The Role of Nitric Oxide in Reproduction

Abstract

Other papers of this symposium describe the discovery of the various forms of nitric oxide synthase (NOS). All forms of NOS convert arginine in the presence of oxygen to equimolar quantities of nitric oxide (NO) and citrulline. The inducible form is produced in immune cells by bacterial lipopolysaccharide (LPS) or cytokines which act in the nucleus to induce mRNA to synthesize the enzyme. This enzyme is then produced in large quantities. The inducible enzyme does not require activation by calcium and calmodulin since these are intrinsic to the molecule, and consequently, it releases NO without further stimulation of the cell. This NO kills bacteria and viruses but also kills other cells in the region (1).

The next form of the enzyme discovered was the so-called endothelial NOS, which is a constitutive enzyme present in endothelium of blood vessels. It is activated by parasympathetic nerves via the release of acetylcholine, which increases the intracellular free calcium in the endothelial cells. Calcium combines with calmodulin and activates the enzyme. The NO formed diffuses to the overlying smooth muscle where it activates soluble guanylate cyclase and causes the formation of cyclic GMP which relaxes the smooth muscle (2–6).

While incubating hippocampal slices with glutamic acid, Garthwaite discovered that the medium contained endothelial-derived relaxing factor, later shown to be NO, and postulated that it was NO (7). This was proven by mass spectroscopy by Palmer et al. (5). Therefore, there is also a neural form of the enzyme (neural NOS). It is also a constitutive enzyme and is activated by an increase in intracellular free calcium that combines with calmodulin activating the enzyme (7–10). Bredt and Synder isolated the enzyme (11), developed antibodies against it and showed by immunocytochemistry its wide distribution in the nervous system (12).