Study for detection of intracellular sodium transients and their pathophysiological roles in myocytes

心肌细胞内钠瞬变检测及其病理生理作用的研究

• 批准号: 15590733
• 负责人: SATOH Hiroshi
• 金额: $ 2.18万
• 依托单位: Hamamatsu University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590733/
• 关键词: Sodium ion; Calcium ion; Myocytes; Na^+; Ca^<2+> exchange; Excitation-contraction coupling

In cardiac myocytes the Ca^<2+>-induced Ca^<2+> release (CICR) from the sarcoplasmicr reticulum (SR) plays pivotal roles in Ca transients. However, the changes in intracellular Na^+ concentration ([Na^+]_i) also contribute significantly to CICR via Na^+/Ca^<2+> exchange. The negative inotropic effect of Na^+ channel blockers (NCB) is mediated by disturbance of intracellular Ca^<2+> regulation. The Na^+ channel gating could induce intracellular Na^+ accumulation, thereby increasing Ca^<2+> influx via the reverse-mode Na^+/Ca^<2+> exchange (rNCX). The primary aim of this study was to investigate whether the reduction of cellular Na^+ accumulation by NCB actually contributes to the negative inotropic effects through the elimination of Ca^<2+> influx via rNCX. To elucidate the involvement of rNCX in the negative inotropic effects of Na^+ channel blockers, we examined the effects of a pure Na^+ channel blocker, pilsicainide, on the frequency-dependent increases in twitch cell shortenings (C … More S) and Ca^<2+> transients (CaT) in Indo-1 or fluo-3 loaded guinea pig ventricular myocytes. The changes in [Na^+]_i was also evaluated with Sodium-Green and laser scanning confocal microscopy. Na^+/Ca^<2+> exchange current (I_<NCX>) was measured by the whole cell patch clamp method. (1) Pilsicainide (>5 μM) significantly reduced CaT at all stimulation rates, and the reduction was more prominent use-dependently (p<0.05 vs. control, n=7). (2) An inhibitor of rNCX, 1 μM KB-R7943 decreased CS and CaT only at 2 Hz (peak indo-1 ratio ; from 1.02±0.13 to 0.98±0.11 at 0.5 Hz, n.s., 1.96±0.11 to 1.45±0.11 at 2 Hz, p<0.05, n=7). (3) On diminishing CS and CaT by 30 μM plisicainide at 2 Hz, the following addition of 1 μM KB-R7943 had no further effects. (4) 100 μM Pilsicainide did not affect to I_<NCX>. (5) The significant cytosolic Na^+ accumulation was observed only at 2 Hz in control, and Pilsicainide suppressed the accumulation in [Na^+]_i dose-dependently at 2 Hz. (p<0.05 vs. control, n=5). The negative inotropic effects of NCB could involve the reduction of Ca^<2+> influx via rNCX by preventing cytosolic (not only subsarcolemmal) Na^+ accumulation. The mechanism would have a more important implication in failed heart with tachyarrhythmia. Less

在心肌细胞中，肌浆网（SR）的Ca^<2 +>诱导的Ca^<2+>释放（CICR）在Ca瞬变中起着关键作用。然而，细胞内Na^+浓度（[Na^+] i）的变化也通过Na^+/Ca^<2+>交换对CICR起重要作用。Na^+通道阻滞剂（NCB）的负性肌力作用是通过干扰细胞内Ca^<2+>的调节来介导的。Na^+通道门控可诱导细胞内Na^+蓄积，从而通过反向Na^+/Ca^2+交换（rNCX）增加Ca^2+内流。本研究的主要目的是研究NCB减少细胞Na^+积聚是否真的通过rNCX消除Ca^<2+>内流而导致负性肌力作用。为了阐明rNCX在Na^+通道阻滞剂负性肌力作用中的作用，我们检测了纯Na^+通道阻滞剂吡西卡尼对频率依赖性增加的收缩细胞缩短（C ...更多信息 S）和Ca^<2+>瞬变（CaT）。用钠绿和激光扫描共聚焦显微镜观察[Na^+] i的变化。全细胞膜片钳法测定Na^+/Ca^&lt;2+&gt;交换电流（I_<NCX>）。(1)在所有刺激率下，匹西卡尼（&gt;5 μM）均显著降低CaT，并且这种降低具有更显著的使用依赖性（p&lt;0.05，与对照组相比，n=7）。(2)rNCX的抑制剂1 μM KB-R7943仅在2 Hz时降低CS和CaT（峰值indo-1比值;在0.5 Hz时从1.02±0.13降至0.98±0.11，n.s.，1.96±0.11至1.45±0.11，p&lt;0.05，n=7）。(3)在2 Hz下，30 μM plisicainide减少CS和CaT，随后加入1 μM KB-R7943没有进一步的影响。(4)100 μM吡西卡尼对I_2无影响<NCX>。(5)对照组仅在2 Hz时观察到显著的胞浆Na^+蓄积，而Pilsicainide在2 Hz时剂量依赖性地抑制[Na^+] i的蓄积。（p&lt;0.05相对于对照，n=5）。NCB的负性肌力作用可能涉及通过阻止胞浆（不仅是肌膜下）Na^+蓄积，减少经由rNCX的Ca^2+内流。这一机制对心力衰竭合并快速性心律失常的发生具有重要意义。少

项目成果

Protective effects of hydrogen peroxide against ischemia/repeifusion injury in perfused rat hearts.

