Biomedical subjects

A S Foutz

Publications and source records attributed to A S Foutz.

At least 19 recordsLinked to original sources

PubMed1995

Involvement of NMDA receptors in inspiratory termination in rodents: effects of wakefulness.

We investigated the role of N-methyl-D-aspartate (NMDA) receptors in the off-switching of inspiration in rodents. Respiratory activity was measured by the plethysmographic method in Swiss and Balb c mice, Hartley guinea pigs, Wistar and Sprague-Dawley rats. The NMDA channel blocker dizocilpine (MK-801) administered systemically, had little effect on the timing of respiratory phases in intact animals. When dizocilpine was associated with a vagotomy performed under anesthesia, an apneustic respiratory pattern was obtained in all species and strains. As the anesthetic dissipated, the inspiratory pauses disappeared and the apneustic respiratory pattern was replaced by an eupneic respiratory pattern. Apneuses were re-instated by small doses of anesthetic (halothane, pentobarbital, alphaxolone-alphadolone or chloral hydrate) and suppressed by larger doses. We conclude that (i) the central NMDA-receptor dependent inspiratory off-switching mechanism previously described in cats and primates, also exists in rodents; (ii) wakefulness maintains a normal respiratory pattern after suppression of both the NMDA-receptor mediated and the vagally-mediated off-switching mechanisms; (iii) deep anesthesia suppresses inspiratory pauses in rodents.

Animals↗

PubMed1995

Involvement of NMDA receptors in the respiratory phase transition is different in the adult guinea pig in vivo and in the isolated brain stem preparation.

1. We investigated the involvement of N-methyl-D-aspartate (NMDA) receptors in the respiratory pattern in an in vitro preparation of adult brain stem compared with in vivo conditions in the guinea pig. 2. In vivo, combining administration of the NMDA channel blocker dizocilpine (MK-801) (3 mg/kg) with a surgical section of the vagus nerves induced an apneustic type of respiration characterized by long inspiratory "holds," as has been shown in other species. The same effect was observed in hypothermic animals (30 degrees C). 3. The isolated in vitro brain stems from these apneustic animals did not present a prolonged inspiratory phase. A second dose of dizocilpine (100 microM perfused vascularly did not induce apneusis, even after increasing brain stem temperature to 35.5 degrees C. 4. In another group of isolated brain stems of adult guinea pigs anesthetized with pentobarbital sodium before decapitation, we perfused dizocilpine and NMDA through the basilar artery. The duration of periodic inspiratory motor activity recorded from the hypoglossal nerve was unaffected by dizocilpine (1-100 microM) or the competitive NMDA antagonist D- or DL-2-amino-5-phosphonopentanoic acid (100 microM and 1 mM), although respiratory frequency decreased. The increase in respiratory activity produced by vascularly perfused NMDA (25-100 microM) was blocked by dizocilpine (100 microM). 5. We conclude that the central mechanism of inspiratory termination in the vagotomized adult guinea pig requires the activation of NMDA receptors in vivo but not in vitro. This difference is not due to the hypothermic environment in vitro. Possible mechanisms for phase switching in vitro are discussed.

Animals↗

PubMed1994

Respiratory rhythm generation in chick hindbrain: effects of MK-801 and vagotomy.

Hindbrain mechanisms generating the respiratory rhythm in chicks were analysed. In vivo, ventilation and intercostal muscle activity were recorded in chicks (1 and 2.5 weeks-old), vagotomized and treated with the NMDA receptor blocker MK-801 (dizocilpine). In vitro, synaptic transmission from vagal to second-order sensory neurones was studied in the nucleus of the solitary tract, using whole-cell recordings in slices. Vagal afferents were found to act through GABAergic synapses and control two hindbrain systems: a dizocilpine-sensitive control system and a rhythm generator. Although this organization is the same as in mammals, after vagotomy entirely different respiratory patterns emerge: (i) expiratory-inspiratory efforts triggered by the rhythm generator and (ii) periods of apnoea produced by the dizocilpine-sensitive system.

