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Am J Physiol Heart Circ Physiol (November 14, 2002). doi:10.1152/ajpheart.00722.2002
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Articles in PresS, published online ahead of print November 14, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00722.2002
Submitted on August 19, 2002
Accepted on December 31, 1969

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

Masateru Kohno1, Masafumi Yano1, Shigeki Kobayashi1, Masahiro Doi1, Tetsuro Oda1, Takahiro Tokuhisa1, Shinichi Okuda1, Tomoko Ohkusa1, Michihiro Kohno1, and Masunori Matsuzaki1*

1 Department of Medical Bioregulation, Yamaguchi University School of Medicine, Ube, Japan

* To whom correspondence should be addressed. E-mail: masunori{at}po.cc.yamaguchi-u.ac.jp.

Defective interaction between FKBP12.6 and ryanodine receptors (RyR) is a possible cause of cardiac dysfunction in heart failure (HF). Here, we assess whether a new cardioprotective agent, JTV519 can correct it in tachycardia-induced HF. HF was induced in dogs by 4-weeks rapid RV pacing, and sarcoplasmic reticulum (SR) was isolated from LV 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 (MCA). In failing SR, the polylysine-induced rapid change in MCA fluorescence ({Delta}F), presumably due to 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.




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