title: Kir6.2-deficient mice are susceptible to stimulated ANP secretion: K(ATP) channel acts as a negative feedback mechanism?
abstract: OBJECTIVE
  While atrial natriuretic peptide (ANP) has been shown to be released mainly from cardiac muscle cells in response to atrial distension, the regulatory mechanisms of ANP secretion are still not fully understood. We sought to determine whether the ATP-sensitive K+ (K(ATP)) channel modulates the secretion of ANP, using mice with homozygous knockout of the Kir6.2 (a pore-forming subunit of cardiac K(ATP) channel) gene.
  
  
  METHODS
  K(ATP) channel currents were recorded from isolated mouse atrial cells with patch-clamp techniques. Plasma ANP concentrations in anesthetized mice and ANP content and secretion in isolated atrial preparations were determined by radioimmunoassay. Action potentials were recorded from the isolated atria.
  
  
  RESULTS
  Exposure to 2,4-dinitrophenol (100 microM) evoked a glibenclamide-sensitive K(ATP) channel current in atrial cells from wild-type (WT) but not Kir6.2 knockout (Kir6.2 KO) mice. Although there were no significant differences in the basal plasma ANP levels between WT and Kir6.2 KO mice, volume expansion caused a significant elevation of plasma ANP concentration in Kir6.2 KO but not WT mice with accompanying hypotension. When isolated left atria were stretched, ANP secreted into the bath from Kir6.2 KO atria was significantly higher than that from WT atria. Furthermore, stretching the atria from WT but not Kir6.2 KO mice significantly shortened the action potential duration. A hypotonic stretch of the membrane induced the glibenclamide-sensitive K(ATP) channel current in atrial cells from WT but not Kir6.2 KO mice.
  
  
  CONCLUSIONS
  Kir6.2 is essential for the function of K(ATP) channel in mouse atrial cells. Given that Kir6.2 KO mice are susceptible to stretch-induced secretion of ANP, our results suggest that K(ATP) channels may act as a negative feedback mechanism for the control of ANP secretion.
authors.affiliation: Department of Pharmacology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Saegusa
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sato
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Saito
authors.forename: Masaji
authors.initials: M
authors.lastname: Tamagawa
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.forename: Haruaki
authors.initials: H
authors.lastname: Nakaya
mesh_terms: D000200:Action Potentials; D000818:Animals; D001011:Aorta; D009320:Atrial Natriuretic Factor / Q000032:analysis / Q000378:metabolism*; D002478:Cells, Cultured; D025461:Feedback, Physiological; D006325:Heart Atria; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D013268:Stimulation, Chemical; D000099161:Kcnj11 Channel
chemical_list: D009320:Atrial Natriuretic Factor; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel