ANESTHETICS & ENDOTHELIUM-DEPENDENT CIRCULATORY CONTROL

麻醉剂

• 批准号: 3303102
• 负责人: ALEX L LOEB
• 金额: $ 17.1万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-02-01 至 1996-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3303102
• 关键词: anesthetics; animal tissue; arginine; biological signal transduction; calcium flux; cardiovascular pharmacology; drug interactions; enflurane; halothane; inositol phosphates; isoflurane; ketamine; microcirculation; microscopy; peripheral blood vessel; tissue /cell culture; ultrasound blood flow measurement; vascular endothelium; vascular resistance; vascular smooth muscle; vasodilators; video recording system

There is significant heterogeneity among clinically used anesthetics with respect to their vascular effects in specific organs. Our hypothesis is that anesthetic interactions with vascular endothelium alter regional blood flows via differential effects on endothelium-dependent modulation of smooth muscle tone; these alterations may account for the specific differences in regional blood flow induced by the different anesthetics. Inhibition of endothelium-derived relaxing factor (EDRF) with N(G)- monomethyl-L-arginine (NMMA) markedly increased blood pressure and systemic and regional vascular resistance in awake and in isoflurane (ISO) and halothane (HAL) anesthetized rats. These effects were reversed by L-arginine, indicating an EDRF-related mechanism. During ISO, NMMA increased blood pressure (54%) and regional resistance in kidney(156%), skin (234%), and hepatic artery (93%) to a significantly greater degree than was seen in HAL or awake groups. These results indicated ISO enhanced EDRF action while HAL did not. In addition, NMMA decreased responses to endothelium-dependent vasodilators in the rat cremaster muscle microcirculation. In cultured bovine arterial endothelial cells, we observed that halothane inhibited the increase in cytosolic calcium that was stimulated by the endothelium-dependent vasodilator bradykinin, whereas isoflurane did not. These results indicate that the endothelium exerts significant control over the peripheral vasculature in anesthetized rats and that alterations in receptor activation/coupling may be important mechanisms by which anesthetics produce their differential vascular effects. The first aim of this proposal is to determine the effects of anesthetics (halothane, enflurane, isoflurane, ketamine, desflurane) on endothelium-dependent control of vessel diameter and blood flow in the rat cremaster muscle microcirculation using the EDRF inhibitor, NMMA. The second aim is to determine the effects of the test anesthetics on signal transduction (basal and agonist-stimulated concentrations of cytosolic calcium and inositol trisphosphate) and on the subsequent release of vasodilators (prostacyclin, EDRF) from cultured endothelial cells. Understanding the mechanisms by which anesthetics modify circulatory control will allow the anesthesiologist to pharmacologically manipulate organ blood flows and/or choose agents that will benefit patients when specific organs are at risk for ischemia or cellular hypoxia.

临床使用的麻醉药之间存在显着的异质性 关于它们对特定器官的血管作用。 我们的假设是 麻醉剂与血管内皮的相互作用改变了局部血液 通过对内皮依赖性调节的不同影响来流动 平滑肌张力；这些改变可能会导致具体的 不同麻醉药引起的局部血流差异。 用 N(G)- 抑制内皮源性舒张因子 (EDRF) 单甲基-L-精氨酸（NMMA）显着升高血压和全身 以及清醒状态和异氟烷 (ISO) 状态下的局部血管阻力 氟烷（HAL）麻醉大鼠。 这些影响被逆转了 L-精氨酸，表明与 EDRF 相关的机制。 ISO、NMMA 期间 血压升高（54%）和肾脏局部阻力升高（156%）， 皮肤（234%）和肝动脉（93%）的程度明显更高 比在 HAL 或清醒组中看到的要多。 这些结果表明 ISO 增强 EDRF 采取行动，而 HAL 没有采取行动。 此外，NMMA 减少了对 大鼠提睾肌中的内皮依赖性血管扩张剂 微循环。 在培养的牛动脉内皮细胞中，我们 观察到氟烷抑制细胞质钙的增加， 受到内皮依赖性血管舒张剂缓激肽的刺激，而 异氟烷没有。 这些结果表明内皮发挥 对麻醉大鼠外周血管系统的显着控制 受体激活/偶联的改变可能很重要 麻醉药产生差异化血管的机制 影响。 该提案的首要目的是确定以下措施的影响： 麻醉剂（氟烷、安氟烷、异氟烷、氯胺酮、地氟烷） 大鼠血管直径和血流量的内皮依赖性控制 使用 EDRF 抑制剂 NMMA 改善提睾肌微循环。 这 第二个目标是确定测试麻醉剂对信号的影响 转导（基础和激动剂刺激的胞质浓度 钙和肌醇三磷酸）和随后的释放 来自培养的内皮细胞的血管扩张剂（前列环素，EDRF）。 了解麻醉药改变循环的机制 控制将允许麻醉师进行药理学操作 器官血流和/或选择有利于患者的药物 特定器官面临缺血或细胞缺氧的风险。