Mitochondrial ATP-Sensitive Potassium Channel Plays a Dominant Role in Ischemic Preconditioning of Rabbit Heart

Abstract

Background: The ATP-sensitive potassium (K_ATP) channel has been shown to be important in the ischemic preconditioning (IPC) response. Recently, the mitochondrial rather than the sarcolemmal K_ATP channel has been focused on due to its energy-modulating property. Hence, this study was undertaken to elucidate the role of the mitochondrial K_ATP channel in IPC by modulating the mitochondrial K_ATP channel in isolated perfused rabbit hearts. Methods: Seven hearts served as a control with no interventions. Seven hearts underwent IPC consisting of two 5-min cycles of global ischemia followed by 5 min of reperfusion. Seven hearts received the selective mitochondrial K_ATP channel blocker 5-dehydroxydecanoate (5-HD, 100 µM) for 5 min before IPC, and 7 hearts received the selective mitochondrial K_ATP channel opener diazoxide (50 µM) for 5 min. Then, all hearts were subjected to 1 h of left anterior descending coronary artery ischemia and 1 h of reperfusion. Left ventricular pressures, monophasic action potentials and coronary flow were measured throughout the experiment and infarct size was detected at the end of experiment. Results: (1) The mitochondria-selective K_ATP channel opener diazoxide reduced infarct size as compared to control (p < 0.05); (2) IPC reduced infarct size and preserved postischemic diastolic function as compared to control (p < 0.05), and (3) the mitochondria-selective K_ATP channel blocker 5-HD reversed these effects. Conclusion: The mitochondrial ATP-sensitive potassium channel may be a potential site of cardioprotection.

In Vivo Characterization of the Mitochondrial Selective KATPOpener (3R)-trans-4-((4-Chlorophenyl)-N-(1H-imidazol-2-ylmethyl)dimethyl-2H-1-benzopyran-6-carbonitril Monohydrochloride (BMS-191095): Cardioprotective, Hemodynamic, and Electrophysiological Effects

“…Nonselective K ATP openers such as bimakalim also opened mitochondrial channels (Garlid et al, 1996), although this occurred within the dose range where sarcolemmal activation was observed. Mitochondrial K ATP have been shown to be important in mediating pharmacological cardioprotection and preconditioning (Liu et al, 1998;Nakai et al, 2001) BMS-191095 was shown to be highly selective for mitochondrial K ATP and has no effects on smooth muscle or pancreatic cells (Grover et al, 2001). Although this compound is of great interest, only in vitro and ex vivo (Langendorff hearts) studies have been reported previously.…”

“…Numerous K ATP subtypes exist and seem to be differentially expressed in various tissues (Inoue et al, 1991;Atwal et al, 1993;Grover et al, 1995a;Chutkow et al, 1996;Inagaki et al, 1996). Pharmacological data suggest that mitochondrial K ATP activation is critical for cardioprotection and that this channel is distinct from sarcolemmal channels (Garlid et al, 1996(Garlid et al, , 1997Liu et al, 1998;Nakai et al, 2001). Clear pharmacological separation between smooth muscle relaxation and cardioprotection has been reported for several K ATP openers such as BMS-180448 and BMS-191095 (Atwal et al, 1993;Grover et al, 1995bGrover et al, , 2001Rovnyak et al, 1997) (chemical structures shown in Fig.…”

The Protective Effect of Mitochondrial ATP-Sensitive K+ Channel Opener, Nicorandil, Combined With Na+/Ca2+ Exchange Blocker KB-R7943 on Myocardial Ischemia–Reperfusion Injury in Rat

“…Recent studies indicate a protective effect of mitochondrial ATP-sensitive K ? channel rather than sarcolemmal sarcK ATP channel opening on myocardial ischemiareperfusion injury [2][3][4][5]. The K ATP channel from cardiac myocyte mitochondria has been reported to be 2000 times more sensitive to diazoxide than the cardiomyocyte sarcolemmal K ATP channels, indicative of the fact that two distinct receptor subtypes coexist within the cardiomyocyte.…”

Is the sarcolemmal or mitochondrial KATP channel activation important in the antiarrhythmic and cardioprotective effects during acute ischemia/reperfusion in the intact anesthetized rabbit model?

“…Thus, it is thought that K ATP channels exert a protective property in myocardial ischemic diseases (Fujita and Kurachi, 2000). Recent studies hint that mitochondrial K ATP channel opening rather than sarcolemmal (surface) K ATP channel opening may play a dominant role in affording cardioprotection in ischemic hearts due to its energy-modulating property (Liu et al, 1998;Garlid et al, 1997Garlid et al, , 1996Nakai et al, 2001). The K ATP channel from cardiac myocyte mitochondria has been reported to be 2000 times more sensitive to diazoxide than the cardiomyocyte sarcolemmal K ATP channels, indicative of the fact that two distinct receptor subtypes coexist within the cardiomyocyte (Liu et al, 1998;Garlid et al, 1997Garlid et al, , 1996.…”