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.

ArrhythmoGenoPharmacoTherapy

“…The substantial role and investigation of precise mechanisms of NO, both under physiological or pathological conditions, are not a question of debate in cell signaling and myocardial function. A number of studies show that interventions contributed to NO production via different mechanisms significantly reduced the reperfusion-induced injury including the incidence of arrhythmias (Shen et al, 1998;Kawahara et al, 2003;Imaizumi et al, 2008;Egom et al, 2011;Kisvari et al, 2015;Enayati et al, 2018;Jones et al, 2018). Various protective NO-mediated signal mechanisms, including the mitoK-(ATP) (Kawahara et al, 2003), the nuclear factor erythroid 2-related factor (NrF2), the extracellular-signalingregulated-kinase (ERK) (Imaizumi et al, 2008), and Pak1/Akt1 signaling cascade (Egom et al, 2011) have also been reported.…”

Effect of Ischemic Postconditioning and Atorvastatin in the Prevention of Remote Lung Reperfusion Injury

“…Statins also protect other tissues in the presence of IR, such as heart [ 17 - 19 ] , nervous system [ 20 ] and liver [ 21 ] . In the lung, the efficiency of statins was also demonstrated, as published by Matsuo et al [ 22 ] , however, with a method different from the one used here, since these authors performed IR directly in the pulmonary hilum, thus not being a study of remote protection.…”

Atorvastatin Can Prevent Hepatic Remote Reperfusion Injury

“…Statins also protect other tissues in the presence of IR, such as heart 6 , 9 , 10 , nervous system 5 and lung 14 . The protection mechanism of statin against situations of IR is due to its pleiotropic effect.…”