Anesthesia and Cardiomyocyte Signal Transduction
麻醉与心肌细胞信号转导
基本信息
- 批准号:6435656
- 负责人:
- 金额:$ 25.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-12-01 至 2005-11-30
- 项目状态:已结题
- 来源:
- 关键词:CHO cells acid base balance adrenergic receptor anesthesia anesthetics beta adrenergic receptor kinase biological signal transduction calcium channel cardiac myocytes catecholamines confocal scanning microscopy cyclic AMP electrophysiology enzyme activity fibroblasts heart function inositol phosphates isozymes laboratory rat myosins phosphorylation potassium channel protein kinase C sarcoplasmic reticulum sodium hydrogen exchanger troponin western blottings
项目摘要
The overall goal of this application is to identify fundamental cellular mechanisms by which the intravenous anesthetic, propofol, alters cardiac function. Our objectives are: 1) to investigate the actions of propofol on cellular mechanisms involved in steady state regulation of myocardial contractility and 2) to explore the actions of propofol on catecholamine activation of the heart. The rationale for the study is that induction of anesthesia with propofol is frequently associated with cardiovascular depression in patients with and without cardiac disease. The overarching hypothesis is that propofol alters cellular mechanisms involved in the regulation of intracellular free Ca2+ concentration ([Ca2+]i) and/or myofilament Ca2+ sensitivity at the level of the cardiomyocyte via an activation of distinct PKC isoforms. Using freshly dispersed adult rat ventricular myocytes, we will investigate the extent to which PKC activation is involved in propofol-induced changes in the cellular and subcellular mechanisms that regulate ion channel conductances and [Ca2+]i, sarcoplasmic reticulum (SR) Ca2+ handling and myofilament Ca2+ sensitivity. We present compelling preliminary evidence that propofol alters multiple cellular mechanisms involved in the regulation of [Ca2+]i and/or myofilament Ca2+ sensitivity via activation of PKC. Specific Aim 1 will investigate the effects of propofol on cellular mechanisms that regulate myofilament Ca2+ sensitivity (myofibrillar protein phosphorylation and intracellular pH). Specific Aim 2 will identify actions of propofol on cellular mechanisms that regulate [Ca2+]i (K+ and Ca2+ Currents, SR Ca2+ handling). Specific Aim 3 will identify site(s) in the signal transduction pathway and the cellular mechanism by which propofol alters the inotropic response to beta1 adrenoreceptor activation of cardiomyocytes. Specific Aim 4 will identify site(s) in the signal transduction pathway and the cellular mechanism by which propofol alters the inotropic response to alpha1a adrenoreceptor activation of cardiomyocytes. A variety of experimental preparations and techniques are utilized, including: 1) isolated SR vesicles to directly measure "real time" Ca2+ uptake; 2) purified myofibrils to measure contractile protein phosphorylation and myofibrillar actomyosin ATPase; 3) Western blot analysis and confocal microscopy to monitor translocation of PKC isoforms to distinct intracellular sites; 4) field-stimulated cardiomyocytes to simultaneously measure [Ca2+]i or pHi and shortening; 5) measurement of cAMP and IP3 accumulation; 6) electrophysiological measurements of Ca2+ and K+ channel activity; 7) Rat-1 fibroblasts selectively transfected with the alpha1a or beta1 adrenergic receptor for assessment of ligand binding; 8) inhibitor peptides selective for distinct PKC isoforms to identify isoform-specific changes in cellular mechanisms and function. These studies will yield novel information about cellular mechanisms of propofol-induced changes in myocardial regulation.
