EFFECTS OF NEUROENDOCRINAL FACTORS ON CARDIAC SODIUM-CALCIUM EXCHANGER

神经内分泌因素对心脏钠钙交换的影响

• 批准号: 11670096
• 负责人: KIMURA Junko
• 金额: $ 2.3万
• 依托单位: Fukushima Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670096/
• 关键词: SODIUM-CALCIUM EXCHANGE CURRENT; WHOLECELPATCH CLAMP; GUINEA PIG; PHOSPHORYLATION; DEPHOSPHORYLATION; CALCIUM; SODIUM; ANTIARRHYTHMIC DRUGS; sodium-calcium exchange; cardiac myocytes; whole cell clamp; guinea pig; transporter; inhibitor; hea

1) As neuroendocrine factors, we tested effects on Na^+/Ca^<2+> exchange current (I_<NCX>) of angiotensin II, endothelin, epinephrine and phenylephrine with the whole cell voltage clamp method using single guinea-pig cardiac ventricular cells. However, none of them exerted effects on Na-Ca exchange current (I_<NCX>)2) Butanedione monoxime (BDM) is called a chemical phosphatase. We found that BDM inhibited I_<NCX>. We tested whether the effect of BDM was due to dephosphorylation of NCX. Activation of A-kinase and C kinase did not affect NCX. NCX1 mutants with possible phosphorylation site serines replaced by alanines were also inhibited by BDM. Therefore we concluded that phosphorylation and dephosphorylation mechanisms are not involved in the inhibitory effects of BDM on NCX.3) Interaction of NCX with Na-H exchange was investigated by measuring the reversal potential (E_<NCX>) of I_<NCX> before and after acidification to pH4.9 from pH7.4. E_<NCX> shifted in the negative direction by acidification. The negative shift was inhibited by inhibitors of Na-H exchanger and enhanced by Na-H exchange accelerator. Addition of Na-H exchange inhibitor only during the recovery from acidification also prevented shift in E_<NCX>, indicating that Na-H exchange was inhibited by acid. These results suggest that Na-H exchange and Na-Ca exchange are closely linked to each other. Increase in Na_I increased during recovery from acidification was calculated to be about 3 mM.

1)作为神经内分泌因子，我们<NCX>使用单个豚鼠心室细胞，采用全细胞电压钳方法测试了血管紧张素II、内皮素、肾上腺素和苯肾上腺素对Na^+/Ca^&lt;2+&gt;交换电流（I_）的影响。2<NCX>）丁二酮单肟（Butanedione monoxime，BDM）是一种化学磷酸酶。发现BDM抑制<NCX>I_2。我们测试了BDM的作用是否是由于NCX的去磷酸化。A激酶和C激酶的激活不影响NCX。NCX 1突变体可能的磷酸化位点丝氨酸被丙氨酸取代，也被BDM抑制。因此，BDM对NCX的抑制作用不涉及磷酸化和去磷酸化机制。3）通过测定NCX与Na-H交换的相互作用，研究了NCX与Na-H交换的<NCX>相互作用<NCX>。酸化使E_<NCX>（1-x）向负方向移动。Na-H交换抑制剂可抑制负移，Na-H交换促进剂可增强负移。仅在酸化恢复过程中加入Na-H交换抑制剂也能阻止E_1的移动，<NCX>表明Na-H交换受到酸的抑制。这些结果表明，Na-H交换和Na-Ca交换是密切相关的。计算出酸化恢复过程中Na_I的增加量约为3 mM。

项目成果

Katoh Y,Hashimoto S, Kimura J,Watanabe T.: "Inhibitory action of troglitazone, an insulin-sensitizing agent, on the calcium current in cardiac ventricular cells of guinea pig."Japanese Journal of Pharmacology. 82. 102-109 (2000)

Katoh Y，Hashimoto S，Kimura J，Watanabe T.：“胰岛素增敏剂曲格列酮对豚鼠心室细胞钙电流的抑制作用。”日本药理学杂志。

WATANABE Yasuhide, KIMURA Junko: "Blocking effect of bepridil on Na^+/Ca^<2+> exchange current in guinea pig cardiac ventricular myocytes"Jpn. J. Pharmacol. 85. 370-375 (2001)

WATANABE Yasuhide、KIMURA Junko：“苯普地尔对豚鼠心室肌​​细胞 Na^ /Ca^2 > 交换电流的阻断作用”Jpn。

Kimura J.: "Sodium-calcium exchanger heart cells"11th International Conference of Women Engineers and scieutists. 969-974 (1999)

Kimura J.：“钠钙交换心脏细胞”第11届国际女工程师和科学家会议。

Kimura J.: "Cardiac Na^+/Ca^<2+> exchanger : Pathophysiology and pharmacology.In : Heart Physiology and Pathology"Sperelakis N, Kurachi Y, Terzic A, Cohen MV. 419-425 (2000)

Kimura J.：“心脏Na ^ /Ca ^ 2 >交换器：病理生理学和药理学。在：心脏生理学和病理学”Sperelakis N，Kurachi Y，Terzic A，Cohen MV。

TAKANO Shizuko, KIMURA Junko, ONO Tomoyuki: "Inhibition of aggregation of rabbit and human platelets induced by adrenaline and 5-hydroxytryptamine by KB-R7943, a Na^+/Ca^<2+> exchange inhibitor"Br. J. Pharmacol. 132. 1383-1388 (2001)

TAKANO Shizuko、KIMURA Junko、ONO Tomoyuki：“Na ^ /Ca ^ 2 交换抑制剂 KB-R7943 对肾上腺素和 5-羟色胺诱导的兔和人血小板聚集的抑制”Br。