Animals↗

PubMed1994

NMDA and non-NMDA receptors may play distinct roles in timing mechanisms and transmission in the feline respiratory network.

1. Activation of N-methyl-D-aspartate (NMDA) glutamate receptors in the brainstem network of respiratory neurones is required to terminate inspiration in the absence of lung afferents, but it is not required in the inspiratory motor act of lung inflation. In the present study we examined the involvement of non-NMDA ionotropic glutamate receptors in these two mechanisms in the adult mammal. 2. Adult cats were either decerebrated or anaesthetized with sodium pentobarbitone, paralysed and ventilated. Inspiratory motor output was recorded from the phrenic nerve and central respiratory activity from neurones in the bulbar ventral respiratory group. 3. In decerebrate vagotomized cats, ionophoretic application of 2,3-dihydroxy-6-nitro-7-sulphamoylbenzo(F)quinoxaline (NBQX) onto single respiratory neurones decreased their spontaneous discharge rate and abolished the excitatory effect of exogenously applied (RS) alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) but not NMDA. 4. In these animals, intravenous infusion (12 mg kg-1) of the non-NMDA receptor blockers GYKI 52466 (1-(4-aminophenyl)-4-methyl-7,8-methylene-dioxy-5-H-2,3-benzodi aze pine) or NBQX: (1) decreased (in 10/15 cats) or abolished (in 5/15 cats) the inspiratory-related discharge of the phrenic nerve; (2) did not prolong the inspiratory phase; (3) reduced or abolished the spontaneous discharge of respiratory neurones; and (4) profoundly decreased the excitatory effects of AMPA but not NMDA ionophoresed onto these neurones. When both the phrenic nerve and the recorded respiratory neurone were silenced, neuronal excitation by ionophoretic application of NMDA first revealed a subthreshold respiratory modulation without lengthening of the inspiratory phase, then respiratory modulation became undetectable. 5. Additional blockade of NMDA receptors by a small dose (0.15 mg kg-1) of dizocilpine (MK-801), abolished the phrenic nerve activity which persisted after NBQX (apnoea), but the discharge or the subthreshold modulation of the bulbar respiratory neurones showed a lengthening of the inspiratory phase (apneusis). 6. Elevation of FA,CO2 increased or re-established phrenic nerve discharges after blockade of non-NMDA receptors or of both NMDA and non-NMDA receptors. 7. Small doses of NBQX or GYKI 52466 induced apnoea in five of five cats anaesthetized with sodium pentobarbitone. 8. In decerebrate animals with intact vagi, GYKI 52466 and NBQX depressed the Hering-Breuer expiratory-lengthening reflex. 9. The results suggest that: (1) there is a specialization of different classes of glutamate receptors participating in timing mechanisms and transmission within the mammalian respiratory network. Neural transmission predominantly involves activation of non-NMDA receptors, acting in synergy with NMDA receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed1994

Combined blockade of NMDA and non-NMDA receptors produces respiratory arrest in the adult cat.

We studied the effects of the non-NMDA antagonist NBQX and of the NMDA antagonist dizocilpine (MK-801), administered separately or together, on the respiratory function of conscious cats. NBQX (20 mg kg-1) did not affect minute ventilation nor the timing of inspiratory and expiratory phases, but the addition of a small dose of dizocilpine (0.15 mg kg-1) induced inspiratory pauses and respiratory arrest in the inspiratory phase (apneusis). Similarly, larger doses of either NBQX or dizocilpine did not induce apneusis but the addition of a small dose of the other compound provoked an apneusis. Thus, a blockade of either non-NMDA or NMDA receptors is well tolerated, but the combined blockade of both receptor types severely disrupts the respiratory function in the cat.

Animals↗

PubMed1994

Maturation of brain stem neurons involved in respiratory rhythmogenesis: biochemical, bioelectrical and morphological properties.

Neonatal and adult respiratory-related functions of brain stem were compared using in vivo or in vitro approaches. The control of inspiratory off-switch by glutamate-like neurotransmitters was found active at birth. However, neurons from the nucleus tractus solitarius (NTS) are immature at birth because they present growth cones and the transient potassium current appears progressively during the first week of life in association with modification of the dendritic tree. These data support the hypothesis that the mechanisms of respiratory rhythmogenesis are different at birth and in the adult.

