or BH4 deficiency, all the NOSs can generate superoxide as well as NO [6]. Appreciation of the role of NO in the cardiovascular system dates back to 1980 and the seminal report by Furchgott & Zawadzki of a labile endothelium-derived relaxing factor (EDRF) responsible for acetylcholine-induced vasodilatation [7]. In 1987, Salvador Moncada and colleagues [8] as well as Ignarro and co-workers [9] independently demonstrated that NO accounted for the biological activity of EDRF. Around the same time, it was shown that NO was involved in macrophage-induced cytotoxicity [10,11]. Endothelial NO synthesis was Ca2+-regulated and produced small amounts of NO, whereas the macrophage enzyme was Ca2+-independent and generated much larger amounts of NO. Furthermore, the macrophage enzyme was detectable only after exposure to cytokines or endotoxin (lipopolysaccharide, LPS), ie, was inducible. In 1989, Patrick Vallance and colleagues had used local intra-arterial infusion of a specific NOS inhibitor, N G-monomethyl l-arginine (l-NMMA), into the forearm to show that endogenous NO contributed to resting arteriolar vasodilator ‘tone’ and mediated acetylcholine-induced vasodilatation in …