Role of mitochondrial KATP channels and protein kinase C in ischaemic preconditioning.
1. Activation of mitochondrial KATP (mitoKATP) channels and protein kinase C (PKC) has been implicated in cardioprotective mechanisms of ischaemic preconditioning (IPC). However, the exact role of these events in early IPC remains unclear. 2. Isolated and perfused rat hearts underwent IPC with three cycles of 5 min ischaemia and 5 min reperfusion. The heart was subjected to 30 min global ischaemia followed by 120 min reperfusion. Flavoprotein oxidation was monitored to assess mitoKATP channel activity. Cardioprotection was evaluated by recovery of isovolumic left ventricular (LV) function and infarct size. 3. Diazoxide (50 mgr;mol/L) increased flavoprotein oxidation and conferred cardioprotection in a manner sensitive to the selective mitoKATP channel blocker 5-hydroxydecanoate (5-HD; 0.5 mmol/L). 4. Pretreatment with 0.5 mmol/L 5-HD abrogated IPC-induced flavoprotein oxidation and cardioprotection, whereas late treatment with 5-HD after IPC required a higher dose (2 mmol/L) to abolish flavoprotein oxidation and cardioprotection afforded by IPC. 5. Pretreatment with the PKC inhibitors Ro318425 (1 micro mol/L) and chelerythrine (5 micro mol/L) abolished IPC-induced flavoprotein oxidation and cardioprotection, whereas late treatment with Ro318425 required a higher dose (4 micro mol/L) to abolish flavoprotein oxidation and cardioprotection. 6. In conclusion, these results suggest that activation of mitoKATP channels is the trigger and the mediator of IPC and that PKC plays a crucial role in both phases of mitoKATP channel activation, although mitoKATP channels and PKC may be more activated during the mediator phase.
Uchiyama
Yuka
Y
Departments of Anaesthesiology and Thoracic and Cardiovascular Surgery, Kansai Medical University, Moriguchi City, Japan.
Otani
Hajime
H
Wakeno
Mayu
M
Okada
Takayuki
T
Uchiyama
Takamichi
T
Sumida
Tomohiko
T
Kido
Masakuni
M
Imamura
Hiroji
H
Nakao
Shinichi
S
Shingu
Koh
K
D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels / Q000502:physiology*; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000517:prevention & control*; D015221:Potassium Channels; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; C015482:protein kinase modulator; D011493:Protein Kinase C