Animals↗

PubMed1992

The bulbar network of respiratory neurons during apneusis induced by a blockade of NMDA receptors.

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 other neuronal types demonstrated the evolving state of the respiratory network in the plateau phase. There was a slowed but continued decrease of the activity of early-inspiratory decrementing neurons, accompanied by an increasing activity and/or excitability of "off-switch", post-inspiratory and late-expiratory neurons. In apneusis there was a decoupling of the duration of inspiration and expiration.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1991

Endogenous activation of NMDA and non-NMDA glutamate receptors on respiratory neurones in cat medulla.

The aim of this study was to evaluate the involvement of dicarboxylic amino acid neurotransmission in the periodic discharges of respiratory neurones. Respiratory neurones of the ventral and dorsal respiratory groups in the medulla of the cat were subjected to iontophoretic applications of (1) N-methyl-D-aspartate (NMDA) and a blocker of the NMDA subtype of glutamate receptor, D-2-amino-7-phosphonoheptanoic acid (AP7) and (2) an agonist and an antagonist of the non-NMDA subtypes of receptor: quisqualate and 6,7-dinitroquinoxaline-2,3-dione (DNQX), respectively. All five main types of respiratory neurones (all-, early- and late-inspiratory, transitional "off-switch", late expiratory) were excited by NMDA and quisqualate. Both agonists increased the peak firing rate but exerted different effects on the discharge pattern of respiratory neurones, within the respiratory cycle. Quisqualate induced discharges in the "silent" period of the neurone more readily than did NMDA which, in turn had a more pronounced effect during the burst period of the neurone. The effects of quisqualate and NMDA were suppressed by prior application of their selective antagonists, AP7 and DNQX. These antagonists decreased the spontaneous neuronal discharge of all cell types, throughout the entire firing phase, by a maximum of 24-63% with AP7 and by 30-50% with DNQX. The non-selective antagonist, gamma-D-glutamyl-glycine and the selective NMDA antagonists, CPP and MK-801, were also effective. It is concluded that respiratory neurones, of all types, within the medullary respiratory network are subjected to endogenous glutamate-like excitations, which may possibly shape the respiratory train of action potentials through the sequential activation of non-NMDA and NMDA subtypes of receptor.

2-Amino-5-phosphonovalerate↗

PubMed1990

Effects of N-methyl-D-aspartate (NMDA) receptor blockade on breathing pattern in newborn cat.

We gave newborn kittens the N-methyl-D-aspartate (NMDA) receptor blocker MK-801 systemically while recording their breathing patterns by the barometric method. Unlike pentobarbital, MK-801 at an anaesthetic dose increased the relative length of inspiration within the respiratory cycle. The section of both vagus nerves under MK-801 produced apneustic breathing, whereas vagotomy under pentobarbital had no such effect. We conclude that the central inspiratory-termination mechanism mediated through NMDA receptors and the vagally-mediated mechanism that independently 'switches off' inspiration are both functional at birth.

Animals↗

PubMed1990

Pneumotaxic mechanisms in the non-human primate: effect of the N-methyl-D-aspartate (NMDA) antagonist ketamine.

We tested the possible involvement of N-methyl-D-aspartate (NMDA) receptors in the central inspiratory-termination mechanism in non-human primates. Inspiratory bursts were recorded from the phrenic nerve in Macaca fascicularis monkeys paralyzed and ventilated by means of a servoventilator driven by the inspiratory discharge of the phrenic nerve. The central inspiratory termination mechanism was tested by withholding lung inflation. This transiently suppressed the vagal feedback from the lungs which produces inspiratory off-switching independent from the central mechanism. Under anaesthesia with ketamine, a potent NMDA antagonist, non inflation increased inspiratory time to 4s (1s with lungs inflated) whereas no such effect was observed during halothane anaesthesia. We conclude that the termination of inspiration in primates is controlled via central mechanisms in which NMDA receptors are involved.

