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Short- and Long-Term Amiodarone Treatments Regulate Ca_v3.2 Low-Voltage-Activated T-type Ca²⁺ Channel through Distinct Mechanisms

Department of Cardiovascular Science (N.Y., T.K., T.U., S.I., K.O.) and Internal Medicine (N.Y., H.Y.), Oita University School of Medicine, Oita, Japan

Low-voltage-activated T-type Ca²⁺ channels have been recognized recently in the mechanisms underlying atrial arrhythmias. However, the pharmacological effects of amiodarone on the T-type Ca²⁺ channel remain unclear. We investigated short- and long-term effects of amiodarone on the T-type (Ca_v 3.2) Ca²⁺ channel. The Ca_v3.2 _1H subunit derived from human heart was stably transfected into cells [human embryonic kidney (HEK)-Ca_v3.2] cultured with or without 5 µM amiodarone. Patch-clamp recordings in the conventional whole-cell configuration were used to evaluate the actions of amiodarone on the T-type Ca²⁺ channel current (I_Ca.T). Amiodarone blockade of I_Ca.T occurred in a dose- and holding potential-dependent manner, shifting the activation and the steady-state inactivation curves in the hyperpolarization direction, when amiodarone was applied immediately to the bath solution. However, when the HEK-Ca_v3.2 cells were incubated with 5 µM amiodarone for 72 h, I_Ca.T density was significantly decreased by 31.7 ± 2.3% for control,-93.1 ± 4.3 pA/pF (n = 8), versus amiodarone,-56.5 ± 3.2 pA/pF (n = 13), P < 0.001. After the prolonged administration of amiodarone, the activation and the steadystate inactivation curves were shifted in the depolarization direction by -7.1 (n = 41) and -5.5 mV (n = 37), respectively, and current inactivation was significantly delayed [time constant (): control, 13.3 ± 1.1 ms (n = 6) versus amiodarone, 39.6 ± 5.5 ms (n = 6) at -30 mV, P < 0.001)]. Nevertheless, short-term inhibitory effects of amiodarone on the modified T-type Ca_v3.2 Ca²⁺ channel created by long-term amiodarone treatment were functionally maintained. We conclude that amiodarone exerts its short- and long-term inhibitory actions on I_Ca.T via distinct blocking mechanisms.

Address correspondence to: Dr. Katsushige Ono, Department of Cardiovascular Science, Oita University School of Medicine, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan. E-mail: ono{at}med.oita-u.ac.jp

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				L. Wu, S. Rajamani, J. C. Shryock, H. Li, J. Ruskin, C. Antzelevitch, and L. Belardinelli Augmentation of late sodium current unmasks the proarrhythmic effects of amiodarone Cardiovasc Res, February 1, 2008; 77(3): 481 - 488. [Abstract] [Full Text] [PDF]