title: Acute administration of vitamin E triggers preconditioning via K(ATP) channels and cyclic-GMP without inhibiting lipid peroxidation.
abstract: Vitamin E (VitE) is considered an antioxidant agent. One or more brief periods of ischemia (isc), followed by short reperfusion (rep), increase the tolerance of the heart to a subsequent prolonged ischemia, a phenomenon known as ischemic preconditioning (PC). Mitochondrial KATP channels (mitoKATP), cyclic-GMP (cGMP), and free radicals are involved in the mechanism of PC, whereas some antioxidants abolish this benefit. The purpose of this study was to evaluate the effect of VitE on infarct size, PC, and the oxidative status in vivo. Male rabbits were divided into seven groups and were subjected to myocardial ischemia (isc) and reperfusion (rep) with the following interventions: (1) control (no intervention); (2) E150 (iv VitE at a dose of 150 mg/kg for 75 min, starting 40 min before index isc and lasting through 5 min of rep); (3) E300 (iv VitE 300 mg/kg as previously described); (4) PC (two cycles of 5 min isc and 10 min rep), (5) combined E150-PC; and (6) combined E300-PC. In the last two groups VitE was given 40 min before index ischemia. Blood samples were taken for malondialdehyde (MDA) and conjugated dienes (CDs) measurement. In a second series of experiments heart tissue samples were taken at the time of long ischemia for MDA and CD determination and for cGMP assay. In order to test whether combined treatment with VitE (as the E150 group) and the mitoKATP blocker 5-hydroxydecanoic acid (5-HD) changes the infarct size, an additional group was assessed in the first series of experiments. Tissue VitE concentration was evaluated in myocardium. VitE at both doses reduced the infarct size (19.7 +/- 2.8% for E150 and 18.8 +/- 4.9% for E300 vs 47.4 +/- 2.6% in control, P < 0.05) without attenuating the effect of PC (10.2 +/- 3.1% for E150-PC, 12.4 +/- 2.2% for E300-PC, vs 13.5 +/- 3.3% for PC). Combined VitE and 5-HD treatment abrogates this benefit (37.4 +/- 6.5%, P < 0.05 vs E150 and NS vs control). VitE increases intracellular cGMP and CDs levels (P < 0.05 vs control) to the same extent as PC (P < 0.05 vs control), with no effect on MDA (P = NS between all the groups). Peripheral markers of oxidative stress are increased during reperfusion in all groups (P < 0.05 vs baseline). Overall, VitE limits infarct size via mitoKATP and cGMP, while preserving the benefit of ischemic PC.
authors.affiliation: Second University Department of Cardiology, Medical School, Attikon General Hospital, University of Athens, Rimini 1, 124 62 Athens, Greece. jandread@pharm.uoa.gr
authors.forename: Ioanna
authors.initials: I
authors.lastname: Andreadou
authors.forename: Efstathios K
authors.initials: EK
authors.lastname: Iliodromitis
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Tsovolas
authors.forename: Ioanna-Katerina
authors.initials: IK
authors.lastname: Aggeli
authors.forename: Anastasia
authors.initials: A
authors.lastname: Zoga
authors.forename: Catherine
authors.initials: C
authors.lastname: Gaitanaki
authors.forename: Ioannis A
authors.initials: IA
authors.lastname: Paraskevaidis
authors.forename: Sophia L
authors.initials: SL
authors.lastname: Markantonis
authors.forename: Isidoros
authors.initials: I
authors.lastname: Beis
authors.forename: Dimitrios Th
authors.initials: DT
authors.lastname: Kremastinos
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D023421:Models, Animal; D009206:Myocardium / Q000737:chemistry; D015221:Potassium Channels / Q000378:metabolism*; D011817:Rabbits; D014810:Vitamin E / Q000008:administration & dosage* / Q000494:pharmacology*
chemical_list: D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D014810:Vitamin E; D008315:Malondialdehyde; D006152:Cyclic GMP