Pajewski T N, DiFazio C A, Moscicki J C, Johns R A
Department of Anesthesiology, University of Virginia Health Sciences Center, Charlottesville, USA.
Anesthesiology. 1996 Nov;85(5):1111-9. doi: 10.1097/00000542-199611000-00020.
Nitric oxide (NO), a recognized cell messenger for activating soluble guanylate cyclase, is produced by the enzyme NO synthase in a wide variety of tissues, including vascular endothelium and the central nervous system. The authors previously reported the possible involvement of the NO pathway in the anesthetic state by showing that a specific NO synthase inhibitor, nitroG-L-arginine methyl ester (L-NAME), dose dependently and reversibly decreases the minimum alveolar concentration (MAC) for halothane anesthesia. The availability of a structurally distinct inhibitor selective for the neuronal isoform of NO synthase, 7-nitro indazole (7-NI), allowed for the possibility of dissociating the central nervous system effects of neuronal NO synthase inhibition from the cardiovascular effects of endothelial NO synthase inhibition.
The effect of two structurally distinct inhibitors of NO synthase, L-NAME and 7-NI, on the MAC of isoflurane was investigated in Sprague-Dawley rats while concurrently monitoring the animals' arterial blood pressure and heart rate. L-NAME (1 to 30 mg/kg given intravenously, dissolved in 0.9% saline) and 7-NI (20 to 1,000 mg/kg given intraperitoneally, dissolved in arachis oil) were administered after determining control MAC and 30 min before determining MAC in the presence of NO synthase inhibitor.
L-NAME and 7-NI caused a dose-dependent decrease from isoflurane control MAC (maximal effect: 35.5 +/- 2.5% and 43.0 +/- 1.7%, respectively) with a ceiling effect observed for both NO synthase inhibitors (above 10 mg/kg and 120 mg/kg, respectively). L-NAME administration significantly increased systolic and diastolic blood pressures (maximal effect: 39.9 +/- 2.2% and 64.3 +/- 4.0%, respectively), which were not accompanied by any changes in heart rate. 7-NI administration resulted in no changes in blood pressure and a small but clinically insignificant decrease in heart rate.
Inhibition of the NO synthase pathway decreased the MAC for isoflurane, which suggests that inhibition of the NO pathway decreases the level of consciousness and augments sedation, analgesia, and anesthesia. The MAC reduction by two structurally distinct NO synthase inhibitors supports that this is a specific effect on NO synthase. Furthermore, the action of the neuronal NO synthase inhibitor 7-NI supports an effect selective for neuronal NO synthase and also avoids the hypertensive response of generalized NO synthase inhibitors.
一氧化氮（NO）是一种公认的可激活可溶性鸟苷酸环化酶的细胞信使，由一氧化氮合酶在包括血管内皮和中枢神经系统在内的多种组织中产生。作者之前报道了NO途径可能参与麻醉状态，通过表明一种特异性一氧化氮合酶抑制剂，硝基-L-精氨酸甲酯（L-NAME），剂量依赖性且可逆地降低氟烷麻醉的最低肺泡浓度（MAC）。一种对一氧化氮合酶神经元同工型具有选择性的结构不同的抑制剂7-硝基吲唑（7-NI）的可得性，使得有可能将神经元一氧化氮合酶抑制的中枢神经系统效应与内皮一氧化氮合酶抑制的心血管效应区分开来。
在Sprague-Dawley大鼠中研究了两种结构不同的一氧化氮合酶抑制剂L-NAME和7-NI对异氟烷MAC的影响，同时监测动物的动脉血压和心率。在确定对照MAC后并在存在一氧化氮合酶抑制剂的情况下确定MAC前30分钟，静脉注射L-NAME（1至30mg/kg，溶于0.9%盐水中）和腹腔注射7-NI（20至1000mg/kg，溶于花生油中）。
L-NAME和7-NI导致异氟烷对照MAC剂量依赖性降低（最大效应分别为：35.5±2.5%和43.0±1.7%），两种一氧化氮合酶抑制剂均观察到有天花板效应（分别在10mg/kg和120mg/kg以上）。给予L-NAME显著升高收缩压和舒张压（最大效应分别为：39.9±2.2%和64.3±4.0%），但心率无任何变化。给予7-NI导致血压无变化，心率有小幅但临床上无显著意义的降低。
抑制一氧化氮合酶途径降低了异氟烷的MAC，这表明抑制NO途径降低了意识水平并增强了镇静、镇痛和麻醉作用。两种结构不同的一氧化氮合酶抑制剂使MAC降低支持了这是对一氧化氮合酶的特异性作用。此外，神经元一氧化氮合酶抑制剂7-NI的作用支持了对神经元一氧化氮合酶的选择性作用，并且还避免了全身性一氧化氮合酶抑制剂的高血压反应。
