CELLULAR EFFECTS OF ANESTHETICS IN THE HEART

麻醉药对心脏的细胞影响

• 批准号: 3356659
• 负责人: Zeljko J. Bosnjak
• 金额: $ 14.8万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3356659
• 关键词: action potentials; adrenergic agents; anesthetics; arrhythmia; catecholamines; dosage; drug interactions; drug metabolism; electrophysiology; enflurane; fluorescent dye /probe; halothane; heart Purkinje's fiber; inhalation anesthesia; isoflurane; isoproterenol; membrane channels; myocardial infarction; neural conduction; neuromuscular junction; norepinephrine; single cell analysis; sodium potassium exchanging ATPase; tissue /cell culture; voltage /patch clamp

The objective of this proposed research is to investigate the mechanisms of the interaction between volatile anesthetic agents and catecholamines on the cellular electrophysiologic properties and ionic currents of cardiac Purkinje fibers to better understand their combined effects on generation of arrhythmias with a history of prior myocardial infarction in association with activation or reflex sympathetic activity or during the administration os exogenous catecholamines to support the circulation. Our knowledge of the electrophysiologic mechanisms generating these arrhythmias would be enhanced by use of in vitro models to examine the interactions between the volatile anesthetics and the abnormal electrical activity induced by norepinephrine and selective alpha- and beta-adrenergic agonists in ischemic and nonischemic hearts. Specific objectives are: 1) To determine effects of halothane and isoflurane in combination with adrenergic agonists on electrophysiology of Purkinje fiber and Purkinje fiber-ventricular muscle junction conduction and on regional action potential characteristics. 2) To determine effects of halothane, isoflurane and enflurane on the intracellular calcium changes associated with catecholamine stimulated automaticity of normal Purkinje fibers and the triggered activity of ischemic Purkinje fibers. 3) To determine the mechanisms underlying the separate and combined effects of these drugs by direct measurements of their actions on whole cell ionic currents and single channel activity. Our major achievement over the last several years has been the ability to perform electrophysiological studies of Ca2+, Na+ and K+ currents, single channel K+ kinetics and intracellular calcium ([Ca2+]i) and electrophysiologic properties of Purkinje fibers in the presence of catecholamine. The proposed studies of this application are coordinated as a major effort to understand the mechanisms by which anesthetics in combination with catecholamines modulate cardiac electrophysiology. Previous work on catecholamine-anesthetic interactions has been largely descriptive and focused on adrenergic effects in vivo with less attention paid to cellular electrophysiology. Determination of catecholamine- anesthetic interactions on normal and ischemic cardiac tissues may permit development of specific therapeutic approaches for the perioperative management of cardiac arrhythmias. GRANT=R01HL35027 A continuing investigation of physiological mechanisms underlying regional coronary and myocardial responses to altered O2 supply and demand is proposed. These mechanisms will be delineated for the first time in the working, in situ right ventricle (RV), and differences between right coronary (RC) and left coronary (LC) control mechanisms will be related to differences in right and left ventricular function. The investigation will define: 1) mechanisms which regulate RC blood flow, and will define contributions of RC flow and O2 extraction reserves in supplying O2 to RV myocardium when a) O2 demand is increased and b) RC arterial O2 content is reduced; 2) the role of the pericardium in the RC response to altered RC perfusion pressure, RC vasomotor tone, and RV preload; 3) potencies of alpha adrenoceptor subtypes in the RC circulation, and will define their respective roles in RC pressure-flow autoregulation, modulation of RC oxygen extraction reserve, and possible limitation of RC oxygen supply; 4) the role of myocardial PO2 compared to that of vasoactive metabolites, especially purine nucleosides, in the regulation of RC and LC vascular resistance, and will define subcellular adjustments triggered by states of oxygen deficiency and providing for metabolic control of coronary blood flow; 5) the role of adenosine or its breakdown products in limiting myocardial oxygen demand under conditions of reduced myocardial oxygen supply. Branches of the RC and LC circulations of anesthetized dogs will be perfused selectively with blood of controlled O2 content, and venous blood from the perfused tissue will be collected. O2 supply will be altered by varying selectively and in combination perfusate O2 content, perfusion pressure, and by infusing coronary vasodilators. Myocardial O2 demand will be altered by varying selectively heart rare, ventricular preload and afterload, and myocardial inotropic state. Variables to be measured: 1) coronary blood flow (flowmeter and microsphere distribution); 2) coronary arterial and venous O2 tension and content; 3) coronary arterial and venous concentrations of nucleosides, lactate, and pyruvate (HPLC and enzymatic techniques); 4) coronary small vessel and total vascular volumes (isotope dilution); 5) right and left ventricular diastolic and systolic pressures; 6) systemic and pulmonary arterial pressures and heart rate; 7) regional myocardial diastolic and systolic segment lengths (ultrasonic crystals), PO2 (polarographic electrode), concentrations of high energy phosphates and nucleosides (HPLC and enzymatic techniques), and electrograms. The investigation is in accordance with long term objectives to define mechanisms which adjust coronary blood flow to meet myocardial O2 requirements under changing conditions of O2 demand and supply. The results will have clinical relevance to conditions which alter ventricular and coronary function and to conditions of which alter the O2 content of arterial blood.

