Original ArticlePre- and Delayed Treatments With Ranolazine Ameliorate Ventricular Arrhythmias and Nav1.5 Downregulation in Ischemic/Reperfused Rat HeartsWei, Xin MD; Zhu, Afang MD; Zhang, Yali MD; Yao, Shanglong MD, PhD; Mao, Weike MDAuthor Information Department of Anesthesiology and Intensive Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Reprints: Weike Mao, MD, Department of Anesthesiology and Intensive Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China (e-mail: [email protected]). Supported by grants from the National Natural Science Foundation of China (No. 81270239). The authors report no conflicts of interest. Journal of Cardiovascular Pharmacology: October 2016 - Volume 68 - Issue 4 - p 269-279 doi: 10.1097/FJC.0000000000000412 Buy Metrics Abstract Enhanced late sodium current (late INa) and intracellular Nav1.5 redistribution contribute to ischemia/reperfusion (I/R)-induced arrhythmias. Ranolazine can reduce lethal arrhythmias by inhibiting late INa. However, little is known regarding its role in regulating the distribution of Nav1.5 during I/R. Therefore, we investigated the roles of ranolazine in post-I/R Nav1.5 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. Nav1.5 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 Nav1.5, GS967, another late INa 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 Nav1.5 decreased by 31.63% after I/R. Ranolazine and GS967 remained Nav1.5 protein expression and Nav1.5 redistribution on intercalated discs and lateral membranes, without affecting Nav1.5 mRNA level. In conclusion, upregulating Nav1.5 expression and redistribution on the intercalated discs and lateral membranes of cardiomyocytes may underlie the antiarrhythmic effects of ranolazine in I/R rats. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.