hERG K+ channel-associated cardiac effects of the antidepressant drug desipramine
| Autor: | Kathrin Staudacher, Patrick Koelsch, Ronald Koschny, Patrick A. Schweizer, Lu Wang, Sabrina Obers, Eckhard Ficker, Hugo A. Katus, Xiaoping Wan, Jana Kisselbach, Dierk Thomas, Ingo Staudacher, Frank Tristram, Wolfgang Wenzel |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty ERG1 Potassium Channel Patch-Clamp Techniques Cell Survival Long QT syndrome Voltage clamp hERG Blotting Western Guinea Pigs Action Potentials Pharmacology Antidepressive Agents Tricyclic Transfection Xenopus laevis Internal medicine Desipramine medicine Myocyte Animals Humans Computer Simulation Myocytes Cardiac cardiovascular diseases Patch clamp NATURAL sciences & mathematics Ion channel Microscopy Confocal biology Dose-Response Relationship Drug business.industry HEK 293 cells General Medicine medicine.disease Immunohistochemistry Ether-A-Go-Go Potassium Channels Endocrinology HEK293 Cells biology.protein Oocytes ddc:500 business medicine.drug |
| Zdroj: | Naunyn-Schmiedeberg's archives of pharmacology, 383, 119-139 |
| ISSN: | 1432-1912 0365-2009 0365-5423 0340-5249 0028-1298 |
| Popis: | Cardiac side effects of antidepressant drugs are well recognized. Adverse effects precipitated by the tricyclic drug desipramine include prolonged QT intervals, torsade de pointes tachycardia, heart failure, and sudden cardiac death. QT prolongation has been primarily attributed to acute blockade of hERG/I(Kr) currents. This study was designed to provide a more complete picture of cellular effects associated with desipramine. hERG channels were expressed in Xenopus laevis oocytes and human embryonic kidney (HEK 293) cells, and potassium currents were recorded using patch clamp and two-electrode voltage clamp electrophysiology. Ventricular action potentials were recorded from guinea pig cardiomyocytes. Protein trafficking and cell viability were evaluated in HEK 293 cells and in HL-1 mouse cardiomyocytes by immunocytochemistry, Western blot analysis, or colorimetric MTT assay, respectively. We found that desipramine reduced hERG currents by binding to a receptor site inside the channel pore. hERG protein surface expression was reduced after short-term treatment, revealing a previously unrecognized mechanism. When long-term effects were studied, forward trafficking was impaired and hERG currents were decreased. Action potential duration was prolonged upon acute and chronic desipramine exposure. Finally, desipramine triggered apoptosis in cells expressing hERG channels. Desipramine exerts at least four different cellular effects: (1) direct hERG channel block, (2) acute reduction of hERG surface expression, (3) chronic disruption of hERG trafficking, and (4) induction of apoptosis. These data highlight the complexity of hERG-associated drug effects. |
| Databáze: | OpenAIRE |
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