title: A new cardioprotective agent, JTV519, improves defective channel gating of ryanodine receptor in heart failure.
abstract: 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.
authors.affiliation: Department of Medical Bioregulation, Division of Cardiovascular Medicine, Yamaguchi University School of Medicine, Yamaguchi 755-8505, Japan.
authors.forename: Masateru
authors.initials: M
authors.lastname: Kohno
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yano
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Doi
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Oda
authors.forename: Takahiro
authors.initials: T
authors.lastname: Tokuhisa
authors.forename: Shinichi
authors.initials: S
authors.lastname: Okuda
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ohkusa
authors.forename: Michihiro
authors.initials: M
authors.lastname: Kohno
authors.forename: Masunori
authors.initials: M
authors.lastname: Matsuzaki
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism / Q000493:pharmacokinetics; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002304:Cardiac Pacing, Artificial; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003374:Coumarins / Q000737:chemistry; D004195:Disease Models, Animal; D004285:Dogs; D005456:Fluorescent Dyes / Q000737:chemistry; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects*; D011107:Polylysine / Q000494:pharmacology; D011487:Protein Conformation / Q000187:drug effects; D011869:Radioligand Assay; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D013841:Thiazepines / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002121:Calcium Channel Blockers; D002316:Cardiotonic Agents; D003374:Coumarins; D005456:Fluorescent Dyes; D007166:Immunosuppressive Agents; D019837:Ryanodine Receptor Calcium Release Channel; D013841:Thiazepines; C109183:K201 compound; D011107:Polylysine; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D002118:Calcium; D016559:Tacrolimus