Potentiation of MK-801-induced breathing impairment by 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F) quinoxaline

Abstract

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 ( V E), tidal volume ( V t) respiratory rate ( ƒ), inspiratory and expiratory durations, and end tidal CO 2 (FeCO 2) 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 V E , V t , ƒ and increases in inspiratory duration and FeCO 2. 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.