Anesthesia↗

PubMed1989

Involvement of N-methyl-D-aspartate (NMDA) receptors in respiratory rhythmogenesis.

The involvement of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors in the control of inspiratory termination was studied in paralyzed decerebrated cats. Cats were either vagotomized, or had intact vagus nerves and were ventilated with a ventilator driven by the discharge of the phrenic nerve. The systemic administration of NMDA antagonists acting non-competitively (MK-801, ketamine, phencyclidine) or competitively (2-amino-7-phosphonoheptanoic acid: AP7), produced an apneusis in vagotomized animals or in animals transiently deprived of vagal pulmonary feedback by the 'no inflation test'. After NMDA receptor blockade, the inspiratory phase could be terminated by lung inflation or sensory stimulation. Thus pharmacologically distinct mechanisms control the termination of inspiration: vagal afferents which are NMDA-independent, and a central mechanism acting through the activation of NMDA receptors. The apneustic pattern induced by NMDA receptor blockade was characterized by a decrease of the amplitude of integrated phrenic nerve activity, the persistence of CO2 sensitivity and an enhancement of apneusis by anaesthesia. After injection of NMDA antagonists there was a decrease of the duration of expiration which thereafter remained constant and dissociated from inspiratory duration. The possible mechanisms by which NMDA receptors may contribute to respiratory rhythmogenesis are discussed.

2-Amino-5-phosphonovalerate↗

PubMed1989

Differentiation of phencyclidine and sigma receptor types affecting the central inspiratory termination mechanism in cat.

The effects of 1) the phencyclidine receptor ligand TCP, 2) sigma receptor ligands (+)3-PPP and DTG, and 3) N-methyl-D-aspartate receptor blockers MK-801 and dextrorphan were determined on a brainstem mechanism which controls the termination of the inspiratory phase of the breathing cycle. Inspiratory bursts were recorded from the phrenic nerve in decerebrate paralyzed cats ventilated by means of a phrenic driven servoventilator. The central mechanism which terminates inspiration was tested by withholding lung inflation, thus suppressing the contribution of the vagal feedback from the lungs to inspiratory termination. TCP increased the duration of test inspiration (tTi) by 17% at 0.03 mg/kg and by 14-fold (from 1.6 to 23 s) at 1 mg/kg. With dextrorphan, tTi was significantly increased at 3 mg/kg. In contrast, (+)3-PPP and DTG did not increase tTi at doses up to 10 mg/kg, although MK-801 (0.03 mg/kg), given after the sigma ligands, increased tTi by 59-90%. It is concluded that phencyclidine but not sigma receptor ligands block the central mechanism which terminates inspiration and that the likely site of action is the NMDA receptor complex.

Animals↗

PubMed1989

Persistence of central respiratory rhythmogenesis after maximal acetylcholinesterase inhibition in unanaesthetized cats.

Cats were given systemically the anticholinesterase paraoxon at a dosage (3 mg/kg i.v.) that produced a maximal (over 90%) inhibition of brainstem acetylcholinesterase. All paralyzed and artificially ventilated animals were either unanaesthetized (decerebrated or ventilated with 70% nitrous oxide and 30% oxygen) or anaesthetized (with pentobarbital, alpha-chloralose, or halothane). In unanaesthetized cats, paraoxon produced an immediate rise in arterial blood pressure and did not suppress phrenic nerve respiratory discharges, while in anaesthetized animals it produced an immediate and long-lasting hypotension and a complete arrest of central respiratory activity. It is concluded that acetylcholine accumulation may not suppress respiratory rhythmogenesis and that most anaesthetics may considerably alter the response of cardiorespiratory cholinergic mechanisms to anticholinesterase administration.

Acetylcholinesterase↗

PubMed1988

Respiratory effects of the N-methyl-D-aspartate (NMDA) antagonist, MK-801, in intact and vagotomized chronic cats.

