Basic research for regulation and disorder of cardiac Ca signal
心脏Ca信号调控与紊乱的基础研究
基本信息
- 批准号:14370778
- 负责人:
- 金额:$ 9.09万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (B)
- 财政年份:2002
- 资助国家:日本
- 起止时间:2002 至 2003
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
In cardiovascular disorders, including myocardial infarction and heart failure, various endogenous regulators are released from divergent types of cell, such as endothelial cells, and play crucial role in progress and recovery of diseases. In chronic congestive heart failure, it has been considered that the myocardial contractile dysfunction is the key process of the disorder and the cardiotonic agents that reverse the dysfunction may be the primary target of drug therapy of the disease. The current therapeutic target has been recognized to be addressed to the suppression of modulatory mechanisms, such as adrenergic regulation, rennin-angiotensin and aldosterone system, in addition to cardiac unloading by reduction of pre-load and after-load. In heart failure it has been elucidated that the plasma levels of norepinephrine (NE) and endothelin-1 (ET-1) are elevated in the course of progress of severity of the disease. It is highly likely that NE and ET-1 regulate the myocardial contracti … More lity in patients with heart failure. We investigated, therefore, the regulation of myocardial contractility and Ca^<2+> by crosstalk of NE with ET-1 in canine ventricular myocardium and single myocytes. ET-1 alone did not cause any inotropic effect on canine ventricular myocardium, but induced complex regulation depending on the co-existing concentrations of NE. In the presence of NE around threshold concentrations (10^<-10>〜10^<-9>mol/L) ET-1 elicited a concentration-dependent positive inotropic effect (PIE) in association with an increase in myofilament Ca^<2+> sensitivity. The PIE of ET-1 is unique in that it requires simultaneous activation of both PKA and PKC. It is of interest that the activation of PKA has been established to shift the relationship of contractile force and [Ca^<2+>]_i to the right to direction implying a decrease in myofilament Ca^<2+> sensitivity due to phosphorylation of troponin I and phosphlamban (leading to SERCA2a activation). In contrast, it became evident that the activation of PKA by crosstalk with PKC activation elicits a PIE in association with an increase in myofilament Ca^<2+> sensitivity. The PIE of ET-1 was abolished by the PKA inhibitor, PKC inhibitor, PLC inhibitor or β-blocker. The present results imply that the crosstalk of NE and ET-1 plays a crucial role in contractile regulation in patients with heart failure. Less
在包括心肌梗死和心力衰竭在内的心血管疾病中,不同类型的细胞(如内皮细胞)释放各种内源性调节因子,在疾病的进展和恢复中起着至关重要的作用。在慢性充血性心力衰竭中,心肌收缩功能障碍一直被认为是该疾病的关键过程,而逆转心肌收缩功能障碍的强心剂可能是该疾病药物治疗的主要目标。目前的治疗目标被认为是抑制调节机制,如肾上腺素能调节、肾素-血管紧张素和醛固酮系统,以及通过减少负荷前和负荷后的心脏卸载。在心力衰竭中,血浆中去甲肾上腺素(NE)和内皮素-1 (ET-1)的水平随着病情的加重而升高。NE和ET-1极有可能调节心衰患者的心肌收缩功能。因此,我们研究了NE与ET-1的串扰对犬心室心肌和单个肌细胞心肌收缩力和Ca^<2+>的调节。单独的ET-1对犬心室心肌没有任何肌力作用,但根据NE的共存浓度诱导复杂的调节。当NE在阈值浓度(10^<-10> ~ 10^<-9>mol/L)附近存在时,ET-1引起浓度依赖的正性肌力效应(PIE),与肌丝Ca^<2+>敏感性的增加有关。ET-1的PIE是独特的,它需要同时激活PKA和PKC。有趣的是,PKA的激活将收缩力和[Ca^<2+>]_i的关系向右转移,这意味着肌丝Ca^<2+>敏感性的降低,这是由于肌钙蛋白I和磷蛋白的磷酸化(导致SERCA2a激活)。相反,很明显,通过串扰激活PKA与PKC激活引发PIE,并增加肌丝Ca^<2+>敏感性。PKA抑制剂、PKC抑制剂、PLC抑制剂或β-阻滞剂均可使ET-1的PIE消失。目前的结果表明,NE和ET-1的串扰在心力衰竭患者的收缩调节中起着至关重要的作用。少
