Biomedical subjects

A S Foutz

Publications and source records attributed to A S Foutz.

At least 19 recordsLinked to original sources

PubMed1996

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

1. In the vagotomized cat, blockade of NMDA receptors by dizocilpine (MK-801) produces an apneustic pattern of respiration characterized by a large increase in the duration of inspiration. 2. To identify dizocilpine-induced disfacilitations and disinhibitions in respiratory neurones generating the respiratory rhythm, membrane potential and input resistance of augmenting inspiratory (I; n = 11) and post-inspiratory (PI; n = 9) neurones were examined in the ventral respiratory group area, before and after administration of dizocilpine (0.1-0.3 mg kg-1 i.v.) in decerebrate, vagotomized, paralysed and artificially ventilated cats. 3. In I neurones, dizocilpine decreased the ramp depolarization and an 82% increase in input resistance was observed during inspiration. The inspiratory phase was prolonged, leading to a sustained level of depolarization during apneusis. The amplitude of stage 1 expiratory hyperpolarization decreased and its decay, which is normally slow, was faster. Throughout the remainder of expiration (stage 2) the membrane potential levelled off and the input resistance increased slightly (by 15%). 4. In PI neurones, dizocilpine depressed depolarization and suppressed firing in eight out of nine cells during the stage 1 expiratory phase. This was associated with a large (91%) increase of input resistance. The membrane potential switched quickly to stage 2 expiratory repolarization, during which a slight (19%) increase in input resistance occurred. 5. The hyperpolarization of PI neurones during early inspiration was reduced in amplitude by dizocilpine and input resistance was increased by 75% during inspiration, indicating that dizocilpine reduced the activity of the presynaptic inhibitory early-inspiratory (eI) neurones. 6. We conclude that NMDA receptor blockade in the respiratory network disfacilitates eI, I and PI neurones during their active phase. Decreased inhibitory processes during the inspiratory phase probably play a major role in the prolongation of inspiration.

Animals↗

PubMed1996

Pharmacological properties of peripherally induced postsynaptic potentials in bulbar respiratory neurons of decerebrate cats.

Intracellular recordings of bulbar inspiratory and post-inspiratory neurons, combined with extracellular iontophoresis of antagonists of putative neurotransmitters, were performed in decerebrate cats. Inhibitory postsynaptic potentials (IPSPs) evoked by stimulation of the superior laryngeal nerve or vagus nerve were depressed by bicuculline in all 22 neurons tested, but not modified by strychnine. The non-N-methyl-D-aspartate (NMDA) glutamate antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) decreased the neurally evoked excitatory postsynaptic potentials (EPSPs) in 23 out of 26 neurons tested, while the NMDA antagonist dizocilpine had no notable effect. The present results suggest that the peripherally induced IPSPs are mediated through gamma-aminobutyric acid (GABA)A receptors and the EPSPs through non-NMDA glutamate receptors in bulbar respiratory neurons.

Animals↗

PubMed1996

Inhibitions mediated by glycine and GABAA receptors shape the discharge pattern of bulbar respiratory neurons.

Experiments were performed to identify the glycinergic or GABAergic nature, and the timing of discharge, of the neurons which produce chloride-dependent inhibitions on other bulbar respiratory neurons (RNs) during their silent and active phases. RNs recorded extracellularly in pentobarbital-anesthetized or decerebrate cats, were subjected to iontophoretic applications of glutamate, of the glycine antagonist strychnine, and of the GABAA receptor antagonist bicuculline. Both antagonists induced discharge or increased discharge frequency in restricted parts of the respiratory cycle without affecting the discharge frequency in other parts of the cycle. Strychnine most often elicited activity in late-inspiration and early-expiration, but also in early inspiration and in late expiration. Bicuculline was most often effective throughout the entire discharge period of each neuron with no effect during the silent period, although it also acted selectively during late-inspiration in inspiratory neurons, an effect attributed to GABAA receptor blockade. The convergence of glycinergic afferent inputs during late inspiration and early expiration suggests that glycinergic neurons may play an important role in the inspiratory to expiratory phase transition.

Animals↗

PubMed1995

Developmental changes of NADPH-diaphorase neurons in the forebrain of neonatal and adult cat.

We examined morphological changes of neurons stained for NADPH-diaphorase (a marker for nitric oxide synthase, NOS) in maturing cat brains. In the newborn and 2-week-old kittens reactive neurons were dispersed throughout the cortical layers, in the white matter and in subcortical structures, with dense staining in some thalamic nuclei. In the adult, the density of reactive neurons was considerably decreased in the cortex and the white matter. In the thalamus, only some nuclei retained a faint labeling. Morphological changes also occurred at the cellular level. In the neonate, stained cells had prominent, thick processes with numerous beads and varicosities. In the adult, the processes were longer and thinner, with smaller varicosities. These observations provide further evidence that NOS may play a role during development.

Animals↗

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↗

PubMed1993

Effects of GABAB receptor agonists and antagonists on the bulbar respiratory network in cat.

We examined the involvement of the GABAB receptor in central respiratory mechanisms. Respiratory neurons (RNs) from the ventral respiratory group in the medulla of the cat were subjected to iontophoretic applications of the GABAB receptor agonist baclofen and the antagonists saclofen and CGP 35348. In all types of RNs baclofen decreased the firing rate. This reduction was antagonized by CGP 35348. Application of either antagonist increased the spontaneous discharge in both inspiratory and expiratory RNs. CGP 35348 excited 57% of the neurons tested, on the average by 34% with ejection currents of 100 nA. Saclofen excited 6 of 9 neurons tested. Baclofen administered systemically (8-12 mg/kg i.v.) to either anesthetized, decerebrate or intact freely moving cats, induced a selective lengthening of the inspiratory phase, an effect comparable to the apneusis induced by the NMDA antagonist MK-801. Baclofen also produced either a pronounced decrease in the amplitude of phrenic nerve discharge or an apnea, both of which were reversed by increasing paCO2. The results suggest that endogenously released GABA acting on GABAB receptors may be involved in the control of respiratory neuronal discharge.

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↗