ANESTHETICS & ENDOTHELIUM-DEPENDENT CIRCULATORY CONTROL

临床使用的麻醉药之间存在显著的异质性 关于它们在特定器官中的血管效应。我们的假设是 麻醉剂与血管内皮细胞的相互作用改变局部血液 血流通过差异性效应对内皮细胞依赖的调节作用 平滑肌张力；这些变化可能解释了特定的 不同麻醉药所致局部血流的差异。 N(G)-对血管内皮源性松弛因子的抑制作用 单甲基L精氨酸(NMMA)显著升高血压和全身 清醒时和异氟醚(ISO)中的局部血管阻力 氟烷(HAL)麻醉大鼠。这些影响被以下因素逆转 L-精氨酸，提示一种与EDRF相关的机制。在ISO期间，NMMA 血压升高(54%)和肾脏局部阻力增加(156%)， 皮肤(234%)和肝动脉(93%) 比HAL或清醒组更多。这些结果表明ISO增强了 EDRF采取行动，而HAL则没有。此外，NMMA降低了对 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 观察到氟烷抑制了细胞内钙离子的增加 被内皮依赖的血管扩张剂缓激肽刺激，而 异氟醚没有。这些结果表明，内皮细胞施加了 麻醉大鼠对周围血管系统的显著控制 受体激活/偶联的改变可能是重要的 麻醉药产生不同血管的机制 效果。这项提案的第一个目标是确定 麻醉药物(氟烷、安氟醚、异氟醚、氯胺酮、地氟烷) 大鼠血管内径和血流量的内皮依赖性调控 使用EDRF抑制剂NMMA的提睾肌微循环。这个 第二个目的是确定测试麻醉药对信号的影响。 转导(基础和激动剂刺激的胞浆浓度 钙和肌醇三磷酸)和随后的释放 血管扩张剂(前列环素，EDRF)来自培养的内皮细胞。 了解麻醉药改变循环的机制 控制将允许麻醉师在药理上操纵 器官血流和/或选择将使患者受益的药物 特定的器官处于缺血或细胞缺氧的风险中。

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.