Role of sarcolemmal K(ATP) channels in cardioprotection against ischemia/reperfusion injury in mice.
Recently it has been postulated that mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channels rather than sarcolemmal K(ATP) (sarcK(ATP)) channels are important as end effectors and/or triggers of ischemic preconditioning (IPC). To define the pathophysiological significance of sarcK(ATP) channels, we conducted functional experiments using Kir6.2-deficient (KO) mice. Metabolic inhibition with glucose-free, dinitrophenol-containing solution activated sarcK(ATP) current and shortened the action potential duration in ventricular cells isolated from wild-type (WT) but not KO mice. MitoK(ATP) 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 sarcK(ATP) channel blocker, but not 5-hydroxydecanoate, a mitoK(ATP) 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 sarcK(ATP) channels during ischemia, prompting caution in the extrapolation of the conclusions to larger mammals.
Suzuki
Masashi
M
Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan.
Sasaki
Norihito
N
Miki
Takashi
T
Sakamoto
Naoya
N
Ohmoto-Sekine
Yuki
Y
Tamagawa
Masaji
M
Seino
Susumu
S
Marbán
Eduardo
E
Nakaya
Haruaki
H
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D003652:Decanoic Acids / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism*
D001549:Benzamides; D003652:Decanoic Acids; D006880:Hydroxy Acids; D024661:Potassium Channels, Inwardly Rectifying; C052853:5-hydroxydecanoic acid; C410297:HMR 1098