TY - JOUR T1 - Short- and Long-Term Amiodarone Treatments Regulate Ca<sub>v</sub>3.2 Low-Voltage-Activated T-type Ca<sup>2+</sup> Channel through Distinct Mechanisms JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1684 LP - 1691 DO - 10.1124/mol.105.021253 VL - 69 IS - 5 AU - Noboru Yamashita AU - Toshihiko Kaku AU - Tomoko Uchino AU - Shojiro Isomoto AU - Hironobu Yoshimatsu AU - Katsushige Ono Y1 - 2006/05/01 UR - http://molpharm.aspetjournals.org/content/69/5/1684.abstract N2 - 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 (Cav 3.2) Ca2+ channel. The Cav3.2 α1H subunit derived from human heart was stably transfected into cells [human embryonic kidney (HEK)-Cav3.2] 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 (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 immediately to the bath solution. However, when the HEK-Cav3.2 cells were incubated with 5 μM amiodarone for 72 h, ICa.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 &lt; 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 (τ): control, 13.3 ± 1.1 ms (n = 6) versus amiodarone, 39.6 ± 5.5 ms (n = 6) at -30 mV, P &lt; 0.001)]. Nevertheless, short-term 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 short- and long-term inhibitory actions on ICa.T via distinct blocking mechanisms. ER -