这项拟议的研究的目的是研究 挥发性麻醉剂与儿茶酚胺之间的相互作用 心脏的细胞电生理特性和离子电流 Purkinje纤维可以更好地理解它们对世代的综合影响 心律不齐的有史前心肌梗塞的病史 激活或反射交感活动或在给药期间 OS外源性儿茶酚胺支持循环。 我们的知识 产生这些心律不齐的电生理机制将是 通过使用体外模型来研究 挥发性麻醉和由异常的电活动 去甲肾上腺素和选择性α-和β-肾上腺素能激动剂 缺血性和非缺血性心脏。 特定目标是： 1）确定氟烷和异氟烷的影响 purkinje纤维和浦肯野电生理学的肾上腺素能激动剂 纤维 - 室里肌肉连接传导和区域作用 潜在特征。 2）确定氟烷，异氟烷和enflurane对 与儿茶酚胺相关的细胞内钙变化刺激 普通浦肯野纤维的自动性和触发的活动 缺血性浦肯野纤维。 3）确定单独和组合效应的基础机制 通过直接测量其对全细胞离子的作用的直接测量 电流和单个通道活动。 在过去几年中，我们的重大成就是能够 对Ca2+，Na+和K+电流进行电生理研究，单个 通道K+动力学和细胞内钙（[Ca2+] I）和 在存在的情况下，Purkinje纤维的电生理特性 儿茶酚胺。 该应用的拟议研究被协调为 了解麻醉剂中的机制的主要努力 结合儿茶酚胺调节心脏电生理学。 先前关于儿茶酚胺 - 麻省相互作用的工作在很大程度上是 描述性，专注于体内的肾上腺素能作用，而关注较少 支付给细胞电生理学。 儿茶酚胺的确定 正常和缺血性心脏组织上的麻醉相互作用可能允许 开发围手术期的特定治疗方法 心律不齐的管理。 格兰特= R01HL35027 对区域基础的生理机制的持续调查 冠状动脉和心肌对O2供求改变的反应是 建议的。 这些机制将首次在 工作，原位右心室（RV）以及右侧的差异 冠状动脉（RC）和左冠状动脉（LC）控制机制将与 左右心室功能的差异。 调查将 定义：1）调节RC血流并定义的机制 RC流量和O2提取储备在向RV提供O2方面的贡献 当A）O2需求增加并且b）RC动脉O2含量为 减少； 2）心包在RC对RC改变的反应中的作用 灌注压力，RC血管舒适音调和RV预紧力； 3）效力 RC循环中的Alpha adrenoceptor子类型，并将定义其 在RC压力流动调节中的各自作用，RC的调节 氧气提取储备，以及RC氧供应的可能限制； 4） 与血管活性代谢物相比，心肌PO2的作用， 特别是嘌呤核苷，在RC和LC血管的调节中 电阻，并将定义由 氧缺乏并为冠状动脉血液的代谢控制提供 流动; 5）腺苷或其崩溃产品在限制中的作用 在减少心肌氧的条件下，心肌氧需求 供应。 麻醉狗的RC和LC循环的分支将 用受控的O2含量和静脉有选择性地灌注 将收集来自灌注组织的血液。 O2电源将是 通过选择性变化和在灌注液含量o2含量中变化而改变， 灌注压力，并通过注入冠状动脉血管扩张剂。 心肌O2 需求将通过选择性变化的心脏稀有，心室来改变需求 预加载和后负荷以及心肌肌力状态。 变量是 测量：1）冠状动脉血流（流量计和微球分布）； 2）冠状动脉和静脉O2张力和含量； 3）冠状动脉 核苷，乳酸和丙酮酸的动脉和静脉浓度 （HPLC和酶促技术）； 4）冠状动脉小容器和总船只 血管体积（同位素稀释）； 5）左右心室 舒张压和收缩压； 6）系统性和肺动脉 压力和心率； 7）区域心肌舒张压和收缩期 段长度（超声晶体），PO2（光学电极）， 高能磷酸盐和核苷的浓度（HPLC和 酶促技术）和电图。 调查正在 根据长期目标来定义调整机制 在更改下满足心肌O2要求的冠状动脉血流 O2需求和供应条件。 结果将有临床 与改变心室和冠状动脉功能以及 在其条件下改变动脉血的O2含量。