过氧化氢对灌注大鼠心脏缺血/再灌注损伤的保护作用。

• 发表时间: 2003
• 期刊: Circ J 67
• 作者: Morishita R.;Yamasaki K.;Shimamura M.;Ohtani K.;Ahn JD.;Tomita N.;Tomita N.;Morishita R.;Morishita R.;Shimamura M;Yamasaki K;Koike H;Matsumoto K;Tomita N;Namba T;Makino H;Azuma H;Ogushi I;Shimamura M.;Yamasaki K.;Koike H.;Masao Saotome.;Matsumoto K.;Nobuyuki Wakahara;Tomita N.;Nobuyuki Wakahara.;Namba T.;Makino H.;Toshihiko Sugi.;Azuma H.;Hiroshi Satoh.;Ogushi I.;Hiroshi Satoh.;Tomita N.;Kazuhiro Takeuchi.;Morishita R.;Yasuhiro Yaguchi.
• 通讯作者: Yasuhiro Yaguchi.

Effects of cytochrome P450 inhibitors on agonist-induced Ca2+ responses and production of NO and PGI2 in vascular endothelial cells

细胞色素 P450 抑制剂对激动剂诱导的 Ca2+ 反应以及血管内皮细胞中 NO 和 PGI2 产生的影响

• DOI: 10.1023/a:1024136318779
• 发表时间: 2003
• 期刊: Molecular and Cellular Biochemistry
• 影响因子: 4.3
• 作者: K. Takeuchi;Hiroshi Watanabe;Q. Tran;Mariko Ozeki;A. Uehara;H. Katoh;H. Satoh;H. Terada;K. Ohashi;H. Hayashi
• 通讯作者: H. Hayashi

Resumption of intracellular Ca^<2+> cycling as a therapeutic strategy for heart failure

恢复细胞内Ca^2循环作为心力衰竭的治疗策略

• 期刊: Research Trends, Current Topics in Pharmacology (In press)
• 作者: Morishita R.;Yamasaki K.;Shimamura M.;Ohtani K.;Ahn JD.;Tomita N.;Tomita N.;Morishita R.;Morishita R.;Shimamura M;Yamasaki K;Koike H;Matsumoto K;Tomita N;Namba T;Makino H;Azuma H;Ogushi I;Shimamura M.;Yamasaki K.;Koike H.;Masao Saotome.;Matsumoto K.;Nobuyuki Wakahara;Tomita N.;Nobuyuki Wakahara.;Namba T.;Makino H.;Toshihiko Sugi.;Azuma H.;Hiroshi Satoh.;Ogushi I.;Hiroshi Satoh.;Tomita N.;Kazuhiro Takeuchi.;Morishita R.;Yasuhiro Yaguchi.;Tomita N.;Shu Yoshihara;Tomita N.;Masao Saotome;Miwa K;Hiroshi Satoh
• 通讯作者: Hiroshi Satoh

Post-challenge hyperinsulinemia rather than hyperglycemia is associated with the severity of coronary artery disease in patients without previous diagnosis of diabetes mellitus.

对于既往没有糖尿病诊断的患者，攻击后高胰岛素血症而不是高血糖与冠状动脉疾病的严重程度相关。

• 期刊: Heart (in press)
• 作者: Morishita R.;Yamasaki K.;Shimamura M.;Ohtani K.;Ahn JD.;Tomita N.;Tomita N.;Morishita R.;Morishita R.;Shimamura M;Yamasaki K;Koike H;Matsumoto K;Tomita N;Namba T;Makino H;Azuma H;Ogushi I;Shimamura M.;Yamasaki K.;Koike H.;Masao Saotome.;Matsumoto K.;Nobuyuki Wakahara;Tomita N.;Nobuyuki Wakahara.;Namba T.;Makino H.;Toshihiko Sugi.;Azuma H.;Hiroshi Satoh.;Ogushi I.;Hiroshi Satoh.;Tomita N.;Kazuhiro Takeuchi.;Morishita R.;Yasuhiro Yaguchi.;Tomita N.;Shu Yoshihara;Tomita N.;Masao Saotome;Miwa K;Hiroshi Satoh;Miwa K.;Hiroshi Satoh.
• 通讯作者: Hiroshi Satoh.

Mitochondrial membrane motential modulates regulation of mitochondrial Ca^<2+> in skinned rat ventricular myocytes.

线粒体膜运动调节带皮大鼠心室肌细胞中线粒体Ca 2+ 的调节。

• 发表时间: 2005
• 期刊: Am J Physiol Heart Circ Physiol 288
• 作者: Morishita R.;Yamasaki K.;Shimamura M.;Ohtani K.;Ahn JD.;Tomita N.;Tomita N.;Morishita R.;Morishita R.;Shimamura M;Yamasaki K;Koike H;Matsumoto K;Tomita N;Namba T;Makino H;Azuma H;Ogushi I;Shimamura M.;Yamasaki K.;Koike H.;Masao Saotome.
• 通讯作者: Masao Saotome.