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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding, Competitive / drug effects
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Calcium / metabolism
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Calcium / pharmacokinetics
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Calcium Channel Blockers / pharmacology
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Cardiac Pacing, Artificial
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Cardiotonic Agents / pharmacology*
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Cardiotonic Agents / therapeutic use
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Coumarins / chemistry
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Disease Models, Animal
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Dogs
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Fluorescent Dyes / chemistry
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Heart Failure / drug therapy*
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Heart Failure / physiopathology
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Hemodynamics / drug effects
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Immunosuppressive Agents / pharmacology
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Ion Channel Gating / drug effects*
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Polylysine / pharmacology
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Protein Conformation / drug effects
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Radioligand Assay
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Ryanodine Receptor Calcium Release Channel / chemistry
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Ryanodine Receptor Calcium Release Channel / drug effects*
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Ryanodine Receptor Calcium Release Channel / metabolism
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Sarcoplasmic Reticulum / chemistry
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Sarcoplasmic Reticulum / drug effects
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Sarcoplasmic Reticulum / metabolism
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Tacrolimus / pharmacology
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Tacrolimus Binding Proteins / metabolism
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Thiazepines / pharmacology*
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Thiazepines / therapeutic use
Substances
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Calcium Channel Blockers
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Cardiotonic Agents
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Coumarins
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Fluorescent Dyes
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Immunosuppressive Agents
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Ryanodine Receptor Calcium Release Channel
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Thiazepines
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K201 compound
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Polylysine
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Tacrolimus Binding Proteins
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tacrolimus binding protein 1B
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Calcium
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Tacrolimus