TY - JOUR
T1 - Role of sarcolemmal KATP channels in cardioprotection against ischemia/reperfusion injury in mice
AU - Suzuki, Masashi
AU - Sasaki, Norihito
AU - Miki, Takashi
AU - Sakamoto, Naoya
AU - Ohmoto-Sekine, Yuki
AU - Tamagawa, Masaji
AU - Seino, Susumu
AU - Marbán, Eduardo
AU - Nakaya, Haruaki
PY - 2002
Y1 - 2002
N2 - Recently it has been postulated that mitochondrial ATP-sensitive K+ (mitoKATP) channels rather than sarcolemmal KATP (sarcKATP) channels are important as end effectors and/or triggers of ischemic preconditioning (IPC). To define the pathophysiological significance of sarcKATP channels, we conducted functional experiments using Kir6.2-deficient (KO) mice. Metabolic inhibition with glucose-free, dinitrophenol-containing solution activated sarcKATP current and shortened the action potential duration in ventricular cells isolated from wild-type (WT) but not KO mice. MitoKATP channel function was preserved in KO ventricular cells. In anesthetized mice, IPC reduced the infarct size in WT but not KO mice. Following global ischemia/reperfusion, the increase of left ventricular end-diastolic pressure during ischemia was more marked, and the recovery of contractile function was worse, in KO hearts than in WT hearts. Treatment with HMR1098, a sarcKATP channel blocker, but not 5-hydroxydecanoate, a mitoKATP channel blocker, produced a deterioration of contractile function in WT hearts comparable to that of KO hearts. These findings suggest that sarcKATP channels figures prominently in modulating ischemia/reperfusion injury in the mouse. The rapid heart rate of the mouse (>600 beats per minute) may magnify the relative importance of sarcKATP channels during ischemia, prompting caution in the extrapolation of the conclusions to larger mammals.
AB - Recently it has been postulated that mitochondrial ATP-sensitive K+ (mitoKATP) channels rather than sarcolemmal KATP (sarcKATP) channels are important as end effectors and/or triggers of ischemic preconditioning (IPC). To define the pathophysiological significance of sarcKATP channels, we conducted functional experiments using Kir6.2-deficient (KO) mice. Metabolic inhibition with glucose-free, dinitrophenol-containing solution activated sarcKATP current and shortened the action potential duration in ventricular cells isolated from wild-type (WT) but not KO mice. MitoKATP channel function was preserved in KO ventricular cells. In anesthetized mice, IPC reduced the infarct size in WT but not KO mice. Following global ischemia/reperfusion, the increase of left ventricular end-diastolic pressure during ischemia was more marked, and the recovery of contractile function was worse, in KO hearts than in WT hearts. Treatment with HMR1098, a sarcKATP channel blocker, but not 5-hydroxydecanoate, a mitoKATP channel blocker, produced a deterioration of contractile function in WT hearts comparable to that of KO hearts. These findings suggest that sarcKATP channels figures prominently in modulating ischemia/reperfusion injury in the mouse. The rapid heart rate of the mouse (>600 beats per minute) may magnify the relative importance of sarcKATP channels during ischemia, prompting caution in the extrapolation of the conclusions to larger mammals.
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U2 - 10.1172/JCI200214270
DO - 10.1172/JCI200214270
M3 - Article
C2 - 11854323
AN - SCOPUS:0036179325
SN - 0021-9738
VL - 109
SP - 509
EP - 516
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 4
ER -