Mitochondrial KATP opening confers protection against lethal myocardial injury and ischaemia-induced arrhythmias in the rat heart via PI3K/Akt-dependent and -independent mechanisms.
Opening of mitochondrial KATP channels (mitoKATP) has been reported to underlie protection against ischaemia-reperfusion injury induced by ischaemic preconditioning (I-PC); however, the molecular mechanisms of its antiarrhythmic effect have not been fully elucidated. We explored the involvement of phosphatidylinositol 3-kinase (PI3K)/Akt in the PC-like effect of mitoKATP opener diazoxide with particular regard to its role in protection against ischaemia-induced arrhythmias. Langendorff-perfused rat hearts were subjected to 30 min LAD occlusion with or without a prior 15 min of perfusion with diazoxide (50 micromol/L) given either alone (D-PC) or in combination with the PI3K/Akt inhibitor wortmannin (100 nmol/L). In an additional protocol, ischaemia was followed by 2 h reperfusion for infarct size (IS) determination (tetrazolium staining). The total number of premature ventricular complexes over the whole period of ischaemia, episodes of ventricular tachycardia and its duration were significantly lower in the D-PC group than in the non-preconditioned controls (158 +/- 20, 2 +/- 0.6 and 4.6 +/- 1.8 s vs. 551 +/- 61, 11 +/- 2 and 42 +/- 8 s, respectively; p < 0.05), concomitant with a 62% reduction in the size of infarction. Wortmannin modified neither arrhythmogenesis nor IS in the non-preconditioned hearts. Bracketing of diazoxide with wortmannin did not reverse the antiarrhythmic protection, whereas the IS-limiting effect was blunted. The results indicate that in contrast with the positive role of PI3K/Akt in protection against lethal myocardial injury, its activity is not involved in suppression of ischaemia-induced arrhythmias conferred by mitoKATP opening in the rat heart.
Matejíková
Jana
J
Institute for Heart Research, Slovak Academy of Sciences, Centre of Excellence for Cardiovascular Research, Bratislava, Slovak Republic. usrdjama@savba.sk
Ravingerová
Tána
T
Pancza
Dezider
D
Carnická
Slávka
S
Kolár
Frantisek
F
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000503:physiopathology*; D003981:Diazoxide / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000502:physiology*; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000502:physiology*; D015221:Potassium Channels / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D015221:Potassium Channels; D047428:Protein Kinase Inhibitors; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D003981:Diazoxide; D000077191:Wortmannin