title: Ouabain inhibits tubuloglomerular feedback in mutant mice with ouabain-sensitive alpha1 Na,K-ATPase.
abstract: Initiation of tubuloglomerular feedback (TGF) depends on Na-K-2Cl co-transport in the macula densa (MD), but it is less clear whether Na,K-ATPase is responsible for establishing the inward Na+ gradient. It has been proposed that apical colonic H,K-ATPase, perhaps in concert with the Na/H exchanger (NHE2), may account for MD Na+ exit in these cells. This study evaluated TGF responses by micropuncture in mutant mice with altered ouabain sensitivity of the alpha1 and alpha2 Na,K-ATPase isoforms. TGF responses in alpha1-sensitive/alpha2-resistant mice were inhibited by intravenous ouabain (control stop-flow pressure = 9.7 +/- 0.9 versus 1.6 +/- 0.5 mmHg with intravenous ouabain). Subsequent inclusion of cyclohexyladenosine (10 microM) in the tubule perfusate confirmed the ability of the afferent arteriole to contract in the presence of ouabain. In alpha1-resistant/alpha2-resistant mice, ouabain infusion had no effect on TGF responses. In separate experiments, loop of Henle perfusion with 50 microM ouabain decreased TGF responses (control stop-flow pressure) from 10.5 +/- 1.1 to 3.9 +/- 1.0 mmHg in alpha1-sensitive/alpha2-resistant mice but had no effect in alpha1-resistant/alpha2-resistant mice, and afferent arteriole responsiveness again was confirmed by cyclohexyladenosine. TGF responses in NHE2 and colonic H,K-ATPase knockout mice were not different from those of wild-type mice. These data indicate that TGF requires activity of the alpha1 Na,K-ATPase, presumably in the MD. Furthermore, the data show that neither NHE2 nor colonic H,K-ATPase is essential for initiation of TGF responses.
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0576, USA. john.lorenz@ucmail.uc.edu
authors.forename: John N
authors.initials: JN
authors.lastname: Lorenz
authors.forename: Iva
authors.initials: I
authors.lastname: Dostanic-Larson
authors.forename: Gary E
authors.initials: GE
authors.lastname: Shull
authors.forename: Jerry B
authors.initials: JB
authors.lastname: Lingrel
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001826:Body Fluids / Q000502:physiology; D025461:Feedback, Physiological / Q000187:drug effects; D017506:H(+)-K(+)-Exchanging ATPase / Q000502:physiology; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007678:Kidney Glomerulus / Q000187:drug effects / Q000502:physiology*; D007686:Kidney Tubules, Distal / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010042:Ouabain / Q000494:pharmacology*; D021122:Protein Subunits / Q000037:antagonists & inhibitors; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*
chemical_list: D007527:Isoenzymes; D021122:Protein Subunits; C513111:Slc9a2 protein, mouse; D017923:Sodium-Hydrogen Exchangers; C027513:N(6)-cyclohexyladenosine; D010042:Ouabain; D017506:H(+)-K(+)-Exchanging ATPase; D000254:Sodium-Potassium-Exchanging ATPase; D000241:Adenosine