Copyright © 2005, European Society of Cardiology
Kir6.2-deficient mice are susceptible to stimulated ANP secretion: KATP channel acts as a negative feedback mechanism?
aDepartment of Pharmacology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
bDepartment of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
* Corresponding author. Tel.: +81 43 226 2051; fax: +81 43 226 2052. Email address: nakaya{at}faculty.chiba-u.jp
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+ (KATP) channel modulates the secretion of ANP, using mice with homozygous knockout of the Kir6.2 (a pore-forming subunit of cardiac KATP channel) gene.
Methods: KATP 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 µM) evoked a glibenclamide-sensitive KATP 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 KATP channel current in atrial cells from WT but not Kir6.2 KO mice.
Conclusions: Kir6.2 is essential for the function of KATP channel in mouse atrial cells. Given that Kir6.2 KO mice are susceptible to stretch-induced secretion of ANP, our results suggest that KATP channels may act as a negative feedback mechanism for the control of ANP secretion.
KEYWORDS Natriuretic peptide; K-ATP channel; Myocytes
Time for primary review 21 days
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