title: Reduced susceptibility to ischemia-induced arrhythmias in the preconditioned rat heart is independent of PI3-kinase/Akt.
abstract: We examined the involvement of phosphatidylinositol 3-kinase (PI3K) and its effector protein kinase B (Akt) in cardioprotective effects of ischemic preconditioning (PC) with particular regards to its role in the protection against ischemia-induced arrhythmias in isolated perfused rat heart. PI3K/Akt inhibitor wortmannin (100 nM) was administered 15 min prior to 30-min regional (left anterior descending coronary artery occlusion) ischemia for the study of ischemic arrhythmias in the hearts perfused at constant coronary flow or prior to 30-min global ischemia followed by 2-h reperfusion for the infarct size (IS) determination (tetrazolium staining) in the hearts perfused at constant pressure. PC procedure (one cycle of ischemia/reperfusion, 5 min each) significantly reduced the total number of ventricular premature complexes (PVC) and severity of arrhythmias (arrhythmia score; AS) over the whole period of left anterior descending coronary artery occlusion in comparison with non-PC controls (PVC 166+/-40; AS 1.6+/-0.2 vs. 550+/-60 and 3.2+/-0.2; respectively; P<0.05). In a setting of global ischemia/reperfusion, PC decreased IS (in % of the left ventricle, LV) by 73 %. Pretreatment with wortmannin modified neither arrhythmogenesis nor IS in the non-PC hearts. Bracketing of PC with wortmannin did not abolish antiarrhythmic protection (PVC 92+/-25; AS 1.7+/-0.2; P<0.05 vs. non-PC hearts). On the other hand, wortmannin increased IS/LV in the PC hearts to 24+/-1.2 % as compared with 9 +/- 0.6 % in the untreated ones (P<0.05). In conclusion, PI3K/Akt inhibition did not affect reduced arrhythmogenesis during ischemia in the PC hearts indicating that in contrast to its positive role in the irreversible myocardial injury, PI3K/Akt activity is not required for protection induced by PC against ischemic arrhythmias in the rat heart.
authors.affiliation: Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovak Republic. usrdravi@savba.sk
authors.forename: T
authors.initials: T
authors.lastname: Ravingerova
authors.forename: J
authors.initials: J
authors.lastname: Matejikova
authors.forename: D
authors.initials: D
authors.lastname: Pancza
authors.forename: F
authors.initials: F
authors.lastname: Kolar
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000150:complications / Q000201:enzymology / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010477:Perfusion; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin