EFFECTS OF VOLATILE ANESTHETICS ON ENDOTHELIAL NITRIC OXIDE SYNTHESIS AND VASODILATION MEDIATED THOROUGH THE CaィイD12+ィエD1 INFLUX PROMOTED BY THE DEPLETION OF CaィイD12+ィエD1 IN ENDOPLASMIC RETICULUM

挥发性麻醉剂对内质网 CaiD12+D1 耗竭促进的 CaiD12+D1 内流介导的内皮一氧化氮合成和血管舒张的影响

• 批准号: 10671440
• 负责人: MIZUMOTO Kazuhiro
• 金额: $ 1.28万
• 依托单位: Wakayama Medical College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671440/
• 关键词: Volatile Anesthetics; Nitric Oxide; Endoplasmic Reticulum; CaィイD12+ィエD1 influx; Vasodilation; Cyclic GMP; 内皮; チトクローム P450; Ca流入因子; cGMP; 血管内皮; Ca^<2+>(カルシウムイオン); チトクロームP450

Elevation of intracellular CaィイD12+ィエD1 level is and essential requisite for endothelial nitric oxide (NO) synthesis. As one of these pathways, it has been reported that the depletion of CaィイD12+ィエD1 in endoplasmic reticulum (ER) activated microsomal cytochrome P450 mono-oxygenase (P450 MO) and induces the biosynthesis of 5, 6-eopoxyeicosatrienoic acid (5, 6-EET), which in turn promote CaィイD12+ィエD1 influx from extracelluar fluids. Thapsigargin is one of the agents to induce this pathway. Volatile anesthetics have been demonstrated inhibit P450 MO activity in liver. However, little is known about their effects on vascular smooth muscle relaxation mediated though P450 MO in endothelium. The purpose of this study was to examine the effects of volatile anesthetics on endothelial P450 MO-mediated vasodilation.With institutional approval, rings with endothelium from isolated rat thoracic aorta were suspended under a resting tension of 3.0 g in Krebs' bicarbonate solution. The rings were prec … More ontracted with phenylephrine (3X10ィイD1-7ィエD1M ) and the relaxant effect of thapsigargin (10ィイD1-7ィエD1 to 10ィイD1-6ィエD1 M), which depletes CaィイD12+ィエD1 in ER, and that of 5, 6-EET (5X10ィイD1-6ィエD1 M) were tested in the presence or absence of volatile anesthetics (Halothane, Isoflurane, and Sevoflurane, 1 to 3 MAC in human). Thapsigargin-induced relaxation was also tested in the presence or absence of pretreatment with inhibitors, which were econazole (P450 MO inhibitor, 2X10ィイD1-5ィエD1 M) and NィイD1GィエD1-nitro-L-arginine (L-NA, 10ィイD1-5ィエD1 M).Thapsigargin caused a concentration-dependent relaxation, and that at 10ィイD1-6ィエD1 M was compatible with 5, 6-EET (5X10ィイD1-6ィエD1 M)-induced relaxation. Removal of endothelium or pretreatment with L-NA attenuated thapsigargin-induced relaxation significantly. The pretreatment with econazole also inhibited it significantly. Thapsigargin-induced relaxation was attenuated by Hal, Iso, and Sevo (1 to 3MAC) in a concentration-dependent manner. The potency of inhibitory effect of anesthetics on thapsigargin-induced relaxation was ranked as Hal > Iso > Sevo at 3 MAC. Relaxation induced by 5, 6-EET was not influenced by volatile anesthetics. The results of the current study confirm that thapsigargin-induced vasodilation is NO-dependent and regulated by endothelial P450 MO. It is indicated that volatile anesthetics attenuate endothelium-dependent vasodilation mediated via the CaィイD12+ィエD1 depletion in ER-induced CaィイD12+ィエD1 influx, and 3) this attenuation is mediated by the inhibition of P450 MO in endothelium by anesthetics. Less

细胞内CAIY D12+IE D1水平的升高是内皮一氧化氮（NO）合成必需的必需条件。 As one of these pathways, it has been reported that the depletion of Caiy D12+Ie D1 in endoplasmic reticulum (ER) activated microsomal cytochrome P450 mono-oxygenase (P450 MO) and induces the biosynthesis of 5, 6-eopoxyeiicosatrienoic acid (5, 6-EET), which in turn promote Caiy D12+IE D1对外卢尔液的影响。 ThapseGargin是诱导这一途径的代理之一。挥发性麻醉已经证明了肝脏中的P450 MO活性。然而，关于它们对森林中p450 mo介导的血管平滑肌松弛的影响知之甚少。这项研究的目的是检查挥发性麻醉药对森林P450 mo介导的血管舒张的影响。随着机构的批准，在Krebs的二氯苯甲酸盐溶液中，在3.0 g的静息张力下悬挂了分离的大鼠胸主动脉的内皮响起。环是先进的……更多地用苯肾上腺素（3x10 d1-7 d1m）和thapigargin（10 d1-7 d1至10 d1 d1-6 d1 m）的松弛作用，这会消耗ER中的Cai d12+ d1，而在ER中消耗了5、6- eet（5x10 d1-6 d1 m）的暂停（5x10 d1-d1 d1 d1 disters）。异氟烷和Sevoflurane，人类1至3 Mac）。在存在或不存在抑制剂的情况下，thapsegargin诱导的弛豫也进行了测试，这些抑制剂（P450 MO抑制剂，2x10i D1-5i D1 M）和NYI D1GIE D1GIE D1-NITRO-L-L-Arginine（L-NA，L-NA，10i D1-5I D1 M）。 ThapseGargin引起了浓度依赖性的松弛，并且在10i D1-6i D1 M处与5，6-EET（5x10II D1-6IE D1 M）诱导的弛豫兼容。用L-NA降低了thapigargin诱导的松弛，去除内皮或预处理。依康唑的预处理也大大抑制了它。 HAL，ISO和Sevo（1至3MAC）以浓度依赖性方式减弱了Thapigargin诱导的弛豫。麻醉剂对Thapigargin诱导的松弛的抑制作用的增强作用被排名为Hal> iso> sevo，在3 Mac处。由5，6-诱导的放松不受挥发性麻醉的影响。当前研究的结果证实，thapigargin诱导的血管舒张不依赖于内皮P450 mo。据表明，挥发性麻醉剂减弱了通过CAIY D12+IE D1介导的内皮依赖性血管舒张，在ER诱导的CAIY D12+IE D1中介导的D1耗尽，而3）3）3）这种衰减是由p450 MO在p450 mo中通过动脉消费的抑制作用介导的。较少的