Effects of Sevoflurane on Excitatory Neurotransmission to Medullary Expiratory Neurons and on Phrenic Nerve Activity in a Decerebrate Dog Model

Background Sevoflurane is a new volatile anesthetic with a pronounced respiratory depressant effect. Synaptic neurotransmission in canine expiratory bulbospinal neurons is mainly mediated by excitatory N-methyl-D-aspartatic acid (NMDA) receptor input and modulated by inhibitory gamma-aminobutyric acid type A (GABA(A)) receptors. The authors investigated the effect of sevoflurane on these mechanisms in decerebrate dogs. Methods Studies were performed in decerebrate, vagotomized, paralyzed and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 minimum alveolar concentration (MAC; 2.4%) sevoflurane on extracellularly recorded neuronal activity was measured during localized picoejection of the glutamate agonist NMDA and the GABA(A) receptor blocker bicuculline in a two-part protocol. First, complete blockade of the GABA(A)ergic mechanism by bicuculline allowed differentiation between the effects of sevoflurane on overall GABA(A)ergic inhibition and on overall glutamatergic excitation. In a second step, the neuronal response to exogenous NMDA was used to estimate sevoflurane's effect on postsynaptic glutamatergic neurotransmission. Results One minimum alveolar concentration sevoflurane depressed the spontaneous activity of 16 expiratory neurons by 36.7+/-22.4% (mean +/- SD). Overall glutamatergic excitation was depressed 19.5+/-16.2%, and GABA(A)ergic inhibition was enhanced 18.7+/-20.6%. However, the postsynaptic response to exogenous NMDA was not significantly altered. In addition, 1 MAC sevoflurane depressed peak phrenic nerve activity by 61.8+/-17.7%. Conclusions In the authors' in vivo expiratory neuronal model, the depressive effect of sevoflurane on synaptic neurotransmission was caused by a reduction of presynaptic glutamatergic excitation and an enhancement of GABA(A)ergic inhibition. The effects on expiratory neuronal activity were similar to halothane, but sevoflurane caused a stronger depression of phrenic nerve activity than halothane.

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Effects of Halothane and Sevoflurane on Inhibitory Neurotransmission to Medullary Expiratory Neurons in a Decerebrate Dog Model

Anesthesiology ◽

10.1097/00000542-200204000-00025 ◽

2002 ◽

Vol 96 (4) ◽

pp. 955-962 ◽

Cited By ~ 14

Author(s):

Astrid G. Stucke ◽

Eckehard A. E. Stuth ◽

Viseslav Tonkovic-Capin ◽

Mislav Tonkovic-Capin ◽

Francis A. Hopp ◽

...

Keyword(s):

Spontaneous Activity ◽

Gabaa Receptor ◽

Neuronal Activity ◽

Neuronal Response ◽

Inhibitory Input ◽

Gamma Aminobutyric Acid ◽

Receptor Function ◽

Presynaptic Site ◽

Gabaa Receptor Antagonist ◽

Expiratory Neurons

Background In canine expiratory bulbospinal neurons, 1 minimum alveolar concentration (MAC) halothane and sevoflurane reduced the glutamatergic excitatory drive at a presynaptic site and enhanced the overall gamma-aminobutyric acid (GABA)-mediated inhibitory input. The authors investigated if this inhibitory enhancement was mainly caused by postsynaptic effects. Methods Two separate anesthetic studies were performed in two sets of decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 MAC halothane or sevoflurane on extracellularly recorded neuronal activity was measured during localized picoejection of the GABAA receptor agonist muscimol and the GABAA receptor antagonist bicuculline. Complete blockade of GABAA-mediated inhibition with bicuculline was used to assess the prevailing overall inhibitory input to the neuron. The neuronal response to muscimol was used to estimate the anesthetic effect on postsynaptic GABAA receptor function. Results Halothane at 1 MAC depressed the spontaneous activity of 12 expiratory neurons 22.2 +/- 14.8% (mean +/- SD) and overall glutamatergic excitation 14.5 +/- 17.9%. Overall GABA-mediated inhibition was enhanced 14.1 +/- 17.9% and postsynaptic GABAA receptor function 74.2 +/- 69.2%. Sevoflurane at 1 MAC depressed the spontaneous activity of 23 neurons 20.6 +/- 19.3% and overall excitation 10.6 +/- 21.7%. Overall inhibition was enhanced 15.4 +/- 34.0% and postsynaptic GABAA receptor function 65.0 +/- 70.9%. The effects of halothane and sevoflurane were not statistically different. Conclusion Halothane and sevoflurane at 1 MAC produced a small increase in overall inhibition of expiratory premotor neuronal activity. The increase in inhibition results from a marked enhancement of postsynaptic GABAA receptor function that is partially offset by a reduction in presynaptic inhibitory input by the anesthetics.

