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Dual effects of amiodarone on pacemaker currents in hypertrophied ventricular myocytes isolated from spontaneously hypertensive rats

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Clinical and Experimental Pharmacology and Physiology

Published online on


The pacemaker current (If) conducted by hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels plays a critical role in the regulation of cardiac automaticity, with If density increased in hypertrophied ventricular myocytes. Amiodarone, a highly effective antiarrhythmic agent, blocks human HCN currents and native If under normal conditions. To determine the effects of amiodarone under pathologic conditions, we monitored If under both acute and chronic treatment conditions in ventricular myocytes from spontaneously hypertensive rats (SHR) with left ventricular hypertrophy using the whole‐cell patch‐clamp technique. If current density was significantly greater in SHR ventricular myocytes than in cells from healthy normotensive control Wistar‐Kyoto (WKY) rats. Acute application of amiodarone significantly decreased If density in both SHR and WKY myocytes. The inhibition was concentration‐dependent with an IC50 of 4.9 (±1.2) μM in SHR and 6.9 (±1.3) μM in WKY myocytes. Amiodarone increased the activation and deactivation times of If in SHR myocytes, although it did not alter the relationship of voltage‐dependent activation and the reversal potential of If in SHR myocytes. Chronic exposure of SHR myocytes to amiodarone potently inhibited If and downregulated HCN2 and HCN4, the major channel subtypes underlying native If, at both mRNA and protein levels. These findings indicate that amiodarone inhibits If under hypertrophied conditions through dual mechanisms: direct channel blockade of If currents and indirect suppression via negative regulation of HCN channel gene expression. These unique properties of amiodarone may contribute to its antiarrhythmic properties under pathologic conditions. This article is protected by copyright. All rights reserved.