a b s t r a c tThe present study has examined the effects and the possible mechanisms of a single dose of simvastatin on the severity of arrhythmias resulting from a 25 min occlusion and reperfusion of the left anterior descending coronary artery in anaesthetized (chloralose and urethane) dogs. The control animals (n ¼16) were given the solvent of simvastatin by slow (over 5 min) intracoronary (ic.) injection just prior to the occlusion. Twenty-six dogs were treated with simvastatin (0.1 mg/kg) by the same route, both in the absence (n ¼15) and in the presence (n ¼11) of L-NAME. This latter was administered (5 mg/kg, ic.) either alone (n ¼12) or 10 min before the simvastatin treatment. The severity of ischaemia (epicardial STsegment, inhomogeneity) and ventricular arrhythmias (ventricular premature beats [VPBs], ventricular tachycardia [VT] and fibrillation [VF]), plasma nitrite/nitrate levels, myocardial superoxide production and eNOS activity were assessed. Compared with controls simvastatin significantly reduced the number of VPBs (289 7 34 vs. 947 25) and the episodes of VT (5.67 1.3 vs. 0.3 70.2), the incidence of VT (88% vs. 20%) and VF (56% vs. 0%) during occlusion and increased survival (0% vs. 33%) on reperfusion. There were also less marked ischaemic changes in the simvastatin-treated dogs than in the controls. Simvastatin preserved eNOS activity and nitric oxide (NO) bioavailability during occlusion and attenuated superoxide production following reperfusion. All these effects of simvastatin (except for the protection against VF) were reversed by L-NAME. We conclude that simvastatin given just prior to ischaemia/reperfusion reduces the severity of arrhythmias. This effect involves both NO-dependent and NO-independent mechanisms.

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.

No abstract

No abstract

SUMMARYVentricular tachyarrhythmia is one of the main causes responsible for sudden cardiac death. The prevention and treatment of these severe tachyarrhythmias is still remained a big challenge of cardiology in the industrialized countries. There is increasing evidence that statins, which represent the first-line therapy for hyperlipidaemia, may possess lipidindependent pleiotropic actions, which are associated with an increased release of nitric oxide (NO) through the activation of eNOS, and contribute to cardioprotection following chronic statin treatment. There is lack of evidence, however, whether statins administered acutely influence the severity of arrhythmias, resulting from ischaemia and reperfusion (I/R).Therefore, the aim of the present study was to examine the effects and mechanisms of acute statin administration on arrhythmias resulting from a 25 min coronary artery occlusion and reperfusion (I/R) in chloralose/urethane anaesthetized dogs. In a group of dogs activated simvastatin (0.1 mg/kg) was administrated in slow intracoronary injection just prior to the occlusion of the left anterior descending coronary artery. The severity of ischaemia (degree of inhomogeneity of electrical activation, epicardial ST-segment) and of arrhythmias, as well as the plasma NOx levels in blood samples taken from the coronary sinus were assessed. From the myocardial tissue samples the activity of eNOS (Western blot) and superoxide production (confocal microscopy) were determined.We have shown that compared to the control group, in which the dogs were treated only with the solvent of simvastatin, the administration of simvastatin significantly decreased the severity of ischaemia and of ventricular arrhythmias, increased the activity of eNOS and the plasma concentration of NO metabolites, and significantly reduced the production of superoxide during reperfusion. We have also pointed out that the protective effects of simvastatin are mediated through the rapid activation of eNOS, most probably via the stimulation of PI-3 kinase/Akt pathway, since the inhibition of NOS by L-NAME, and the inhibition PI-3 kinase by wortmannin abolished the protective effects of simvastatin.Thus we conclude that the antiarrhythmic effect of acute simvastatin administration can certainly be associated with an increased NO bioavailability during occlusion, due to the rapid activation of eNOS via the stimulation of the PI3/Akt pathway by simvastatin.