Kohno Masateru, Yano Masafumi, Kobayashi Shigeki, Doi Masahiro, Oda Tetsuro, Tokuhisa Takahiro, Okuda Shinichi, Ohkusa Tomoko, Kohno Michihiro, Matsuzaki Masunori
Department of Medical Bioregulation, Division of Cardiovascular Medicine, Yamaguchi University School of Medicine, Yamaguchi 755-8505, Japan.
Am J Physiol Heart Circ Physiol. 2003 Mar;284(3):H1035-42. doi: 10.1152/ajpheart.00722.2002. Epub 2002 Nov 14.
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.
FKBP12.6与兰尼碱受体（RyR）之间的相互作用缺陷可能是心力衰竭（HF）中心脏功能障碍的一个原因。在此，我们评估新型心脏保护剂JTV519是否能在心动过速诱导的HF中纠正这一问题。通过4周快速心室起搏在犬中诱导HF，并从左心室肌肉中分离出肌浆网（SR）。在衰竭的SR中，JTV519增加了Ca(2+)释放速率和[(3)H]兰尼碱结合。然后用荧光构象探针甲基香豆素乙酰胺以位点定向方式标记RyR。在衰竭的SR中，聚赖氨酸诱导甲基香豆素乙酰胺荧光快速变化，推测是因为Ca(2+)释放前的通道开放比正常SR中的小（与衰竭SR中Ca(2+)释放速率降低一致），而JTV519增加了该变化。总之，新型1,4 - 苯并噻氮䓬衍生物JTV519纠正了HF中RyR的通道门控缺陷（快速构象变化和随后的Ca(2+)释放速率均增加）。
