Synaptic interaction between medullary respiratory neurones during apneusis induced by NMDA‐receptor blockade in cat.

Abstract

SUMMARY1. Termination of inspiration is an essential component of respiratory rhythm generation and its perturbation can result in apneusis, i.e. significant prolongation of inspiratory activity. In an effort to further analyse inspiratory termination mechanisms, we studied the p'ostsynaptic events in respiratory neurones during apneustic respiratory periods, and compared them to normal respiratory cycles.2. Experiments were performed in pentobarbitone-anaesthetized, paralysed, thoracotomized cats ventilated with a constant volume or a cycle-triggered constant pressure pump. Apneusis, separated by normal cycles, was induced as follows: the animal was ventilated by a cycle-triggered pump that normally inflated the lungs during the inspiratory burst of phrenic nerve discharge. The NMDA-receptor blocker MK-801 [(+ )-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-iminemaleate] (0-3-0-7 mg/kg) was administered intravenously, and, for designated breaths, inflation of the lungs was withheld during neural inspiration.3. Membrane potential trajectories of forty-one late expiratory (E-2) and eight postinspiratory (PI) neurones of the caudal ventral respiratory group were analysed before and/or after MK-801 administration, during normal and apneustic periods.4. Before MK-801 administration, withholding lung inflation caused modest (10-20%) lengthening of the inspiratory period; after MK-801 administration, withholding inflation caused apneusis. Provided that the lungs were inflated during the inspiratory phase, the temporal pattern of phrenic nerve, recurrent laryngeal nerve and membrane potential trajectories of E-2 and PI neurones were not significantly altered by MK-801. Apneusis following NMDA-receptor blockade produced consistent changes in the synaptic activation patterns of E-2 neurones. In particular, the slow late inspiratory-related depolarization pattern of E-2 neurones was consistently retarded during apneustic inspiratory phases when compared to normal inspiratory phases. This was due to continuation of Cl--mediated synaptic inhibition of E-2 neurones. Superior laryngeal nerve stimulation stopped apneusis and sustained membrane hyperpolarization of E-2 neurones similar to lung inflation. 6. We conclude that: (i) the prolonged inhibition of E-2 neurones during apneusis is indicative of the process responsible for the prolongation of the inspiratory phase.(ii) Synaptic interactions between medullary respiratory neurones and spinal respiratory motoneurones producing burst patterns of motor output do not require NMDA-receptor-mediated pathways. (iii) Pathways used by pulmonary and laryngeal afferents to terminate inspiration also do not require NMDA-receptormediated function. (iv) NMDA-receptor controlled pathways necessary for inspiratory termination seem to be activated in the absence of lung inflation and to involve the pontine respiratory group of neurones. (v) MK-801-induced apneusis affects the interaction between early-inspiratory and late-inspiratory neurones resulting in oscillations.

Membrane potentials of respiratory neurones during dizocilpine‐induced apneusis in adult cats.

“…Disfacilitation of I neurones by dizocilpine did not result in the elimination of the HFO waves of around 80 Hz that were recorded during inspiration in PI neurones. However, we did not observe correlated waves oscillating at a frequency of 10-20 Hz, which were clearly demonstrated during MK-801-induced apneusis in anaesthetized cats (Feldman, Windhorst, Anders & Richter, 1992). Because the frequency of HFO waves was not significantly altered during dizocilpine-induced apneusis and because HFO waves were not consistently present in all PI neurones, this kind of oscillation is not likely to be the consequence of NMDA receptor blockade, as was suggested in the previous study for the low frequency oscillation (Feldman et al 1992).…”

“…However, we did not observe correlated waves oscillating at a frequency of 10-20 Hz, which were clearly demonstrated during MK-801-induced apneusis in anaesthetized cats (Feldman, Windhorst, Anders & Richter, 1992). Because the frequency of HFO waves was not significantly altered during dizocilpine-induced apneusis and because HFO waves were not consistently present in all PI neurones, this kind of oscillation is not likely to be the consequence of NMDA receptor blockade, as was suggested in the previous study for the low frequency oscillation (Feldman et al 1992). Effects of dizocilpine resulting from an action at presynaptic inhibitory early-inspiratory neurones An important result of the present study is that dizocilpine reduced the inhibition occurring during inspiration in PI neurones (75% increase in input resistance).…”

“…(Pierrefiche et al 1992). This obviously results from changes in the respiratory network during apneusis, possibly a decreased inhibition from PI neurones, because during eupnoea, the discharge of E2 cells is decreased, not increased, by NMDA antagonists applied either systemically (Feldman et al 1992) or directly by iontophoresis (Pierrefiche et al 1991). Reduced stage 1 expiratory phase An important perturbation during dizocilpine-induced apneusis was the depression of PI neuronal activity, and the concomitantly shortened stage 1 expiratory hyperpolarization of I neurones.…”

Pulmonary stretch receptor afferents activate excitatory amino acid receptors in the nucleus tractus solitarii in rats.

“…However, NMDA-receptor activation does not appear to be required for vagal afferent-mediated termination of inspiration. In vagotomized rats and cats, NMDA receptor blockade by the systemic administration of antagonists which cross the blood-brain barrier produces an apneustic breathing pattern but, at least in cats, does not prevent the vagal afferent-mediated termination of inspiration (Foutz, Champagnat & Denavit-Saubie, 1989;Monteau, Gauthier, Rega & Hilaire, 1990;Feldman, Windhorst, Anders & Richter, 1992). Thus, activation of vagal afferents appears to activate a heterogeneous group of EAA receptors in the NTS but only non-NMDA EAA receptors are likely candidates for mediation of the BH reflex termination of inspiration.…”

The mechanisms of sudden-onset type adverse reactions to oseltamivir

“…It should also be considered that apnoea can be cause by apneusis that is induced by NMDA-receptor blockade [79]. …”