Inhibition of Na(+)/K(+)-atpase by endothelin-1 in human nonpigmented ciliary epithelial cells.
Endothelin-1 (ET-1), a potent vasoconstrictor, lowers intraocular pressure in mammals, either by enhancing the outflow of aqueous humor (AH) via the trabecular meshwork and Schlemm's canal or by reducing AH formation at the ciliary epithelium. Aqueous humor production occurs by passive diffusion of water coupled with active transport of ions, mainly involving Na(+):K(+):2Cl(-) cotransporter and Na(+)/K(+)-ATPase pump from serosal to aqueous side. Presently, we have evaluated the effects of ET-1 on Na(+):K(+):2Cl(-) cotransport and Na(+)/K(+)-ATPase activity in HNPE cells using (86)Rb(+) uptake. ET-1 (100 pM-100 nM) decreased mean (86)Rb(+) uptake by 15% during a 15-min uptake period. ET-1's effect was not prevented by BQ610, an ET(A) receptor antagonist, but was blocked by BQ788, an ET(B) receptor antagonist. ET-1's effect was mimicked by sarafotoxin, an ET(B) agonist. ET-1-induced reduction in (86)Rb(+) uptake was additive with bumetanide, a selective inhibitor of Na(+):K(+):2Cl(-) cotransporter but not with ouabain, a selective inhibitor of the Na(+)/K(+)-ATPase. ET-1 did not affect iberiotoxin-sensitive maxi K(+) channels. This suggests that ET-1-induced reduction in (86)Rb(+) uptake is mediated through the inhibition of the Na(+)/K(+)-ATPase via an ET(B)-like receptor. These findings are consistent with an ET-1 effect on active ion transport activity in HNPE cells that could explain the reduction in aqueous humor production and the lowering of intraocular pressure.
Prasanna
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G
Department of Pharmacology, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA. gprasann@molly.hsc.unt.edu
Dibas
A
A
Hulet
C
C
Yorio
T
T
D000959:Antihypertensive Agents / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002034:Bumetanide / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D002924:Ciliary Body / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004232:Diuretics / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D009842:Oligopeptides / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010857:Pigment Epithelium of Eye / Q000187:drug effects* / Q000201:enzymology; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012413:Rubidium / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013997:Time Factors
D000959:Antihypertensive Agents; D002352:Carrier Proteins; D004232:Diuretics; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D009842:Oligopeptides; D010455:Peptides; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D028021:Sodium-Potassium-Chloride Symporters; D002034:Bumetanide; C087220:BQ 610; C086539:BQ 788; D010042:Ouabain; C064719:iberiotoxin; D000254:Sodium-Potassium-Exchanging ATPase; D012413:Rubidium