麻醉剂的相加效应是否表明其具有针对N-甲基-D-天冬氨酸受体的相同分子机制？  

作　　者：Robert J. Brosnan, DVM, PhD Trung L. Pham, BS 谢珺田(译) 宋文阁(校) 

机构地区：[1]University of California, Davis, Davis, California [2]不详

出　　处：《麻醉与镇痛》2013年第6期39-45,共7页Anesthesia & Analgesia

摘　　要：背景异氟烷和二氧化碳（carbondioxide，CO2）都能负性调节N-甲基-D-天冬氨酸受体活性，但经由的途径不同。异氟烷是一种竞争性NMDA受体拮抗剂，结合于甘氨酸靶点，而CO，通过细胞外酸化抑制NMDA受体通道。在大鼠体内异氟烷和CO2表现了最小肺泡有效浓度的加和，但是我们假定由于它们作用于不同靶点，体外抑制NMDA受体通道时并不能表现出加和性。方法NMDA受体由蛙卵母细胞表达，实验采用双电极电压钳技术。并分别检测在有CO2和无CO2时}f起NMDA应答的甘氨酸浓度。分别作出异氟烷、H＋、CO2和氯胺酮的浓度一应答曲线，代表对NMDA的抑制作用，并用希尔方程计算出各自的EC50.结果如果NMDA产生的通道抑制效果在统计学上差异没有超过50％，可再加入含有1／2EC如的二联药物制剂。1／2EC50二联药物制剂降低了NMDA受体通道的部分基线，结果如下（平均值±SD，n=5—6卵母细胞／次）：CO2＋H＋（51％±5％），CO2＋异氟烷（54％±5％），H＋异氟烷（51％±3％），CO2＋氯胺酮（67％±8％），H＋氯胺酮（64％±2％）。结论与我们之前的假定推断相反，CO，和异氟烷对NMDA受体的抑制作用有相加效应。可能的机制是，CO2酸化调节了NMDA受体的pH敏感环路，进而改变了GluNl亚基上甘氨酸靶点的亲和性。然而，氯胺酮既可以和CO，也可以与H＋发挥协同作用抑制NMDA受体。药物作用的不同机制带来对受体的相加或协同作用。不能武断地通过相加作用判断麻醉剂分子机制的共同性。BACKGROUND： Isoflurane and carbon dioxide （CO2） negatively modulate N-methyl-D-aspartate （NMDA） receptors, but via different mechanisms. Isoflurane is a competitive antagonist at the NMDA receptor glycine binding site, whereas CO2 inhibits NMDA receptor current through extracellular acidification. Isoflurane and CO2 exhibit additive minimum alveolar concentration effects in rats, but we hypothesized that they would not additively inhibit NMDA receptor currents in vitro because they act at different molecular sites. METHODS： NMDA receptors were expressed in frog oocytes and studied using 2-electrode voltage clamp techniques. A glycine concentration response for NMDA was measured in the presence and absence of CO2. Concentration-response curves for isoflurane, H ＋, CO2, and ketamine as a function of NMDA inhibition were measured, and a Hill equation was used to calculate the ECs0 for each compound. RESULTS： Binary drug combinations containing 1/2 ECs0 were additive if NMDA current inhibition was not statistically different from 50%. The 1/2 ECs0 binary drug combinations decreased the percentage baseline NMDA receptor current as follows （mean ＋ SD, n = 5 to 6 oocytes each）： CO2 ＋ H ＋ （51% ＋5%）, CO2 ＋ isoflurane （54% ＋ 5 % ）, H ＋ ＋ is o flurane （51% ＋ 3 % ）, CO2 ＋ ketamine （67 % ＋ 8 % ）, and H ＋ ＋ ketamine （64 % ＋ 2 % ）. CONCLUSIONS： In contrast to our hypothesis, NMDA receptor inhibition by CO2 and isoflurane is additive. Possibly, CO2 acidification modulates a pH-sensitive loop on the NMDA receptor that in turn alters glycine binding affinity on the GluN1 subunit. However, ketamine plus either CO2 or H ＋ synergistically inhibits NMDA receptor currents. Drugs acting via different mechanisms can thus exhibit additive or synergistic receptor effects. Additivity may not robustly indicate commonality between molecular anesthetic mechanisms.

关 键 词：N-甲基-D-天冬氨酸受体 相加效应 分子机制 麻醉剂 NMDA受体拮抗剂 NMDA受体通道 双电极电压钳技术 肺泡有效浓度 

分 类 号：R338[医药卫生—人体生理学]