A new cardioprotective agent, JTV519, improves defective channel gating of ryanodine receptor in heart failure
| Autor: | Masahiro Doi, Masafumi Yano, Shinichi Okuda, Masunori Matsuzaki, Takahiro Tokuhisa, Michihiro Kohno, Tetsuro Oda, Masateru Kohno, Tomoko Ohkusa, Shigeki Kobayashi |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
medicine.medical_specialty
Cardiotonic Agents Heart disease Protein Conformation Thiazepines Physiology Pharmacology Binding Competitive Tacrolimus Tacrolimus Binding Proteins Radioligand Assay Dogs Coumarins Physiology (medical) Internal medicine Animals Medicine Polylysine Cardioprotective Agent Ion channel Fluorescent Dyes Heart Failure Channel gating business.industry Ryanodine receptor Endoplasmic reticulum Cardiac Pacing Artificial Hemodynamics Ryanodine Receptor Calcium Release Channel Calcium Channel Blockers medicine.disease Disease Models Animal Sarcoplasmic Reticulum Endocrinology Heart failure Circulatory system Calcium Cardiology and Cardiovascular Medicine business Ion Channel Gating Immunosuppressive Agents |
| Zdroj: | American Journal of Physiology-Heart and Circulatory Physiology. 284:H1035-H1042 |
| ISSN: | 1522-1539 0363-6135 |
| DOI: | 10.1152/ajpheart.00722.2002 |
| Popis: | Defective interaction between FKBP12.6 and ryanodine receptors (RyR) is a possible cause of cardiac dysfunction in heart failure (HF). Here, we assess whether the new cardioprotective agent JTV519 can correct it in tachycardia-induced HF. HF was induced in dogs by 4-wk rapid ventricular pacing, and sarcoplasmic reticulum (SR) was isolated from left ventricular muscles. In failing SR, JTV519 increased the rate of Ca2+release and [3H]ryanodine binding. RyR were then labeled in a site-directed fashion with the fluorescent conformational probe methylcoumarin acetamide. In failing SR, the polylysine induced a rapid change in methylcoumarin acetamide fluorescence, presumably because the channel opening preceding the Ca2+release was smaller than in normal SR (consistent with a decreased rate of Ca2+release in failing SR), and JTV519 increased it. In conclusion, JTV519, a new 1,4-benzothiazepine derivative, corrected the defective channel gating in RyR (increase in both the rapid conformational change and the subsequent Ca2+release rate) in HF. |
| Databáze: | OpenAIRE |
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