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First published on January 27, 2006; DOI: 10.1124/mol.105.021253

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Noboru Yamasita
Toshihiko Kaku
Tomoko Uchino
Shojiro Isomoto
Hironobu Yoshimatsu
Katsushige Ono
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Received for publication November 29, 2005.
Revised January 26, 2006.
Accepted for publication January 26, 2006.

Acute and Chronic Amiodarone Treatments Regulate Cav3.2 Low-Voltage-Activated T-type Ca2+ Channel Through Distinct Mechanisms

Noboru Yamasita 1, Toshihiko Kaku 1, Tomoko Uchino 1, Shojiro Isomoto 1, Hironobu Yoshimatsu 1, Katsushige Ono 1*

1 Oita University School of Medicine

* Address correspondence to: E-mail: ono{at}med.oita-u.ac.jp

Abstract

Low-voltage-activated T-type Ca2+ channels have recently been recognized in the mechanisms underlying atrial arrhythmias. However, the pharmacological effects of amiodarone on the T-type Ca2+ channel remain unclear. We investigated acute and chronic effects of amiodarone on the T-type (Cav3.2) Ca2+ channel. The Cav3.2 ({alpha}1H) subunit derived from human heart was stably transfected into cells (HEK-Cav3.2) cultured with or without 5 µM amiodarone. Patch clamp recordings in the conventional whole-cell configuration were employed to evaluate actions of amiodarone on the T-type Ca2+ channel current (ICa.T). Amiodarone blockade of ICa.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 acutely to the bath solution. However, when the HEK-Cav3.2 cells were incubated with 5 µM amiodarone for 72 hours, ICa.T density was significantly decreased, by 31.7 ± 2.3%, control, 93.1 ± 4.3 pA/pF (n = 8) vs. amiodarone, 56.5 ± 3.2 pA/pF (n = 13), P<0.001. Following the chronic administration of amiodarone, the activation and the steady-state inactivation curves were shifted in the depolarization direction by -7.1 mV (n = 41) and -5.5 mV (n = 37), respectively, and current inactivation was significantly delayed (time constant ({tau}): control, 13.3 ± 1.1 ms (n = 6) vs. amiodarone, 39.6 ± 5.5 ms (n = 6) @-30 mV, P<0.001). Nevertheless, acute inhibitory effects of amiodarone on the modified T-type Cav3.2 Ca2+ channel created by long-term amiodarone treatment were functionally maintained. We conclude that amiodarone exerts its acute and chronic inhibitory actions on ICa.T via distinct blocking mechanisms.


Key words: Ion channel regulation, Calcium (Votage-Gated Channels)


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