title: The effect of acute simvastatin administration on the severity of arrhythmias resulting from ischaemia and reperfusion in the canine: Is there a role for nitric oxide?
abstract: The present study has examined the effects and the possible mechanisms of a single dose of simvastatin on the severity of arrhythmias resulting from a 25min occlusion and reperfusion of the left anterior descending coronary artery in anaesthetized (chloralose and urethane) dogs. The control animals (n=16) were given the solvent of simvastatin by slow (over 5min) intracoronary (ic.) injection just prior to the occlusion. Twenty-six dogs were treated with simvastatin (0.1mg/kg) by the same route, both in the absence (n=15) and in the presence (n=11) of l-NAME. This latter was administered (5mg/kg, ic.) either alone (n=12) or 10min before the simvastatin treatment. The severity of ischaemia (epicardial ST-segment, 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±34vs. 94±25) and the episodes of VT (5.6±1.3vs. 0.3±0.2), 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.
authors.affiliation: Departments 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: Departments 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: First Internal Medicine, University of Szeged, Albert-Szent Györgyi Medical Centre, Szeged, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Gardi
authors.affiliation: Medical Biology, University of Szeged, Albert-Szent Györgyi Medical Centre, Szeged, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Seprényi
authors.affiliation: Institute of Surgical Research, University of Szeged, Albert-Szent Györgyi Medical Centre, Szeged, Hungary.
authors.forename: József
authors.initials: J
authors.lastname: Kaszaki
authors.affiliation: Departments 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: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000503:physiopathology*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D019821:Simvastatin / Q000627:therapeutic use*; D013481:Superoxides / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013481:Superoxides; D009569:Nitric Oxide; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III; D019331:NG-Nitroarginine Methyl Ester
keywords: Arrhythmias; Ischaemia/reperfusion; Nitric oxide; Simvastatin