Nitric oxide-dependent and independent down-regulation of NO-sensitive guanylyl cyclase in neural cells.

NO-sensitive guanylyl cyclase or soluble guanylyl cyclase (sGC) is the major target for NO and cyclic GMP the mediator of its vasodilating and neuromodulatory actions. Studies on the mechanism of nitrovasodilator-induced tolerance have shown that in smooth muscle cells sGC is down-regulated by prolonged exposure to exogenous or endogenous NO. Increased expression of NO synthase (NOS) in CNS glial cells is a landmark of acute and chronic neuroinflammation. Our studies in cultured astroglial cells demonstrate that exposure to neuroinflammatory agents leads to a long-lasting down-regulation of sGC that occurs by NO-dependent and independent mechanisms. Decreased expression of the enzyme at the protein and mRNA level is evident in the brain of adult rats after intracerebral injection of inflammatory compounds. A decreased cGMP synthesizing capacity may contribute to the neurodegenerative process associated to neuroinflammation.