title: Cardioprotective effects of simvastatin on reversing electrical remodeling induced by myocardial ischemia-reperfusion in normocholesterolemic rabbits.
abstract: BACKGROUND
  Recent studies have revealed that pretreatment with statin is effective in preventing arrhythmia, but its electrophysiological mechanism is unclear. This study was conducted to investigate the cardioprotective effects of simvastatin on reversing electrical remodeling in left ventricular myocytes of rabbit heart undergoing ischemia-reperfusion, so as to explore the ionic mechanism responsible for the anti-arrhythmic effect of statin.
  
  
  METHODS
  Forty-five rabbits were randomly divided into three groups: ischemic-reperfusion group (I-R), simvastatin intervention group (Statin) and sham-operated control group (CON). Anesthetized rabbits were subjected to 30-minute ischemia by ligation of the left anterior descending coronary artery and a 60-minute reperfusion after a 3-day administration of oral simvastatin of 5 mg x kg(-1) x d(-1) in the Statin group or a placebo in the I-R group. Single ventricular myocytes were isolated enzymatically from the epicardial zone of the infracted region derived from the hearts in the I-R and Statin group and the same anatomical region in the CON animals. The whole cell patch-clamp technique was used to record membrane ionic currents, including sodium current (I(Na)), L-type calcium current (I(Ca-L)) and transient outward potassium current (I(to)). Simultaneously, the level of serum cholesterol was examined.
  
  
  RESULTS
  There was no significant difference in the serum cholesterol concentration among the three groups. The peak I(Na) current density (at -30 mV) was significantly decreased in I-R ((-22.46+/-5.32) pA/pF, n=12) compared with CON ((-42.78+/-5.48) pA/pF, n=16, P<0.01) and Statin ((-40.66+/-5.89) pA/pF, n=15, P<0.01), while the peak I(Na) current density in the Statin group was not different from CON (P>0.05). The peak I(Ca-L) current density (at 0 mV) was significantly increased in I-R ((-4.34+/-0.92) pA/pF, n=15) compared with CON ((-3.13+/-1.22) pA/pF, n=13, P<0.05) and Statin ((-3.46+/-0.85) pA/pF, n=16, P<0.05), while the Peak I(Ca-L) current density in Statin was not different from CON (P>0.05). The I(to) current density (at +60 mV) was significantly decreased in I-R ((9.49+/-1.91) pA/pF, n=11) compared with CON ((17.41+/-3.13) pA/pF, n=15, P<0.01) and Statin ((14.54+/-2.41) pA/pF, n=11, P<0.01), although there was a slight reduction in the Statin group compared with CON (P<0.05).
  
  
  CONCLUSIONS
  It is implied that ischemia-reperfusion induces significant down-regulation of I(Na) and I(to) and up-regulation of I(Ca-L), which may underlie the altered electrical activity and long abnormal transmembrane action potential duration of the surviving ventricular myocytes, thus contributing to ventricular arrhythmias during acute ischemia-reperfusion period. Pretreatment with simvastatin could attenuate these changes and reverse this electrical remodeling without lowering the serum cholesterol level, contributing to the ionic mechanism of statin in treatment of arrhythmia independent of a decrease in cholesterol.
authors: Department of Cardiology, Second Hospital of Hebei Medical University, Institute of Cardiocerebrovascular Disease of Hebei Province, Shijiazhuang, Hebei 050000, China.
authors: Chao
authors: C
authors: Ding
authors: Xiang-hua
authors: XH
authors: Fu
authors: Zhen-shan
authors: ZS
authors: He
authors: Hui-xiao
authors: HX
authors: Chen
authors: Ling
authors: L
authors: Xue
authors: Jun-xia
authors: JX
authors: Li
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D015221:Potassium Channels / Q000187:drug effects; D011817:Rabbits; D019821:Simvastatin / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects
chemical_list: D020746:Calcium Channels, L-Type; D015221:Potassium Channels; D015222:Sodium Channels; D002784:Cholesterol; D019821:Simvastatin