2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline and Apnea

We hypothesized that functional glutamatergic AMPA receptors are expressed in the intertrigeminal region (ITR) of the lateral pons, and that blockade of these receptors by a specific AMPA receptor antagonist (NBQX) would alter respiratory responses both to ITR glutamate injections as well as to vagally mediated reflex apnea induced by intravenous infusion of serotonin. Non-selective blockade of ITR glutamate receptors using kynurenic acid previously was shown to alter both of these respiratory responses. Unilateral ITR injections in 19 anaesthetized spontaneously breathing adult Sprague-Dawley rats with the vagi intact demonstrated that NBQX (10mM): (1) shortened glutamate-induced apnea duration (p=0.006), (2) reduced glutamate-induced apnea frequency (p=0.034) and (3) decreased glutamate-induced apnea density (p=0.006). The same dose of NBQX did not affect vagally mediated reflex apnea induced by intravenous infusion of serotonin. These results show that functional glutamate AMPA receptors are expressed in the ITR but fail to directly demonstrate any specific physiologic role for these receptors in respiratory control. In contrast to antagonism of NMDA receptors which completely blocked the central apnea evoked by glutamate, antagonism of AMPA receptors only partially blocked the effects of glutamate. In contrast to kynurenic acid, antagonists to NMDA and AMPA receptors given separately did not potentiate the duration of reflex apnea.

Topics: Animals; Apnea; Glutamic Acid; Male; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Reflex; Respiratory Mechanics; Serotonin; Trigeminal Nerve; Trigeminal Nuclei; Vagus Nerve

We determined the conditions (immaturity, species, anesthesia, receptor blockade selectivity) under which glutamate receptor blockade produces respiratory depression in mammals. In unrestrained 0- to 2-day-old neonate and adult mice and cats, ventilation was measured by the barometric method, before and after separate or sequential administration of a non-NMDA receptor antagonist, NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline, 2-200 mg kg(-1) in mice, 10-40 mg kg(-1) in cats), and a NMDA receptor antagonist, dizocilpine (3 mg kg(-1) in mice, 0.15-1.0 mg kg(-1) in cats). NBQX or dizocilpine alone did not decrease ventilation in awake adults, but NBQX strongly depressed ventilation in neonate awake mice and in adult anesthetized animals. Given together, dizocilpine and NBQX always profoundly depressed ventilation by producing a lethal apnea in neonate mice, and an apneustic pattern of breathing in adults of both species and in neonate cats. We conclude that blockade of either NMDA or non-NMDA receptors is innocuous in awake adults. The factors which may potentiate respiratory depression are (1) anesthesia, (2) immaturity, and (3) combined blockade of both receptors types. The mechanism of depression is species-dependent and age-dependent.

Topics: Age Factors; Animals; Animals, Newborn; Apnea; Cats; Dizocilpine Maleate; Drug Synergism; Excitatory Amino Acid Antagonists; Injections, Intraperitoneal; Injections, Subcutaneous; Mice; Plethysmography; Pulmonary Ventilation; Quinoxalines; Receptors, Glutamate; Species Specificity

To determine whether blockade of non-N-methyl-D-aspartate (non-NMDA) excitatory amino acid receptors affects breathing, we administered the non-NMDA receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), to anesthetized cats while monitoring phrenic nerve discharge, blood pressure and heart rate. NBQX, 3 and 10 mg/kg, i.v., reduced phrenic amplitude 59 +/- 20% (n = 3) and 88 +/- 6% (n = 5), respectively, and decreased respiratory rate. Phrenic activity was completely silenced in 3 animals. These effects were accompanied by decreased blood pressure and heart rate. Our data indicate that NBQX, a competitive antagonist of non-NMDA receptors, is a powerful depressant of cardiorespiratory activity.

Topics: Animals; Apnea; Atrial Function; Blood Pressure; Cats; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Heart Rate; Injections, Intravenous; Phrenic Nerve; Quinoxalines; Respiratory Insufficiency; Respiratory Physiological Phenomena; Respiratory System