Zoran Dogas

Modulation of the synaptic drive to respiratory premotor and motor neurons.

The characteristics of GABAergic inhibitory modulation of respiratory bulbospinal neuronal activity and short-term potentiation (STP) of phrenic motoneuronal activity were studied. Extracellular unit recording and picoejection techniques in anesthetized dogs showed that both the spontaneous rhythmic and reflexly induced discharge patterns of inspiratory (I) and expiratory (E) premotor neurons were proportionately amplified by the localized application of picomole amounts of bicuculline (Bic), a competitive GABAA antagonist. Intracellular recording and paired-pulse stimulation techniques in anesthetized rats demonstrated an STP of phrenic motor output that appears to be mediated by NMDA receptors and is associated with facilitation of EPSPs and prolonged depolarization of individual phrenic motoneurons. We speculate that both GABAergic gain modulation of premotor neuronal activity and NMDA-mediated STP of phrenic activity may be neural substrates which are involved with the optimization of respiratory and non-respiratory behaviors, via adaptive and/or differential control of breathing.

NMDA receptor-mediated transmission of carotid body chemoreceptor input to expiratory bulbospinal neurones in dogs.

1. This study tested the hypothesis that excitatory amino acid receptors mediate the excitatory response of expiratory bulbospinal neurones to carotid body chemoreceptor inputs. 2. Studies were carried out in thiopental sodium anaesthetized, paralysed, ventilated, vagotomized dogs. 3. Brisk, short‐duration chemoreceptor activation was produced by bilateral bolus injections of CO2‐saturated saline (PCO2 > 700 mmHg) into the autoperfused carotid arteries. A pressurized‐reservoir‐solenoid valve system was used to deliver the CO2 bolus injections just prior to the onset of the neural expiratory phase, as determined from the phrenic neurogram, about once per minute. 4. Multibarrelled micropipettes were used to record neuronal unit activity and deliver neurotransmitter agents. Net responses of expiratory bulbospinal neurones to peripheral chemoreceptor activation were determined by subtracting the mean discharge frequencies (Fn) during three control expiratory cycles from the Fn during administration of a CO2 test bolus. The role of excitatory amino acid receptors in mediating this response was determined by comparing the baseline and bolus expiratory neuronal Fn before, during and after the pressure microejection of the NMDA receptor antagonist 2‐amino‐5‐phosphonovalerate (AP5) or the non‐NMDA receptor antagonist 2,3‐dihydroxy‐6‐nitro‐7‐sulphamoyl‐ benzo(f)quinoxaline (NBQX). Ejection rates of AP5 and NBQX were measured by monitoring the movement of the pipette meniscus. 5. AP5 reduced Fn during both the control and bolus cycles, as well as reducing the change in Fn between control and bolus cycles. NBQX had no effect on either baseline or bolus responses. 6. AP5 did not prevent excitation of expiratory bulbospinal neurones by AMPA. Coadministration of AMPA with AP5 prevented the AP5‐mediated decrease in Fn but not the dose‐dependent reduction in the CO2 bolus response. 7. Taken together, these data strongly suggest that the carotid chemoreceptor‐mediated excitation of expiratory bulbospinal neurones is dependent on NMDA but not non‐NMDA glutamate receptors.

Dose-dependent effects of halothane on the phrenic nerve responses to acute hypoxia in vagotomized dogs.

