A new cardioprotective agent, JTV519, improves defective channel gating of ryanodine receptor in heart failure

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 284; no. 3; pp. H1035 - H1042
• Main Authors: Kohno, Masateru, Yano, Masafumi, Kobayashi, Shigeki, Doi, Masahiro, Oda, Tetsuro, Tokuhisa, Takahiro, Okuda, Shinichi, Ohkusa, Tomoko, Kohno, Michihiro, Matsuzaki, Masunori
• Format: Journal Article
• Language: English
• Published: United States 01.03.2003
• Subjects: Animals; Binding, Competitive - drug effects; Calcium - metabolism; Calcium - pharmacokinetics; Calcium Channel Blockers - pharmacology; Cardiac Pacing, Artificial; Cardiotonic Agents - pharmacology; Cardiotonic Agents - therapeutic use; Coumarins - chemistry; Disease Models, Animal; Dogs; Fluorescent Dyes - chemistry; Heart Failure - drug therapy; Heart Failure - physiopathology; Hemodynamics - drug effects; Immunosuppressive Agents - pharmacology; Ion Channel Gating - drug effects; Polylysine - pharmacology; Protein Conformation - drug effects; Radioligand Assay; Ryanodine Receptor Calcium Release Channel - chemistry; Ryanodine Receptor Calcium Release Channel - drug effects; Ryanodine Receptor Calcium Release Channel - metabolism; Sarcoplasmic Reticulum - chemistry; Sarcoplasmic Reticulum - drug effects; Sarcoplasmic Reticulum - metabolism; Tacrolimus - pharmacology; Tacrolimus Binding Proteins - metabolism; Thiazepines - pharmacology; Thiazepines - therapeutic use
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00722.2002

Department of Medical Bioregulation, Division of Cardiovascular Medicine, Yamaguchi University School of Medicine, Yamaguchi 755-8505, Japan 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 Ca 2+ release and [ 3 H]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 Ca 2+ release was smaller than in normal SR (consistent with a decreased rate of Ca 2+ 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 Ca 2+ release rate) in HF. sarcoplasmic reticulum; ion channel; binding protein; excitation-contraction coupling