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

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...

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Published inAmerican journal of physiology. Heart and circulatory physiology Vol. 53; 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
LanguageEnglish
Published Bethesda, MD American Physiological Society 01.03.2003
Subjects
Biological and medical sciences
Cardiovascular system
Drug therapy
Heart failure
Medical sciences
Miscellaneous
Pharmacology. Drug treatments
Proteins
Heart
Heart failure
Fissipedia
Carnivora
Excitation contraction coupling
Cardioprotective agent
Ryanodine receptor
Cardiovascular disease
Ionic channel
Biological activity
Binding protein
Vertebrata
Mammalia
Calcium ion
Sarcoplasmic reticulum
ion channel
Heart disease
Animal
Circulatory system
Dog
excitation-contraction coupling
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Summary: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. [PUBLICATION ABSTRACT]
ISSN:0363-6135
1522-1539