Background: Previous studies in dogs and humans suggest that the carotid body chemoreceptor response to hypoxia is selectively impaired by halothane. The present studies in an open‐loop canine preparation were performed to better delineate the effects of anesthetic concentrations of halothane on the carotid body chemoreceptor‐mediated phrenic nerve response to an acute hypoxic stimulus. Methods: Three protocols were performed to study the effects of halothane anesthesia on the phrenic nerve response to 1 min of isocapnic hypoxia (partial pressure of oxygen [PaO2] at peak hypoxia, 35–38 mmHg) in unpremedicated, anesthetized, paralyzed, vagotomized dogs during constant mechanical ventilation. In protocol 1, the dose‐dependent effects of halothane from 0.5–2.0 minimum alveolar concentration (MAC) on the hypoxic response during moderate hypercapnia (partial pressure of carbon dioxide [PaCO2], 60–65 mmHg) were studied in 10 animals. In protocol 2, the hypoxic responses at 1 MAC halothane near normocapnia (PaCO2, 40–45 mmHg) and during moderate hypercapnia were compared in an additional four animals. In protocol 3, the hypoxic response of 4 of 10 dogs from protocol 1 was also studied under sodium thiopental (STP) anesthesia after they completed protocol 1. Results: Protocol 1: Peak phrenic nerve activity (PPA) increased significantly during the hypoxic runs compared with the isocapnic hyperoxic controls at all halothane doses. The phrenic nerve response to the hypoxic stimulus was present even at the 2 MAC dose. Protocol 2: The net hypoxic responses for the two carbon dioxide background levels at 1 MAC were not significantly. Protocol 3: The net hypoxic response of PPA for the STP anesthetic was not significantly different from the 1 MAC halothane dose. Bilateral carotid sinus denervation abolished the PPA response to hypoxia. Conclusions: The phrenic nerve response to an acute, moderately severe isocapnic hypoxic stimulus is dose‐dependently depressed but not abolished by surgical doses of halothane. This analysis does not suggest a selective depression of the carotid body chemoreceptor response by halothane. The observed hypoxic phrenic response was mediated by the carotid body chemoreceptors in vagotomized dogs because bilateral carotid sinus denervation abolished all increases in PPA.

Effects of Halothane on the Phrenic Nerve Responses to Carbon Dioxide Mediated by Carotid Body Chemoreceptors in Vagotomized Dogs

Background: Previous studies in dogs showed that the phrenic nerve response to an acute hypoxic stimulus was dose dependently depressed by 0.5–2.0 minimum alveolar concentration (MAC) of halothane but not abolished. Because a carbon dioxide stimulus is transduced by a different mechanism in the carotid body chemoreceptors (CBCRs) than is a hypoxic stimulus, inhalational anesthetics may preferentially depress one of these transduction processes, the central neuronal processing, or both, of the integrated responses to these two types of inputs. Methods: Carotid body chemoreceptor stimulation was produced by short (1–1.5 s), bilateral, 100% carbon dioxide in saline infusions into the carotid arteries during neural inspiration in unpremeditated, halothane‐anesthetized, paralyzed, vagotomized dogs during constant mechanical ventilation. The phrenic neurogram quantified the neural inspiratory response. Four protocols were performed in the study: (1) the dose‐dependent effects of halothane anesthesia (0.5–2.0 MAC) during hyperoxic hypercapnia on phrenic nerve activity, (2) the effects of three background levels of the partial pressure of carbon dioxide (PaCO2) on the magnitude of the carbon dioxide infusion responses at 1 MAC halothane, (3) the effects of anesthetic type on the magnitude of the carbon dioxide infusion response, and (4) the effects of CBCR denervation. Results: Peak phrenic nerve activity (PPA) increased significantly during the carbon dioxide‐stimulated phrenic burst in protocols 1–3; after denervation there was no response (protocol 4). Halothane produced a dose‐dependent reduction in the PPA of control and carbon dioxide infusion‐stimulated phrenic bursts and in the net carbon dioxide response. The net PPA responses for the different PaCO2 background levels were not different but were somewhat larger for sodium thiopental anesthesia than for 1.0 MAC halothane. Conclusions: The phrenic nerve response to an acute, severe carbon dioxide stimulus was dose dependently depressed by surgical doses of halothane. The observed responses to carbon dioxide infusion were mediated by the CBCRs because they were eliminated by CBCR denervation. These results suggest that the CBCR transduction and central transmission of the carbon dioxide signal in terms of inspiratory excitatory drive are not abolished at surgical levels of halothane anesthesia.