dizocilpine-maleate and Apnea

Theophylline-associated convulsions have been observed most frequently in children with fever, but the mechanism is not fully understood. In this study, we investigated the basic mechanism of aminophylline [theophylline-2-ethylenediamine]-induced convulsions and the effects of Brewer's yeast-induced pyrexia in mice. Diazepam (5-10mg/kg, i.p.), a benzodiazepine receptor agonist, significantly prolonged the onset and significantly decreased the incidence of convulsions induced by aminophylline (350 mg/kg, i.p.). However, the gamma aminobutyric acid (GABA)A receptor agonist muscimol (1-4 mg/kg, i.p.), the GABAB receptor agonist baclofen (2-4 mg/kg, i.p.) and the N-methyl-D-aspartic acid receptor antagonist dizocilpine (0.1-0.3 mg/kg, i.p.) failed to protect against the convulsions. 20% Brewer's yeast (0.02 ml/g, s.c.) increased body temperature by 1.03, and also significantly shortened the onset and significantly increased the incidence of convulsions induced by aminophylline. The anticonvulsant action of diazepam (2.5-10mg/kg, i.p.) on the convulsions induced by aminophylline was reduced by Brewer's yeast-induced pyrexia. The proconvulsant actions of the GABAA receptor antagonists picrotoxin (3-4 mg/kg, i.p.) and pentylenetetrazol (40-60 mg/kg, i.p.) were enhanced by Brewer's yeast. These results suggest that the anticonvulsant action of diazepam against aminophylline is reduced by Brewer's yeast-induced pyrexia, and that GABAA receptors are involved in the aggravation of the convulsions by Brewer's yeast in mice.

Topics: Aminophylline; Animals; Anticonvulsants; Apnea; Bronchodilator Agents; Child; Convulsants; Diazepam; Dizocilpine Maleate; Fever; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; GABA-B Receptor Agonists; Humans; Infant; Japan; Male; Mice; Neuroprotective Agents; Pentylenetetrazole; Picrotoxin; Purinergic P1 Receptor Agonists; Saccharomyces cerevisiae; Seizures

The influences of N-methyl-D-aspartate (NMDA) type glutamate receptor antagonism, by (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine maleate (MK-801), on breathing pattern and ventilatory chemoresponses, were assessed in anaesthetized vagotomized spontaneously breathing golden-mantled ground squirrels, Spermophilus lateralis. MK-801 was administered by either bilateral pressure micro-injection into a region of the rostral dorsolateral pons, containing the medial and lateral Parabrachial and Kölliker-Fuse nuclei (the Parabrachial complex, PbC), or by systemic injection. Both treatments induced apneusis. These data indicate that functional NMDA receptor-mediated processes located within the PbC terminate inspiration and actively prevent apneusis in vagotomized ground squirrels. Although both hypercapnia and hypoxia stimulated breathing during the apneusis, the responses were generally slight. The breathing frequency component of the hypercapnic ventilatory response was completely eliminated supporting the hypothesis that the PbC is an integral component of the control network for CO(2) chemoreflex responses. Differences in the results of systemic versus PbC MK-801 illustrate that NMDA receptor-mediated processes outside the PbC do influence ventilation. Our data also show that such processes outside the PbC lengthen both inspiration and expiration in this species, slowing ventilation, and are necessary for the expression of the hypoxic ventilatory response.

Topics: Animals; Apnea; Dizocilpine Maleate; Drug Administration Routes; Excitatory Amino Acid Antagonists; Female; Hypercapnia; Hypoxia; Injections, Intraperitoneal; Male; Microinjections; Pons; Receptors, N-Methyl-D-Aspartate; Sciuridae; Tidal Volume; Vagotomy; Ventilation; Work of Breathing

