Short- and Long-Term Amiodarone Treatments Regulate Ca v 3.2 Low-Voltage-Activated T-type Ca 2+ Channel through Distinct Mechanisms
Molecular Pharmacology, ISSN: 0026-895X, Vol: 69, Issue: 5, Page: 1684-1691
2006
- 14Citations
- 15Captures
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Metrics Details
- Citations14
- Citation Indexes14
- CrossRef14
- 14
- Captures15
- Readers15
- 15
Article Description
Low-voltage-activated T-type Ca 2+ channels have been recognized recently in the mechanisms underlying atrial arrhythmias. However, the pharmacological effects of amiodarone on the T-type Ca 2+ channel remain unclear. We investigated short- and long-term effects of amiodarone on the T-type (Ca v 3.2) Ca 2+ channel. The Ca v 3.2 α 1H subunit derived from human heart was stably transfected into cells [human embryonic kidney (HEK)-Ca v 3.2] 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 Ca 2+ 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 v 3.2 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 (τ): 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 v 3.2 Ca 2+ 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.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S0026895X24068354; http://dx.doi.org/10.1124/mol.105.021253; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=33645807633&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/16443692; https://linkinghub.elsevier.com/retrieve/pii/S0026895X24068354; https://dx.doi.org/10.1124/mol.105.021253; https://molpharm.aspetjournals.org/content/69/5/1684
Elsevier BV
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