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Effects of Halothane on Synaptic Neurotransmission to Medullary Expiratory Neurons in the Ventral Respiratory Group of Dogs

Anesthesiology ◽

10.1097/00000542-199909000-00033 ◽

1999 ◽

Vol 91 (3) ◽

pp. 804-804 ◽

Cited By ~ 13

Author(s):

Eckehard A. E. Stuth ◽

Mirko Krolo ◽

Mislav Tonkovic-Capin ◽

Francis A. Hopp ◽

John P. Kampine ◽

...

Keyword(s):

Neuronal Activity ◽

Dose Increase ◽

Inhibitory Mechanism ◽

Gaba A ◽

Mechanically Ventilated ◽

Inhibitory Mechanisms ◽

Synaptic Neurotransmission ◽

Expiratory Neurons ◽

Neuronal Output

Background The activity of canine expiratory neurons is primarily dependent on N-methyl-D-aspartic acid (NMDA)-receptor mediated excitatory chemodrive inputs and a powerful inhibitory gain modulatory mechanism mediated via gamma-aminobutyric acidA (GABA(A)) receptors. We examined whether the depressant effect of halothane on expiratory neuronal activity is primarily caused by a reduction in glutamatergic excitation or a potentiation of the inhibitory mechanism. Methods Experiments were performed in halothane-anesthetized, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of a halothane dose increase from one minimum alveolar concentration (MAC) to 2 MAC on extracellularly recorded expiratory neuronal activity was studied before and during complete GABA(A) receptor blockade by localized picoejection of bicuculline close to the neuron. Complete blockade of the inhibitory mechanism allowed differentiation between the effects of halothane on overall NMDA-mediated excitation and on GABA(A)-mediated inhibition. Results The spontaneous activity of 12 expiratory neurons was significantly depressed (18.1%) by the 1-MAC halothane dose increase. Overall glutamatergic excitation was depressed 38.3+/-12.3% (mean +/- SD) by the 1-MAC halothane increase. The prevailing GABA(A)ergic attenuation of neuronal output decreased significantly from 49.5+/-10 to 32.0+/-10.4%. Thus overall inhibition was reduced by halothane by 33.5+/-17.2%. Conclusions These results suggest that the depressive effect of a 1-MAC halothane dose increase on expiratory neuronal activity in our in vivo preparation with an intact neural network was mainly caused by a reduction of synaptic excitatory mechanisms and not an enhancement of synaptic inhibitory mechanisms.

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Microinjections of glycine into the pre-Bötzinger complex inhibit phrenic nerve activity in the rat

Brain Research ◽

10.1016/s0006-8993(02)02902-5 ◽

2002 ◽

Vol 947 (1) ◽

pp. 25-33 ◽

Cited By ~ 7

Author(s):

V.C Chitravanshi ◽

H.N Sapru

Keyword(s):

Phrenic Nerve ◽

Nerve Activity ◽

Phrenic Nerve Activity ◽

Bötzinger Complex

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Daily acute intermittent hypoxia enhances phrenic motor output and stimulus-evoked phrenic responses in rats

Journal of Neurophysiology ◽

10.1152/jn.00112.2021 ◽

2021 ◽

Author(s):

Raphael Rodrigues Perim ◽

Michael D. Sunshine ◽

Joseph F. Welch ◽

Juliet Santiago ◽

Ashley Holland ◽

...

