ANESTHETICS & ENDOTHELIUM-DEPENDENT CIRCULATORY CONTROL

临床使用的麻醉剂之间存在显著的异质性， 关于它们对特定器官的血管影响。 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差异效应的流量 平滑肌张力;这些变化可能解释了特定的 不同麻醉剂诱导的局部血流差异。 用N（G）-抑制内皮源性舒张因子（EDRF） 单甲基-L-精氨酸（NMMA）显着增加血压和全身 和清醒时和异氟烷（ISO）时的局部血管阻力， 氟烷（HAL）麻醉大鼠。 这些影响被逆转， L-精氨酸，表明EDRF相关机制。 ISO期间，NMMA 血压升高（54%），肾局部阻力增加（156%）， 皮肤（234%）和肝动脉（93%），以显着更高的程度 在HAL或清醒组中观察到的。 这些结果表明ISO增强 EDRF行动，而HAL没有。 此外，NMMA降低了对 大鼠提睾肌内皮依赖性血管舒张剂 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， 由内皮依赖性血管舒张剂缓激肽刺激，而 异氟烷则没有。 这些结果表明，内皮细胞发挥 显著控制麻醉大鼠的外周血管 并且受体活化/偶联的改变可能是重要的 麻醉剂产生其差异性血管 方面的影响. 本建议的第一个目的是确定 麻醉剂（氟烷、恩氟烷、异氟烷、氯胺酮、地氟烷） 内皮依赖性调节大鼠血管直径和血流 使用EDRF抑制剂NMMA的提睾肌微循环。 的 第二个目的是确定测试麻醉剂对信号的影响 转导（细胞溶质的基础和激动剂刺激浓度） 钙和三磷酸肌醇）和随后释放的 血管扩张剂（前列环素，EDRF）。 了解麻醉剂改变循环的机制 控制将允许麻醉师手动操作 器官血液流动和/或选择将有益于患者的药剂， 特定器官有缺血或细胞缺氧的危险。

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.