Journal
HEART RHYTHM
Volume 10, Issue 8, Pages 1220-1228Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.hrthm.2013.04.014
Keywords
Action potential; Alternative splicing; Amiloride; I-Ks; KCNQ1
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Funding
- Taiwan National Science Council [NSC 99-2221-E-037-001]
- American Heart Association [0440066N]
- NIH [R01 NS060706]
- NIH-NHLBI [R01-HL-049054-20, R01-HL-033343-28]
- Leducq Foundation
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BACKGROUND Slow delayed-rectifier potassium current (I-Ks) channels, made of the pore-forming KCNQ1 and auxiliary KCNE1 subunits, play a key role in determining action potential duration (APD) in cardiac myocytes. The consequences of drug-induced KCNQ1 splice alteration remain unknown. OBJECTIVE To study the modulation of KCNQ1 alternative splicing by amiloride and the consequent changes in I-Ks and action potentials (APs) in ventricular myocytes. METHODS Canine endocardial, midmyocardial, and epicardial ventricular myocytes were isolated. Levels of KCNQ1a and KCNQ1b as well as a series of splicing factors were quantified by using the reverse transcriptase-polymerase chain reaction and Western blot. The effect of amiloride-induced changes in the KCNQ1b/total KCNQ1 ratio on AP was measured by using whole-cell patch damp with and without isoproterenol. RESULTS With 50 mu mol/L of amiloride for 6 hours, KCNQ1a at transcriptional and translational levels increased in midmyocardial myocytes but decreased in endo- and epicardial myocytes. Likewise, changes in splicing factors in midmyocardial were opposite to that in endo- and epicardial myocytes. In midmyocardial myocytes amiloride shortened APD and decreased isoproterenol-induced early afterdepolarizations significantly. The same amiloride-induced effects were demonstrated by using human ventricular myocyte model for AP simulations under beta-adrenergic stimulation. Moreover, amiloride reduced the transmural dispersion of repolarization in pseudo-electrocardiogram. CONCLUSIONS Amiloride regulates I-Ks and APs with transmural differences and reduces arrhythmogenicity through the modulation of KCNQ1 splicing. We suggested that the modulation of KCNQ1 splicing may help prevent arrhythmia.
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