title: Dual effects of amiodarone on pacemaker currents in hypertrophied ventricular myocytes isolated from spontaneously hypertensive rats.
abstract: 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 anti-arrhythmic agent, blocks human HCN currents and native If under normal conditions. To determine the effects of amiodarone under pathological conditions, we monitored If 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 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 myocytes from both SHR and WKY rats. The inhibition was concentration dependent with an IC50 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 If in myocytes from SHR, although it did not alter the relationship of voltage-dependent activation and the reversal potential of If in myocytes from SHR. Chronic exposure of myocytes from SHR to amiodarone potently inhibited If and downregulated HCN2 and HCN4, the major channel subtypes underlying native If , at both the mRNA and protein level. These findings indicate that amiodarone inhibits If under hypertrophied conditions through dual mechanisms: (i) direct channel blockade of If 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.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Li
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Zhou
authors.forename: Bin
authors.initials: B
authors.lastname: Jiang
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Xun
authors.initials: X
authors.lastname: Li
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Yang
authors.forename: Wenping
authors.initials: W
authors.lastname: Jiang
mesh_terms: D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D001683:Biological Clocks / Q000187:drug effects* / Q000502:physiology; D002469:Cell Separation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004553:Electric Conductivity; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000473:pathology / Q000503:physiopathology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology*; D015221:Potassium Channels / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR
chemical_list: C513836:HCN4 protein, rat; C578712:Hcn2 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D011743:Pyrimidines; C082246:ICI D2788; D000638:Amiodarone
keywords: amiodarone; hyperpolarization-activated cyclic nucleotide-gated channel; hypertrophied ventricular myocytes; pacemaker current If; spontaneously hypertensive rat; whole-cell patch-clamp techniques