本应用的总体目标是确定静脉麻醉剂异丙酚改变心功能的基本细胞机制。我们的目标是:1)研究异丙酚对参与心肌收缩力稳态调节的细胞机制的作用;2)探索异丙酚对心脏儿茶酚胺活化的作用。这项研究的基本原理是,异丙酚诱导麻醉经常与有或无心脏病患者的心血管抑制有关。总的假设是,异丙酚通过激活不同的PKC亚型,在心肌细胞水平上改变参与调节细胞内游离Ca2+浓度([Ca2+]i)和/或肌丝Ca2+敏感性的细胞机制。使用新鲜分散的成年大鼠心室肌细胞,我们将研究PKC激活在多大程度上参与异丙酚诱导的细胞和亚细胞机制的变化,这些机制调节离子通道电导和[Ca2+]i、肌浆网(SR) Ca2+处理和肌丝Ca2+敏感性。我们提出了令人信服的初步证据,表明异丙酚通过激活PKC改变了参与调节[Ca2+]i和/或肌丝Ca2+敏感性的多种细胞机制。特异性目的1将研究异丙酚对调节肌丝Ca2+敏感性(肌纤维蛋白磷酸化和细胞内pH值)的细胞机制的影响。特异性目标2将确定异丙酚对调节[Ca2+]i (K+和Ca2+电流,SR Ca2+处理)的细胞机制的作用。特异性Aim 3将确定信号转导通路中的位点和异丙酚改变心肌细胞对β 1肾上腺素受体激活的肌力反应的细胞机制。特异性Aim 4将确定信号转导通路中的位点和异丙酚改变心肌细胞对α 1a肾上腺素受体激活的肌力反应的细胞机制。利用多种实验制备和技术,包括:1)分离的SR囊泡直接测量“实时”Ca2+摄取;2)纯化肌原纤维,测定收缩蛋白磷酸化和肌原纤维肌动球蛋白atp酶;3) Western blot分析和共聚焦显微镜监测PKC异构体在不同细胞内位点的易位;4)场刺激心肌细胞同时测量[Ca2+]i或pHi和缩短;5)测定cAMP和IP3积累量;6)电生理测量Ca2+和K+通道活性;7)选择性转染α 1a或β a1肾上腺素能受体的大鼠-1成纤维细胞评估配体结合;8)不同PKC亚型的选择性抑制剂肽,以识别亚型特异性的细胞机制和功能变化。这些研究将提供有关异丙酚诱导心肌调节变化的细胞机制的新信息。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('DEREK Scott DAMRON', 18)}}的其他基金
Propofol and Protein Kinase C: Molecular Interactions in Cardiomyocytes
异丙酚和蛋白激酶 C:心肌细胞中的分子相互作用
- 批准号:
7820938 - 财政年份:2009
- 资助金额:
$ 25.61万 - 项目类别:
Plasma Volume, Adrenergic Tone, and Hemodynamics in Nul
Nul 中的血浆容量、肾上腺素张力和血流动力学
- 批准号:
7041548 - 财政年份:2004
- 资助金额:
$ 25.61万 - 项目类别:
Propofol and Protein Kinase C: Molecular Interactions in Cardiomyocytes
异丙酚和蛋白激酶 C:心肌细胞中的分子相互作用
- 批准号:
7671426 - 财政年份:2001
- 资助金额:
$ 25.61万 - 项目类别:
Propofol and Protein Kinase C: Molecular Interactions in Cardiomyocytes
异丙酚和蛋白激酶 C:心肌细胞中的分子相互作用
- 批准号:
7487875 - 财政年份:2001
- 资助金额:
$ 25.61万 - 项目类别:
Propofol and Protein Kinase C: Molecular Interactions in Cardiomyocytes
异丙酚和蛋白激酶 C:心肌细胞中的分子相互作用
- 批准号:
7910441 - 财政年份:2001
- 资助金额:
$ 25.61万 - 项目类别:
Propofol and Protein Kinase C: Molecular Interactions in Cardiomyocytes
异丙酚和蛋白激酶 C:心肌细胞中的分子相互作用
- 批准号:
8127614 - 财政年份:2001
- 资助金额:
$ 25.61万 - 项目类别:
Propofol and Protein Kinase C: Molecular Interactions in Cardiomyocytes
异丙酚和蛋白激酶 C:心肌细胞中的分子相互作用
- 批准号:
7316888 - 财政年份:2000
- 资助金额:
$ 25.61万 - 项目类别:
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