Kir6.2-deficient mice are susceptible to stimulated ANP secretion:: KATP channel acts as a negative feedback mechanism?

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 radio immunoassay. Action potentials were recorded from the isolated atria. Results: Exposure to 2,4-dinitrophenol (100 mu M) 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. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.