ABSTRACT
Nitric oxide (NO) is an inorganic gas that is synthesized in numerous mammalian tissues. Following its generation by NO synthase (NOS), NO readily diffuses beyond its site of origin to influence adjacent cells. NO is synthesized from L-arginine and molecular oxygen (for review, see Griffith and Stuehr, 1995). The reaction requires NADPH, 2 flavins, tetrahydrobiopterin, and a heme complex, and produces stoichiometric amounts of citrulline and NO following a five electron-oxidation of Larginine. Three isoforms of the NOS enzyme have been identified: neuronal (Type 1) and endothelial (Type 3), which are constitutive, and an inducible isoform (Type 2). The constitutive isoforms are calcium/calmodulindependent and are activated by intracellular calcium transients. On the other hand, calmodulin is very tightly bound to the inducible isoform (iNOS), and once expressed, iNOS is continuously active and leads to a long-lasting (several hours to days) NO generation compared to calcium-dependent NO synthesis, which lasts a few minutes. Low output NO synthesis by constitutive NOS regulates a broad spectrum of physiological functions such as blood pressure, vascular tone and permeability, penile erection, and neurotransmission, whereas high output NO synthesis by inducible isoform mediates the inflammatory and cytotoxic actions (Gross and Wolin, 1995). However, neuronal NOS (nNOS) can generate high amounts of NO and cause cytotoxicity under pathological conditions such as cerebral ischemia due to an uncontrolled rise in intracellular calcium (Dawson et al., 1992; Dawson and Dawson, 1995). The role of NO in cerebral ischemia is more complex because, in addition to its cytotoxic effect, NO dilates cerebral blood vessels and increases blood flow (Iadecola et al., 1994). Administering the NO precursor L-arginine or NO donors enhances rCBF in ischemic tissue and reduces infarct volume when given at the onset of the ischemic insult (Morikawa et al., 1994; Zhang, F. et al., 1994). The findings that NO may scavenge superoxide similar to other antioxidants (Niu et al., 1994), and that redox states favoring the formation of NO+ may protect cells by inhibiting NMDA receptor activity (Lipton et al., 1993), add to the complexity of the question.
