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Inhomogeneous downregulation of I Na underlies piceatannol proarrhythmic mechanism in regional ischemia‐reperfusion
Author(s) -
Chang PoCheng,
Huang YuChang,
Lee HuiLing,
Chang GwoJyh,
Chu Yen,
Wen MingShien,
Chou ChungChuan
Publication year - 2018
Publication title -
pacing and clinical electrophysiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.686
H-Index - 101
eISSN - 1540-8159
pISSN - 0147-8389
DOI - 10.1111/pace.13424
Subject(s) - piceatannol , medicine , downregulation and upregulation , ischemia , cardiology , heart failure , reperfusion injury , endocrinology , resveratrol , pharmacology , chemistry , biochemistry , gene
Background Piceatannol, 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. Methods HF 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 μM) 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. Results Peak 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. Conclusions Downregulation 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.