Premium
Dual effects of amiodarone on pacemaker currents in hypertrophied ventricular myocytes isolated from spontaneously hypertensive rats
Author(s) -
Li Hongxia,
Zhou Yafeng,
Jiang Bin,
Zhao Xin,
Li Xun,
Yang Xiangjun,
Jiang Wenping
Publication year - 2014
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12264
Subject(s) - amiodarone , myocyte , medicine , endocrinology , muscle hypertrophy , chemistry , patch clamp , electrophysiology , atrial fibrillation
Summary The pacemaker current I f conducted by hyperpolarization‐activated cyclic nucleotide‐gated ( HCN ) channels plays a critical role in the regulation of cardiac automaticity, with I f density increased in hypertrophied ventricular myocytes. Amiodarone, a highly effective anti‐arrhythmic agent, blocks human HCN currents and native I f under normal conditions. To determine the effects of amiodarone under pathological conditions, we monitored I f under after both acute (0.01, 0.1, 1, 10 and 100 μmol/L) and chronic (10 μmol/L) amiodarone treatment in ventricular myocytes from spontaneously hypertensive rats ( SHR ) with left ventricular hypertrophy using the whole‐cell patch‐clamp technique. The I f current density was significantly greater in SHR ventricular myocytes than in cells from healthy normotensive control W istar‐ K yoto ( WKY ) rats. Acute application of amiodarone significantly decreased I f density in myocytes from both SHR and WKY rats. The inhibition was concentration dependent with an IC 50 of 4.9 ± 1.2 and 6.9 ± 1.3 μmol/L in myocytes from SHR and WKY rats, respectively. Amiodarone increased the activation and deactivation times of I f in myocytes from SHR , although it did not alter the relationship of voltage‐dependent activation and the reversal potential of I f in myocytes from SHR . Chronic exposure of myocytes from SHR to amiodarone potently inhibited I f and downregulated HCN 2 and HCN 4, the major channel subtypes underlying native I f , at both the m RNA and protein level. These findings indicate that amiodarone inhibits I f under hypertrophied conditions through dual mechanisms: (i) direct channel blockade of I f currents; and (ii) indirect suppression via negative regulation of HCN channel gene expression. These unique properties of amiodarone may contribute to its anti‐arrhythmic properties under pathological conditions.