Regulation of inducible nitric oxide synthase in the vasculature

At the time when I started research in Keio University, nitric oxide (NO) was discovered to be the endothelial-derived relaxing factor. Cytokines were known to induce NO synthase in the vasculature, but the magnitude of induction changed largely among experiments. Contamination of a small amount of lipopolysaccharide was found to be the cause of the variation. Under defined concentrations of lipopolysaccharide, we showed that a combination of cytokines induces NO synthase in vascular endothelial (Jpn J Pharmacol 63, 327, 1993) and smooth muscle cells (Jpn J Pharmacol 63, 361, 1993). Since a possible role of vascular factors was suggested in hypertension caused by cyclosporin A, we analyzed the effects of this reagent on NO production. Cyclosporin A reduced NO synthase induction and NO production in vascular smooth muscle cells (Hypretension 25, 764, 1995). We also found that natriuretic peptides ANP, BNP, and CNP augment induction of NO synthase via a cGMP dependent manner in vascular smooth muscle cells. Local production of NO in the vascular wall was suggested to play a role in the progression of vascular lesion formation (Endocrinology 136, 2135, 1995).