NITRIC-OXIDE AND NITROSOTHIOLS IN CEREBROVASCULAR AND NEURONAL REGULATION

Background: Currently prevailing concepts concerning the endothelium-d ependent relaxant effect of acetylcholine and other endothelium-depend ent agonists are that it is mediated by the generation from arginine o f nitric oxide, which is then released into the extracellular space, d iffuses to the vascular smooth muscle, and activates soluble guanylate cyclase by combining with the iron of the heme component of the enzym e. Results and Conclusions: Recent studies show that in the cerebral c irculation these traditional concepts need to be modified in two major areas. First, the activation of soluble guanylate cyclase by nitric o xide, nitroglycerin, or nitroprusside is indirectly mediated via relea se of calcitonin gene-related peptide from sensory nerve fibers. This peptide then activates soluble guanylate cyclase by an unknown mechani sm. Second, the endothelium-derived relaxing factor from cerebral arte rioles is not nitric oxide but a nitric oxide-containing compound, ver y likely a nitrosothiol. Nitrosothiols activate soluble guanylate cycl ase in cerebral arterioles by direct action independent of calcitonin gene-related peptide. The participation of nitric oxide, nitrosothiols , or both in the regulation of basal cerebral vascular tone, in flow-d ependent dilation, in the vascular responses to CO2, and in response t o activation of the N-methyl-D-aspartic acid receptor are considered.