TY - JOUR
T1 - Carbachol inhibits Na+ -K+ -ATPase activity in choroid plexus via stimulation of the NO/cGMP pathway
AU - Ellis, Dorette Z.
AU - Nathanson, James A.
AU - Sweadner, Kathleen J.
PY - 2000
Y1 - 2000
N2 - 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 (NO), which plays important roles in fluid homeostasis. The inhibition of Na+-K+-ATPase was blocked by the NO synthase inhibitor [N(ω)-nitro-L-arginine 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 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase. Inhibition was mimicked by the protein kinase G activator 8-bromo-cGMP and by okadaic acid, an inhibitor of protein phosphatases 1 and 2A. cGMP-dependent protein kinase inhibitors Rp-8-pCPT-cGMP (0.5-5 μM) and KT-5823 (2.0 μM) did not block the effects of SNP, but higher concentrations of the more selective inhibitor (Rp-8-pCPT-cGMP) had a pharmacological inhibitory effect on Na+-K+-ATPase. The data suggest that cholinergic regulation of the Na+-K+-ATPase is mediated by NO and involves activation of guanylate cyclase and elevation of cGMP.
AB - 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 (NO), which plays important roles in fluid homeostasis. The inhibition of Na+-K+-ATPase was blocked by the NO synthase inhibitor [N(ω)-nitro-L-arginine 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 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase. Inhibition was mimicked by the protein kinase G activator 8-bromo-cGMP and by okadaic acid, an inhibitor of protein phosphatases 1 and 2A. cGMP-dependent protein kinase inhibitors Rp-8-pCPT-cGMP (0.5-5 μM) and KT-5823 (2.0 μM) did not block the effects of SNP, but higher concentrations of the more selective inhibitor (Rp-8-pCPT-cGMP) had a pharmacological inhibitory effect on Na+-K+-ATPase. The data suggest that cholinergic regulation of the Na+-K+-ATPase is mediated by NO and involves activation of guanylate cyclase and elevation of cGMP.
KW - Guanosine 3',5'-cyclic monophosphate
KW - Nitric oxide
UR - http://www.scopus.com/inward/record.url?scp=0033638906&partnerID=8YFLogxK
U2 - 10.1152/ajpcell.2000.279.6.c1685
DO - 10.1152/ajpcell.2000.279.6.c1685
M3 - Article
C2 - 11078682
AN - SCOPUS:0033638906
SN - 0363-6143
VL - 279
SP - C1685-C1693
JO - American Journal of Physiology - Cell Physiology
JF - American Journal of Physiology - Cell Physiology
IS - 6 48-6
ER -