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

After anoxia-induced apnea, gasping remains the last operative mechanism for survival. In developing rats, the gasping response to anoxia exhibits triphasic characteristics. Because anoxia is associated with enhanced release of glutamate, we hypothesized that N-methyl-D-aspartate (NMDA) glutamate receptors may underlie components of the gasping response. Rat pups aged 2 d (n = 50), 5 d (n = 43), 10 d (n = 42), and 15 d (n = 45) underwent anoxic challenges with 100% N2 in a whole body plethysmograph, 30 min after intraperitoneal administration of MK801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate; dizocilpine] (3 mg/kg), a noncompetitive NMDA glutamate receptor channel antagonist, or normal saline. In control pups, after primary apnea onset, a triphasic gasping pattern was apparent at all postnatal ages and included two distinct types of gasps (I and II). In 2- and 5-d MK801-treated animals, phase 1 and type I gasps were absent, leading to marked prolongations of the gasp latency and phase 2, the latter displaying type II gasps only. In addition, phase 3 duration was also prolonged with increased type II gasp frequencies. In contrast, in some 10-d-old (40%) and in all 15-d-old MK801-treated pups, although overall gasping duration was prolonged, the triphasic gasping pattern seen in matched controls was also present. We conclude that NMDA glutamate receptors mediate particular phasic components of the gasping response during early postnatal life but not at later stages of development. We speculate that developmental changes occur in both function and expression of NMDA and other neurotransmitters within brainstem regions underlying the neural substrate for gasp generation.

Topics: Analysis of Variance; Animals; Apnea; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Hypoxia, Brain; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Respiratory Mechanics

The local application of cobalt reversibly blocks calcium-channel conductance and therefore synaptic transmission. In this study pretreatment with a solution of cobalt (100 mM) in the nucleus tractus solitarii (NTS) of anaesthetized rats significantly blocked the apnea (P < 0.01) and arterial hypotension induced by L-glutamate (25 mM) and N-methyl-D-aspartate (0.4 mM) microinjected in the NTS. We conclude that cobalt causes these effects by acting at the postsynaptic level.

Topics: Anesthesia; Animals; Apnea; Blood Pressure; Cobalt; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamates; Glutamic Acid; Male; Microinjections; N-Methylaspartate; Rats; Rats, Sprague-Dawley; Solitary Nucleus

Our aim was to study the mechanisms producing the transition from the inspiratory phase to the expiratory phase of the breathing cycle. For this purpose we observed the changes affecting the discharge patterns and excitabilities of the different types of respiratory neurons within the respiratory network in cat medulla, after inducing an apneustic respiration with the N-methyl-D-aspartate (NMDA) antagonist MK-801 given systemically. Respiratory neurons were recorded extracellularly through the central barrel of multibarrelled electrodes, in the ventral respiratory area of pentobarbital-anesthetized, vagotomized, paralyzed and ventilated cats. Inhibitions exerted on each neuron by the pre-synaptic pools of respiratory neurons were revealed when the neuron was depolarized by an iontophoretic application of the excitatory amino-acid analogue quisqualate. Cycle-triggered time histograms of the spontaneous and quisqualate-increased discharge of respiratory neurons were constructed in eupnea and in apneusis induced with MK-801. During apneustic breathing, the activity of the respiratory neuronal network changed throughout the entire respiratory cycle including the post-inspiratory phase, and the peak discharge rates of all types of respiratory neurons, except the late-expiratory type, decreased. During apneusis, the activity of the post-inspiratory neuronal pool, the post-inspiratory depression of other respiratory neurons, and the phrenic nerve after-discharge were reduced (but not totally suppressed), whereas the discharge of some post-inspiratory neurons shifted into the apneustic plateau. The shortened post-inspiration (stage 1 of expiration) altered the organization of the expiratory phase. Late-expiratory neurons (stage 2 of expiration) discharged earlier in expiration and their discharge rate increased. The inspiratory on-switching was functionally unaffected. Early inspiratory neurons of the decrementing type retained a decrementing pattern followed by a reduced discharge rate in the apneustic plateau, whereas early-inspiratory neurons of the constant type maintained a high discharge rate throughout the apneustic plateau. Inspiratory augmenting neurons, late-inspiratory and "off-switch" neurons also discharged throughout the apneustic plateau. During the apneustic plateau, the level of activity was constant in the phrenic nerve and in inspiratory neurons of the early-constant, augmenting, and late types. However, progressive changes in the activity of o

Topics: Animals; Apnea; Cats; Decerebrate State; Dizocilpine Maleate; Evoked Potentials; Inhalation; Iontophoresis; Medulla Oblongata; Neurons; Phrenic Nerve; Quisqualic Acid; Receptors, N-Methyl-D-Aspartate; Respiration; Synapses