title: Reduction in number of sarcolemmal KATP channels slows cardiac action potential duration shortening under hypoxia.
abstract: The cardiovascular system operates under demands ranging from conditions of rest to extreme stress. One mechanism of cardiac stress tolerance is action potential duration shortening driven by ATP-sensitive potassium (K(ATP)) channels. K(ATP) channel expression has a significant physiologic impact on action potential duration shortening and myocardial energy consumption in response to physiologic heart rate acceleration. However, the effect of reduced channel expression on action potential duration shortening in response to severe metabolic stress is yet to be established. Here, transgenic mice with myocardium-specific expression of a dominant negative K(ATP) channel subunit were compared with littermate controls. Evaluation of K(ATP) channel whole cell current and channel number/patch was assessed by patch clamp in isolated ventricular cardiomyocytes. Monophasic action potentials were monitored in retrogradely perfused, isolated hearts during the transition to hypoxic perfusate. An 80-85% reduction in cardiac K(ATP) channel current density results in a similar magnitude, but significantly slower rate, of shortening of the ventricular action potential duration in response to severe hypoxia, despite no significant difference in coronary flow. Therefore, the number of functional cardiac sarcolemmal K(ATP) channels is a critical determinant of the rate of adaptation of myocardial membrane excitability, with implications for optimization of cardiac energy consumption and consequent cardioprotection under conditions of severe metabolic stress.
authors.affiliation: Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhu
authors.forename: Colin M-L
authors.initials: CM
authors.lastname: Burnett
authors.forename: Gennadiy
authors.initials: G
authors.lastname: Maksymov
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Stepniak
authors.forename: Ana
authors.initials: A
authors.lastname: Sierra
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Subbotina
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
authors.forename: William A
authors.initials: WA
authors.lastname: Coetzee
authors.forename: Denice M
authors.initials: DM
authors.lastname: Hodgson-Zingman
authors.forename: Leonid V
authors.initials: LV
authors.lastname: Zingman
mesh_terms: D000200:Action Potentials; D000818:Animals; D006321:Heart / Q000503:physiopathology*; D000860:Hypoxia / Q000378:metabolism*; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D010101:Oxygen Consumption; D011188:Potassium / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism*; D019076:Transgenes
chemical_list: D054086:KATP Channels; C092520:uK-ATP-1 potassium channel; D011188:Potassium
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