McManigle J E, Taveira DaSilva A M, Dretchen K L, Gillis R A
Department of Medicine (Pulmonary Division), Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
Eur J Pharmacol. 1994 Jan 24;252(1):11-7. doi: 10.1016/0014-2999(94)90569-x.
The purpose of our study was to examine whether a significant interaction occurs between NMDA and non-NMDA receptor antagonists on respiratory function. For this purpose chloralose-anesthetized cats were used and respiratory minute volume (VE), tidal volume (Vt) respiratory rate (f), inspiratory and expiratory durations, and end tidal CO2 (FeCO2) were monitored. In some animals, phrenic nerve activity was also continuously recorded. In five spontaneously breathing animals, the NMDA receptor antagonist MK-801 was administered in a dose of 0.1 mg/kg i.v., and produced decreases in VE, Vt, f and increases in inspiratory duration and FeCO2. Using these five animals exhibiting respiratory effects from prior MK-801 dosing, we then administered the non-NMDA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline) i.v. in a dose of 3 mg/kg. This dose is too low to produce a neuroprotective effect in animal models of brain ischemia. In each of the five animals NBQX administration produced an immediate impairment of respiration, culminating in apneusis within 55 s after i.v. injection. In terms of phrenic nerve discharge, inspiratory duration was increased approximately 4-fold by MK-801, and with the addition of NBQX, continuous discharge of the phrenic nerve occurred. Finally, NBQX given i.v. to animals not pretreated with MK-801 had only a slight depressant effect on respiratory activity. These results obtained with co-administration of low doses of two drugs that block NMDA and non-NMDA receptors raise the spector that combined use of these agents to ameliorate disorders in neurological function may be extremely deleterious to respiratory function.
我们研究的目的是检验N-甲基-D-天冬氨酸（NMDA）受体拮抗剂和非NMDA受体拮抗剂在呼吸功能上是否会发生显著的相互作用。为此，我们使用了水合氯醛麻醉的猫，并监测了每分通气量（VE）、潮气量（Vt）、呼吸频率（f）、吸气和呼气持续时间以及呼气末二氧化碳（FeCO2）。在一些动物中，还持续记录了膈神经活动。在5只自主呼吸的动物中，静脉注射剂量为0.1mg/kg的NMDA受体拮抗剂MK-801，结果显示VE、Vt、f下降，吸气持续时间和FeCO2增加。利用这5只先前注射MK-801后出现呼吸效应的动物，我们随后静脉注射剂量为3mg/kg的非NMDA受体拮抗剂NBQX（2,3-二羟基-6-硝基-7-氨磺酰基-苯并(F)喹喔啉）。该剂量过低，无法在脑缺血动物模型中产生神经保护作用。在这5只动物中，每只动物注射NBQX后均立即出现呼吸障碍，静脉注射后55秒内发展为呼吸暂停。就膈神经放电而言，MK-801使吸气持续时间增加了约4倍，加入NBQX后，膈神经出现持续放电。最后，对未用MK-801预处理的动物静脉注射NBQX，对呼吸活动仅有轻微的抑制作用。同时给予低剂量的两种分别阻断NMDA和非NMDA受体的药物所得到的这些结果，使人怀疑联合使用这些药物改善神经功能障碍可能对呼吸功能极为有害。
