Regulation of NOS activity by the endogenous inhibitors and modification of hyperplastic vascular diseases with the inhibitors.

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During the term of project, we obtained the following results : 1.Nicotine at plasma concentrations corresponding to the levels of human smokers would accelerate the intimal hyperplasia after endothelial denudation through the enhanced impairment of the EDRF/NO production, which might be brought about by the enhanced increases in LNMMA (N^G-monomethyl-L-arginine) and ADMA (N^G, N^G-dimethyl-L-arginine) concentrations as inhibitors for NO synthesis, and the enhanced increase in endothelin-1 as a potent mitogen in the vessel wall. 2.The NO synthesized endogenously from L-arginine might play a role for mediating relaxation of the bovine ciliary muscle and that the endogenous ADMA might be involved in inhibiting the biosynthesis of NO when there are increased intracellular concentrations of the methylarginine under certain circumstances. NO causes relaxation of the bovine ciliary muscle through the activation of guanylate cyclase and an increase in cyclic GMP level. 3.ADMA as an endogenous … More inhibitor of NO synthesis may play an important role for the pathogenesis in the hypertension associated with the experimental focal and segmental glomerulosclerosis induced by puromycin aminonucleotide in the rat. 4.Immunohistochemistry for proliferating cell nuclear antigen and Ki-67, both markers for proliferating cell nuclei, showed that tropoelastin transcripts and elastin formation increased when smooth muscle cells enter quiescence after the end of the proliferative phase in the intima, suggesting that elastin synthesis and smooth muscle cell proliferation are tughtly regulated during the repair of arterial wall injury. 5.The expression of osteopontin mRNA in rabbit neointima after balloon endothelial denudation was associated with proliferating smooth muscle cells. In primary cultures of arterial smooth muscle cells.osteopontin mRNA was expressed in cells that had transferred to the synthetic state (G_<1B>, S and G_2 + M), and not in cells in either the contractile (G_0 phase) or intermediate states (G_<1A> phase), indicating that osteopontin mRNA expression provides a useful marker that can be applied to distiguish the phenotypic properties of vascular smooth muscle cells. 6.Increases in p53 protein and p53 gene transcript levels would be closely linked to the proliferation of smooth muscle cells in the thickened intima, and play a key role in the regulation of cell proliferation during the repair process after arterial wall injury. Less