Cardioprotective effects of simvastatin on reversing electrical remodeling induced by myocardial ischemia-reperfusion in normocholesterolemic rabbits.

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.

[Effect of simulated ischemia on activity and heterogeneity of Na+ channel in rabbit ventricular epicardial, midmyocardial and endocardial myocytes].

OBJECTIVE: To study the ionic mechanism of reentrant arrhythmia. METHODS: Single myocytes were enzymatically isolated from the epicardium, midmyocardium and endocardium of the left ventricle free wall of rabbit, followed by whole-cell patch-clamp recording of the Na(+) current (I(Na)) of the 3 cellular subtypes (superfused with normal and then simulated ischemia solution). The currents in the 3 cellular subtypes before and after simulated ischemia lasting for 10, 20, and 30 min, respectively, were compared. RESULTS: No changes was recorded in the configuration of the I-V curves and voltage dependence of I(Na) after simulated ischemia, and the peak I(Na) densities (- 20 mV) were significantly reduced in the 3 cellular subtypes compared with those recorded in normal condition. At the same time, the differences in I(Na) peak current densities in the 3 cellular subtypes underwent variations after simulated ischemia. Simulated ischemia resulted in obvious shift of I(Na) steady-state inactivation curves in the hyperpolarizing direction in the 3 cellular subtypes and inactivation was accelerated, and the differences in the half maximal inactivation voltages (V0.5) between the 3 cellular subtypes were also altered after simulated ischemia. After simulated ischemia, I(Na) recovery from inactivation in the epicardium, endocardium and midmyocardium was all slowed down in comparison with that in normal condition, but without statistical significance. Differences between the recovery curves of three cellular subtypes were noted after ischemia for 30 min. CONCLUSION: Ischemia can affect the activity of Na(+) channel, disrupting the balance of ion channel currents and the heterogeneity of I(Na) among the 3 cellular subtypes, which is responsible for the onset of arrhythmia and partially explains different pharmacological reactions of the 3 cellular subtypes under normal and ischemic conditions.