THE NITRIC OXIDE-CYCLIC GMP SIGNALING PATHWAY IN RAT-BRAIN

Nitric oxide is a novel signalling molecule in the brain and a potent activator of the cyclic GMP-synthesising enzyme, soluble guanylate cyc lase. To determine if stimulation of cyclic GMP formation is a widespr ead mechanism of nitric oxide signal transduction, we have compared th e distribution of the nitric oxide-generating enzyme (nitric oxide syn thase) with that of nitric oxide-stimulated cyclic GMP accumulation, t hroughout the rat brain. The former was done using NADPH diaphorase hi stochemistry and the latter by cyclic GMP immunohistochemistry followi ng perfusion of the nitric oxide donor, nitroprusside, in vivo. At a g ross level, there was generally a good match when the two were compare d in adjacent sections. Although the relative staining intensity varie d from area to area, in no grey matter region did we observe cyclic GM P accumulation in the absence of nitric oxide synthase staining. In de tail, the locations were complementary rather than identical. In some areas, nitric oxide synthase was found in postsynaptic structures and cyclic GMP accumulation in presynaptic elements and fibres; in others, the locations were reversed. Glial cells and their processes also acc umulated cyclic GMP in the cerebellum. The results suggest that solubl e guanylate cyclase is a major nitric oxide ''receptor'' throughout th e brain. They also support the hypothesis that nitric oxide generated therein primarily functions as a mediator of cell-cell signalling rath er than as a conventional second messenger acting within the cells in which it is produced. The types of communication subserved by nitric o xide appear to be extraordinarily diverse.