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

Gábor Kisvári, Mária Kovács, György Seprényi, A. Végh

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 25 min 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 (0.1 mg/kg), were now received wortmannin (1.5 mg/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.

Original languageEnglish
Pages (from-to)185-194
Number of pages10
JournalEuropean Journal of Pharmacology
Volume769
DOIs
Publication statusPublished - Dec 15 2015

Fingerprint

Simvastatin
Phosphatidylinositol 3-Kinases
Reperfusion
Cardiac Arrhythmias
Ischemia
Dogs
Nitric Oxide Synthase Type III
Nitric Oxide
Ventricular Fibrillation
Nitrites
Dimethyl Sulfoxide
Superoxides
Nitrates
Coronary Vessels
Phosphorylation
wortmannin

Keywords

  • Arrhythmias
  • Ischaemia/reperfusion
  • Nitric oxide
  • Simvastatin
  • Wortmannin

ASJC Scopus subject areas

  • Pharmacology

Cite this

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. / Kisvári, Gábor; Kovács, Mária; Seprényi, György; Végh, A.

In: European Journal of Pharmacology, Vol. 769, 15.12.2015, p. 185-194.

Research output: Contribution to journalArticle

@article{c59b905ebdf44999ada37479afd94601,
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 25 min 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 (0.1 mg/kg), were now received wortmannin (1.5 mg/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.",
keywords = "Arrhythmias, Ischaemia/reperfusion, Nitric oxide, Simvastatin, Wortmannin",
author = "G{\'a}bor Kisv{\'a}ri and M{\'a}ria Kov{\'a}cs and Gy{\"o}rgy Sepr{\'e}nyi and A. V{\'e}gh",
year = "2015",
month = "12",
day = "15",
doi = "10.1016/j.ejphar.2015.11.016",
language = "English",
volume = "769",
pages = "185--194",
journal = "European Journal of Pharmacology",
issn = "0014-2999",
publisher = "Elsevier",

}

TY - JOUR

T1 - 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

AU - Kisvári, Gábor

AU - Kovács, Mária

AU - Seprényi, György

AU - Végh, A.

PY - 2015/12/15

Y1 - 2015/12/15

N2 - 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 25 min 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 (0.1 mg/kg), were now received wortmannin (1.5 mg/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.

AB - 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 25 min 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 (0.1 mg/kg), were now received wortmannin (1.5 mg/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.

KW - Arrhythmias

KW - Ischaemia/reperfusion

KW - Nitric oxide

KW - Simvastatin

KW - Wortmannin

UR - http://www.scopus.com/inward/record.url?scp=84949104531&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84949104531&partnerID=8YFLogxK

U2 - 10.1016/j.ejphar.2015.11.016

DO - 10.1016/j.ejphar.2015.11.016

M3 - Article

VL - 769

SP - 185

EP - 194

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

ER -