ABSTRACT
The discovery that the free radical gas nitric oxide (NO*, commonly abbreviated to NO) has multiple biological roles-as a neurotransmitter, in the regulation of blood pressure, and in the host response to infection-has resulted in this mole cule becoming the focus of intense research activity. These studies not only have increased our understanding of the biological function of NO but also suggest that there may be therapeutic benefit in inhibiting the production and/or function of NO in certain clinical indications (1). Nitric oxide, which was defined as the molecule of the year in 1992 in Science, has recently emerged as an important mediator of cellular and molecular events that impact the pathophysiology of cerebral ischemia (2-12). In the central nervous system (CNS), NO is a neuronal messenger and mediator having both neurotoxic and neuromodulator effects (11,13-15). It fulfills most of the criteria of a neurotransmitter (16). NO was first identified as endothelium-derived relaxing factor. It is also involved in /V-methylD-aspartate (NMDA) glutamatergic neurotransmission (8). Since the mid-1970s, it has been known that synaptic excitation in the CNS is associated with eleva tions in the level of the second messenger, cyclic GMP (cGMP) (17,18). These responses are now known to be mediated through the release of the novel messen ger molecule NO, which functions as a powerful activator of the cGMP-synthesizing enzyme, the soluble guanylate cyclase (18). A major primary trigger for NO formation is the increased cytosolic free Ca2+ levels resulting from the activa tion of voltage-gated Ca2+ channels or ligand-gated Ca2+ channels or from the mobilization of intracellular Ca2+ stores. NO has a number of properties that set
it apart from conventional signaling molecules, not the least of which is its ability to diffuse readily across membranes and so act on cellular elements located some distance from its site of formation (18).
