Carbachol inhibits Na+-K+-ATPase activity in choroid plexus via stimulation of the NO/cGMP pathway

Secretion of cerebrospinal fluid by the choroid plexus can be inhibited by its cholinergic innervation. We demonstrated that carbachol inhibits the Na + -K+-ATPase in bovine choroid tissue slices and investigated the mechanism . Many of the actions of cholinergic agents are mediated by nitric oxide (N O), which plays important roles in fluid homeostasis. The inhibition of Na-K+-ATPase was blocked by the NO synthase inhibitor [N-omega-nitro-L-argini ne methyl ester] and was quantitatively mimicked by the NO agonists sodium nitroprusside (SNP) and diethylenetriamine NO. Inhibition by SNP correlated with an increase in tissue cGMP and was abolished by H-1-[1,2,4] oxadiazol o[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase. Inhibi tion was mimicked by the protein kinase G activator 8-bromo-cGMP and by oka daic acid, an inhibitor of protein phosphatases 1 and 2A. cGMP-dependent pr otein kinase inhibitors Rp-8-pCPT-cGMP (0.5-5 muM) and KT-5823 (2.0 mM) did not block the effects of SNP, but higher concentrations of the more select ive inhibitor (Rp-8-pCPT-cGMP) had a pharmacological inhibitory effect on N a+-K+-ATPase. The data suggest that cholinergic regulation of the Na+-K+-AT Pase is mediated by NO and involves activation of guanylate cyclase and ele vation of cGMP.