Keyword(s):

Motor Neurons ◽

Phrenic Nerve ◽

Intermittent Hypoxia ◽

Neural Control ◽

Respiratory Cycle ◽

Evoked Responses ◽

Nerve Activity ◽

Synaptic Inputs ◽

Phrenic Nerve Activity ◽

The Impact

Plasticity is a hallmark of the respiratory neural control system. Phrenic long-term facilitation (pLTF) is one form of respiratory plasticity characterized by persistent increases in phrenic nerve activity following acute intermittent hypoxia (AIH). Although there is evidence that key steps in the cellular pathway giving rise to pLTF are localized within phrenic motor neurons (PMNs), the impact of AIH on the strength of breathing-related synaptic inputs to PMNs remains unclear. Further, the functional impact of AIH is enhanced by repeated/daily exposure to AIH (dAIH). Here, we explored the effects of AIH vs. 2 weeks of dAIH preconditioning on spontaneous and evoked responses recorded in anesthetized, paralyzed (with pancuronium bromide) and mechanically ventilated rats. Evoked phrenic potentials were elicited by respiratory cycle-triggered lateral funiculus stimulation at C2 delivered prior to- and 60 min post-AIH (or an equivalent time in controls). Charge-balanced biphasic pulses (100 µs/phase) of progressively increasing intensity (100 to 700 µA) were delivered during the inspiratory and expiratory phases of the respiratory cycle. Although robust pLTF (~60% from baseline) was observed after a single exposure to moderate AIH (3 x 5 min; 5 min intervals), there was no effect on evoked phrenic responses, contrary to our initial hypothesis. However, in rats preconditioned with dAIH, baseline phrenic nerve activity and evoked responses were increased, suggesting that repeated exposure to AIH enhances functional synaptic strength when assessed using this technique. The impact of daily AIH preconditioning on synaptic inputs to PMNs raises interesting questions that require further exploration.

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Evaluation of a New Valveless all Purpose Ventilator: Effect of Ventilating Frequency PEEP, PACO2 and PAO2 on Phrenic Nerve Activity

Perspectives in High Frequency Ventilation - Developments in Critical Care Medicine and Anesthesiology ◽

10.1007/978-94-009-6711-3_15 ◽

1983 ◽

pp. 140-145 ◽

Cited By ~ 2

Author(s):

M. K. Chakrabarti ◽

J. G. Whitwam

Keyword(s):

Phrenic Nerve ◽

Nerve Activity ◽

Phrenic Nerve Activity

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Effects of hypercapnia and hypoxia on phrenic nerve activity and respiratory timing

Journal of Applied Physiology ◽

10.1152/jappl.1981.51.3.732 ◽

1981 ◽

Vol 51 (3) ◽

pp. 732-738 ◽

Cited By ~ 18

Author(s):

J. F. Ledlie ◽

S. G. Kelsen ◽

N. S. Cherniack ◽

A. P. Fishman

Keyword(s):

Phrenic Nerve ◽

Carotid Sinus ◽

Peak Height ◽

Inspiratory Time ◽

Nerve Activity ◽

Phrenic Nerve Activity ◽

Chemical Stimuli ◽

Proprioceptive Inputs ◽

Spontaneously Breathing ◽

Respiratory Responses

In the spontaneously breathing animal, respiratory responses to chemical stimuli are influenced by phasic proprioceptive inputs from the thorax. We have compared the effects of hypercapnia and hypoxia on the level and timing of phrenic nerve activity while these phasic afferent signals were absent. Progressive hyperoxic hypercapnia and isocapnic hypoxia were produced in anesthetized paralyzed dogs by allowing 3–5 min of apnea to follow mechanical ventilation with 100% O2 or 35% O2 in N2, respectively; during hypoxia, isocapnia was maintained by intravenous infusion of tris(hydroxymethyl)aminomethane buffer. The peak height (P) of nerve bursts, inspiratory time (TI), and expiratory time (TE) were measured from the phrenic neurogram. With the vagi intact or severed, hypoxia decreased TI, whereas hypercapnia did not; both stimuli decreased TE. At the same minute phrenic activity (P x frequency), P, TI, and TE were all less during hypoxia than during hypercapnia. The decreases in TI and TE with hypoxia were significantly less after carotid sinus denervation. The results indicate that the patterns of phrenic nerve activity in response to hypoxia and hypercapnia are different: hypoxia has a greater effect on respiratory timing, whereas hypercapnia has a greater effect on peak phrenic nerve activity. The effect of hypoxia on respiratory timing is largely mediated by the peripheral chemoreceptors.

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