TY - JOUR
T1 - Reduction in number of sarcolemmal K ATP channels slows cardiac action potential duration shortening under hypoxia
AU - Zhu, Zhiyong
AU - Burnett, Colin M.L.
AU - Maksymov, Gennadiy
AU - Stepniak, Elizabeth
AU - Sierra, Ana
AU - Subbotina, Ekaterina
AU - Anderson, Mark E.
AU - Coetzee, William A.
AU - Hodgson-Zingman, Denice M.
AU - Zingman, Leonid V.
N1 - Funding Information:
This work was supported by the National Institutes of Health [ HL092286 to D.H-Z., HL093368 to L.Z., HL085820 to W.A.C.]; The Carver Trust [ 01-224 to D.H-Z. and to L.Z.]; The Central Society for Clinical Research [to D.H-Z.]; and the Fraternal Order of Eagles [to D.H-Z. and L.Z.]
PY - 2011/12/2
Y1 - 2011/12/2
N2 - 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.
AB - 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.
KW - ATP-sensitive potassium channel
KW - Glyburide
KW - Heart
KW - K
KW - Monophasic action potential
UR - http://www.scopus.com/inward/record.url?scp=84855881975&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84855881975&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2011.10.125
DO - 10.1016/j.bbrc.2011.10.125
M3 - Article
C2 - 22079630
AN - SCOPUS:84855881975
SN - 0006-291X
VL - 415
SP - 637
EP - 641
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 4
ER -