Inhomogeneous downregulation of I Na underlies piceatannol proarrhythmic mechanism in regional ischemia-reperfusion.

BackgroundPiceatannol, a grape-derived polyphenol, has been linked to proarrhythmic properties by aggravating inhomogeneous conduction delay in the ischemia-reperfusion (IR) zone to enhance arrhythmogenic alternans in heart failure (HF) rabbits. The underlying molecular mechanisms of piceatannol-induced conduction disturbance were unclear in this model. MethodsHF was induced by 4 weeks' rapid ventricular pacing. IR injury was induced in vivo using a protocol of left coronary artery ligation and release. Left ventricular cardiomyocytes were isolated enzymatically for whole-cell patch-clamp studies. Piceatannol (10 M) was administrated to test its inhibitory effect on sodium current (I-Na). Immunoblots studies and immunoenzymological staining were conducted in tissues sampled from the IR and remote zones. ResultsPeak I-Na density was less in failing cardiomyocytes than control cardiomyocytes. IR injury further reduces peak I-Na density in both groups. Piceatannol showed a greater I-Na inhibitory effect in HF than control cardiomyocytes. Western blots showed reduced Na-V 1.5 protein expression in the HF group compared to the control group but no significant difference between remote and IR zones. Immunostaining showed that IR led to cytosolic redistribution of Na-V 1.5, especially in failing hearts. ConclusionsDownregulation of NaV 1.5 protein expression and reduced peak I-Na density are found in the failing hearts. Piceatannol exerts a greater inhibitory effect on peak I-Na in the failing cardiomyocytes than in the controls. IR injury further decreases peak I-Na density, which is more prominent in the failing hearts than in the control hearts.