Pre- and Delayed Treatments With Ranolazine Ameliorate Ventricular Arrhythmias and Nav1.5 Downregulation in Ischemic/Reperfused Rat Hearts

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.

Hypoxia Produces Pro-arrhythmic Late Sodium Current in Cardiac Myocytes by SUMOylation of NaV1.5 Channels

“…Cells were not studied beyond 600 s to maintain consistent voltage-clamp control of I Na (Figure 1A). These changes are like those observed in isolated rat ventricular myocytes (Ju et al, 1996) and human cardiac muscle (Makielski, 2016;Wei et al, 2016).…”

AMPK‐mediated degradation of Nav1.5 through autophagy

“…Wei et al . (45) reported that the maintenance of Nav1.5 expression levels ameliorates ventricular arrhythmia in I/R‐injured rat hearts, suggesting that decreased Nav1.5 expression is detrimental. However, more studies are needed to clarify the role of Nav1.5 degradation in I/R injury‐induced tissue damage.…”

“…In this study, we report that I/R injury resulted in Nav1.5 degradation through the autophagic pathway, but it is not yet known if Nav1.5 degradation is a protective mechanism or if it exacerbates I/R injury-induced tissue damage. Wei et al (45) reported that the maintenance of Nav1.5 expression levels ameliorates ventricular arrhythmia in I/R-injured rat hearts, suggesting that decreased Nav1.5 expression is detrimental. However, more studies are needed to clarify the role of Nav1.5 degradation in I/R injury-induced tissue damage.…”

Effects of atorvastatin on time-dependent change of fast sodium current in simulated acute ischaemic ventricular myocytes

“…Previous studies have shown that I Na would be decreased or Nav1.5, which is the ion channel protein of I Na , would be downregulated in the ischaemic condition. 5,6 However in our pre-experiment of simulated ischaemia, peak I Na was transiently increased in the very early stage of ischaemia (three to five minutes), suggesting unstable early ischaemic electrical activity. As the decreased I Na demonstrated in ischaemia or simulated ischaemia usually needs myocyte exposure for more than 10 minutes, 5 this indicates that time is a key factor affecting I Na in the ischaemic state.…”