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 (NO), which plays important roles in fluid homeostasis. The inhibition of Na(+)-K(+)-ATPase was blocked by the NO synthase inhibitor [N(omega)-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 microM) and KT-5823 (2.0 microM) 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.
Ellis
D Z
DZ
Neuroscience Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Nathanson
J A
JA
Sweadner
K J
KJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002217:Carbachol / Q000494:pharmacology*; D002417:Cattle; D018679:Cholinergic Agonists / Q000494:pharmacology*; D002831:Choroid Plexus / Q000187:drug effects / Q000201:enzymology*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006868:Hydrolysis; D066298:In Vitro Techniques; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D010042:Ouabain; D010069:Oxadiazoles / Q000494:pharmacology; D010766:Phosphorylation; D011810:Quinoxalines / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D013873:Thionucleotides / Q000494:pharmacology; D014226:Triazenes / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
C105351:1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene; C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C090860:8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; D018679:Cholinergic Agonists; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D013873:Thionucleotides; D014226:Triazenes; D014665:Vasodilator Agents; D009599:Nitroprusside; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D010042:Ouabain; D000255:Adenosine Triphosphate; D002217:Carbachol; D000254:Sodium-Potassium-Exchanging ATPase; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester