title: The activation of PI 3-kinase/Akt pathway is involved in the acute effects of simvastatin against ischaemia and reperfusion-induced arrhythmias in anaesthetised dogs.
abstract: The objective of this study was to examine whether the PI3-kinase/Akt pathway is involved in the activation of endothelial nitric oxide synthase (eNOS) and in the subsequent increase of nitric oxide (NO) production that has been proved to play a role in the antiarrhythmic effect of acute simvastatin treatment in anaesthetised dogs, subjected to a 25min occlusion and reperfusion of the left anterior descending coronary artery. Using the same model, 12 dogs out of the 26 controls (given the solvent of simvastatin) and 11 dogs out of the 23 animals treated with intracoronary administered simvastatin (0.1mg/kg), were now received wortmannin (1.5mg/kg, ic.), a selective inhibitor of PI3-kinase. In another 13 dogs the effects of DMSO (0.1%), the vehicle of wortmannin, were examined. Compared to the controls, simvastatin markedly reduced the severity of ischaemia (epicardial ST-segment, inhomogeneity) and ventricular arrhythmias that were reversed (except the occlusion-induced ventricular fibrillation [VF; 50%, 0%, 0%]) by the administration of wortmannin. Thus in these groups there were 310±45, 62±14, 307±59 ectopic beats, 7.1±1.4, 0.3± 0.2, 4.3±1.3 tachycardiac episodes that occurred 93%, 17% and 73% of the dogs during occlusion, whereas survival following reperfusion was 0%, 67% and 0%, respectively. Simvastatin also increased the phosphorylation of eNOS and the plasma nitrate/nitrite levels, but reduced myocardial superoxide production on reperfusion. These effects of simvastatin were also abolished in the presence of wortmannin. We conclude that the NO-dependent antiarrhythmic effect of simvastatin involves the rapid activation of eNOS through the stimulation of the PI3-kinase/Akt pathway.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Szeged, Albert-Szent Györgyi Medical Centre, Szeged, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Kisvári
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Szeged, Albert-Szent Györgyi Medical Centre, Szeged, Hungary.
authors.forename: Mária
authors.initials: M
authors.lastname: Kovács
authors.affiliation: Department of Medical Biology, University of Szeged, Albert-Szent Györgyi Medical Centre, Szeged, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Seprényi
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Szeged, Albert-Szent Györgyi Medical Centre, Szeged, Hungary. Electronic address: vegh.agnes@med.u-szeged.hu.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Végh
mesh_terms: D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D004285:Dogs; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000150:complications*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
chemical_list: D000889:Anti-Arrhythmia Agents; D013481:Superoxides; D009569:Nitric Oxide; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Arrhythmias; Ischaemia/reperfusion; Nitric oxide; Simvastatin; Wortmannin