项目成果
期刊论文数量(28)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Sakurai, K.: "Negative inotropic effects of angiotensin II, endothelin-1 and phenylephrine in indo-1 loaded adult mouse ventricular myocytes"Life Sci.. 70. 1173-1184 (2002)
Sakurai, K.:“血管紧张素 II、内皮素-1 和去氧肾上腺素对装载 indo-1 的成年小鼠心室肌细胞的负性肌力作用”生命科学 70. 1173-1184 (2002)
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- 影响因子:0
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- 通讯作者:
Ichiyanagi, O.: "Angiotensin II increase L-type Ca^<2+> current ingramicidin D-perforated adult rabbit ventricular myocytes : comparison with conventional patch-clamp method"Pflugers Arch-Eur J. Physiol. 444. 107-116 (2002)
Ichiyanagi, O.:“血管紧张素II增加L-型Ca^2>电流ingramicidin D-穿孔成年兔心室肌细胞:与传统膜片钳方法的比较”Pflugers Arch-Eur J. Physiol。
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- 影响因子:0
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Endoh, M.: "Mechanism of action of sensitizers-Update 2001"Cardiovasc.Drugs and Therapy. 15. 397-403 (2001)
Endoh, M.:“敏化剂的作用机制 - 2001 年更新”Cardiovasc.Drugs and Therapy。
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- 影响因子:0
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Ichiyanagi, O.: "Angiotensin II increases L-type Ca^<2+> current in gramicidin D-perforated adult rabbit ventricular myocytes : comparison with conventional patch-clamp method."Pflugers Arch.-Eur.J.Phyiol.. 444. 107-116 (2002)
Ichiyanagi, O.:“血管紧张素 II 增加短杆菌肽 D 穿孔成年兔心室肌细胞中的 L 型 Ca^2 > 电流:与传统膜片钳方法的比较。”Pflugers Arch.-Eur.J.Phyiol.. 444。
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- 影响因子:0
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Chu, L.: "Signal transduction and Ca^<2+> signaling in contractile regulation induced by crosstalk between endothelin-1 and norepinephrine in dog ventricular myocardium"Cire.Res.. 92. 1024-1032 (2003)
Chu, L.:“犬心室心肌中内皮素-1 和去甲肾上腺素之间的串扰诱导的收缩调节中的信号转导和 Ca^2 > 信号转导”Cire.Res.. 92. 1024-1032 (2003)
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{{ truncateString('ENDOH Masao', 18)}}的其他基金
Molecular pharmacological research for regulation and disorder of cardiac myocytes
心肌细胞调控与紊乱的分子药理学研究
- 批准号:
16390064 - 财政年份:2004
- 资助金额:
$ 9.09万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
MORECULAR PHARMACOLOGICAL STUDY OF SIGNAL TRANSDUCTION
信号转导的更常规药理学研究
- 批准号:
11470021 - 财政年份:1999
- 资助金额:
$ 9.09万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of Novel Therapeutic Agents for Treatment of Congestive Heart Failure by Means of Model Animals
通过模型动物开发治疗充血性心力衰竭的新型治疗剂
- 批准号:
11557203 - 财政年份:1999
- 资助金额:
$ 9.09万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of new drugs for the treatment of congestive heart failure
治疗充血性心力衰竭新药的开发
- 批准号:
07557193 - 财政年份:1995
- 资助金额:
$ 9.09万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
Development of novel cardiotonic agents
新型强心剂的开发
- 批准号:
04557009 - 财政年份:1992
- 资助金额:
$ 9.09万 - 项目类别:
Grant-in-Aid for Developmental Scientific Research (B)
A Molecular Mechanism, of Myocardial alpha-Adrenoceptor-mediated Signaltransductio
心肌α-肾上腺素受体介导的信号转导的分子机制
- 批准号:
03454142 - 财政年份:1991
- 资助金额:
$ 9.09万 - 项目类别:
Grant-in-Aid for General Scientific Research (B)
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