The effects on respiration of MK-801, an N-methyl-D-aspartate (NMDA) non-competitive antagonist, were studied in awake chronic cats by means of the plethysmographic technique. MK-801 (0.01-3.0 mg/kg) was first given i.v. in cumulative doses. The protocol was repeated 10-15 days later in the same animals after bilateral vagotomy. MK-801 selectively increased the duration of inspiration, causing an apneustic respiration but had no effect on the duration of expiration. The maximal inspiratory duration brought about by MK-801 in the intact cat (4.3 s; control 0.9 s) increased 4-fold after bilateral vagotomy (16.4 s; control 1.7 s). Such results suggest that the termination of the inspiratory phase in normal awake cats results from an interaction of pulmonary vagal afferent inputs (inactive on NMDA receptors) with a central mechanism in which NMDA-type glutamate receptors are activated by dicarboxylic amino acid neurotransmission.

Animals↗

PubMed1988

Respiratory rhythm multistability during sleep-wake states.

Respiratory period (RP) changes occurring during sleep-waking states were studied during 5- to 8-h recording sessions in chronic cats. RP distribution was clearly trimodal, the shortest mode occurring essentially during alert wakefulness, the largest mode during slow wave sleep and the intermediate mode during drowsy wakefulness. Immediate shifts were observed at instant awakening, whereas after an EEG arousal lasting a few seconds, the RP could remain short for several minutes. Results suggest that the respiratory pattern generator depends upon several attractors.

Animals↗

PubMed1988

N-methyl-D-aspartate (NMDA) receptors control respiratory off-switch in cat.

Functionally active N-methyl-D-aspartate (NMDA) receptors on cat medullary respiratory neurones were revealed by local iontophoretic application of DL-2-amino-7-phosphonoheptanoic acid (AP7). Blockade of NMDA receptors by systemic administration of NMDA antagonists (MK-801, phencyclidine, ketamine, AP7) in vagotomized cats increased the duration of inspiration (Ti) without increasing expiration and caused an apneustic breathing pattern. The increase in Ti which followed systemic MK-801, was accompanied by a shift and complete reversal of early expiratory neuronal discharge in relation to phrenic nerve discharge.

Action Potentials↗

PubMed1987

Central respiratory depression induced by acetylcholinesterase inhibition: involvement of anaesthesia.

We have studied the effects of anaesthesia on the changes in central respiratory activity following the inhibition of acetylcholinesterase in chronically implanted cats. The organophosphate paraoxon was administered to the brainstem respiratory centres by intracerebroventricular (i.c.v.) injection (3 mg) into the IVth ventricle, thus avoiding peripheral effects such as paralysis of respiratory muscles. Paraoxon had opposite effects on respiratory activity depending on whether the cats were anaesthetized or not: it induced respiratory depression and sometimes respiratory arrest during pentobarbital (30 mg/kg i.v.) or halothane anaesthesia, but in the same animals in the waking state, the same dose of paraoxon always stimulated respiration. These results show a strong interaction between anaesthetics and the effects of acetylcholine (ACh) accumulation on central respiratory activity. This study extends previous results showing an interaction between ACh and pentobarbital on single respiratory neurons and stresses the importance of a 'wakefulness stimulus' for sustaining respiratory activity after organophosphate poisoning.

Anesthesia↗

PubMed1987

Excitability of 'silent' respiratory neurons during sleep-waking states: an iontophoretic study in undrugged chronic cats.

An iontophoretic study of respiratory-related neurons (RN) was conducted in the medullary ventral respiratory area of chronically implanted, undrugged cats during states of sleep and wakefulness. Most RN recorded were unaffected by sleep-wake states but a few RN decreased their firing rate during sleep (sleep sensitive cells). The excitability of RN was assessed in the different states by local application of L-glutamate. Glutamate iontophoresis revealed the presence of 5 cells which were silent during sleep and completely or mostly silent during undisturbed wakefulness but always discharged with a respiratory-modulated pattern of the expiratory type in response to glutamate application. Arousing stimuli induced spontaneous firing of these cells and REM sleep reduced glutamate effectiveness. It was concluded that silent RN and RN which become inactive during sleep permanently receive subthreshold respiratory-modulated inputs which are amplified or depressed by state-dependent tonic inputs.

Animals↗