Pre- And Delayed Treatments With Ranolazine Ameliorate Ventricular Arrhythmias And Na(V)1.5 Downregulation In Ischemic/Reperfused Rat Hearts

Enhanced late sodium current (late I-Na) and intracellular Na(v)1.5 redistribution contribute to ischemia/reperfusion (I/R)-induced arrhythmias. Ranolazine can reduce lethal arrhythmias by inhibiting late I-Na. However, little is known regarding its role in regulating the distribution of Na(v)1.5 during I/R. Therefore, we investigated the roles of ranolazine in post-I/R Na(v)1.5 expression and distribution in myocardium. Male Sprague Dawley rats were randomly assigned to 4 groups: sham, I/R, Ran Pre, and Ran Delay. Electrocardiogram and arterial pressure were recorded during the procedure. Na(v)1.5 mRNA and protein levels in peri-infarct cardiac tissue were determined by real-time polymerase chain reaction, Western blotting, and immunofluorescence. To further confirm the regulation of ranolazine on Na(v)1.5, GS967, another late I-Na inhibitor was used. Both pre- and delayed ranolazine treatments significantly reduced the incidence of severe ventricular arrhythmias, along with shortened corrected QT interval by 29.55% and QRS duration by 18.38% during I/R. The protein level of Na(v)1.5 decreased by 31.63% after I/R. Ranolazine and GS967 remained Na(v)1.5 protein expression and Na(v)1.5 redistribution on intercalated discs and lateral membranes, without affecting Na(v)1.5 mRNA level. In conclusion, upregulating Na(v)1.5 expression and redistribution on the intercalated discs and lateral membranes of cardiomyocytes may underlie the antiarrhythmic effects of ranolazine in I/R rats.