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Over a decade of research has shown nitric oxide (NO) to be a ubiquitous modulator of biological phenomena from cell signal to effector and from physiology to pathophysiology. The involvement of NO in cardiovascular biology has contributed significantly to our understanding of complex disease states including atherosclerosis, systemic and pulmonary hypertension, endotoxic shock, pre-eclampsia,1cardiomyopathy,2 and cardiac allograft rejection.3 However, the emerging role of NO in the maintenance of cell physiology from immunomodulation to calcium signalling has highlighted the importance of this fascinating molecule in cytostasis. This dichotomy of effector function is the “double edged sword” of NO in biological systems. However, the balance between cytostatic and cytotoxic effects of NO may lie in the tissue concentration of NO produced, the particular NO synthase (NOS) isoform activated (that is, “high output” or “low output”), and the complex interaction with other free radicals such as superoxide. However, a much greater understanding of the molecular and cellular actions of NO as a physiological regulator has resulted in a body of recent research increasing our understanding of NO, and thus NO releasing agents, in cytoprotection. Current evidence is outlined below.
The NO dichotomy: physiology versus pathology?
NO is produced by the catalytic action of NOS on the substrateL-arginine. The reaction involves the oxidation of one of the guanidinonitrogens of arginine and the process involves the oxidation of NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) and the reduction of molecular oxygen. Three NOS enzymes have been characterised: type I (ncNOS), type II (iNOS), and type III (ecNOS). ncNOS and ecNOS are calcium dependent and low output enzymes associated with NO production in the picomolar range, whereas iNOS is a calcium independent and high output enzyme associated with NO production in the nanomolar (nmol) range. All three NOS isoforms have been shown to be present in …
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