Short-latency excitation of phrenic motor output mediated by non-NMDA receptors.

This study tested the hypothesis that the short-latency excitation of the phrenic motor output elicited by superior laryngeal nerve (SLN) stimulation requires non-NMDA receptor-mediated neurotransmission in the region of the dorsal respiratory group (DRG) of the adult cat. Injection of the non-NMDA receptor antagonist NBQX into the DRG severely attenuated or abolished the short-latency excitation, indicating that the short-latency excitation requires non-NMDA receptor-mediated neurotransmission within the DRG.

Role of N-methyl-D-aspartate receptors in the pontine pneumotaxic mechanism in the cat.

Systemic injection of MK-801, an N-methyl-D-aspartate (NMDA) receptor-associated channel blocker, induces an apneusis in vagotomized cats similar to that produced by pontine respiratory group (PRG) lesions, suggesting the possible involvement of NMDA receptors in the pontine pneumotaxic mechanism. Previous results from our laboratory indicate that the efferent limb of the pontine pneumotaxic mechanism is unlikely to require NMDA receptor-mediated neurotransmission. Therefore, the present study examined the potential involvement of PRG NMDA receptors in the pontine pneumotaxic mechanism. Experiments were conducted in decerebrate, paralyzed, and ventilated adult cats. The effects on inspiratory time (TI) of MK-801 microinjection into PRG were tested in 12 cats. Pressure microinjection of MK-801 (15 mM, 80-3,000 nl) significantly prolonged TI in all animals when lung inflation was withheld. TI progressively increased in most animals for > or = 30 min. After this period, partial recovery of the effect occurred in eight cats as TI shortened toward predrug levels. In three animals, microinjection of MK-801 induced a complete apneusis in the absence of lung inflation from which there was no detectable recovery. Microinjections into regions approximately 2 mm distant from PRG produced little or no effect. These results provide evidence that NMDA receptors located in the region of PRG play an important functional role in the control of the breathing cycle.

Nucleus tractus solitarius and excitatory amino acids in afferent-evoked inspiratory termination.

This study tested the hypothesis that excitatory amino acid (EAA) neurotransmission at non-N-methyl-D-aspartate (non-NMDA), but not NMDA, receptors within medial regions of the nucleus tractus solitarius (NTS) is required in the inspiratory termination elicited by vagal or intercostal nerve (ICN) stimulation. Adult cats were anesthetized, decerebrated, vagotomized, and ventilated. After control responses to stimulation of the superior laryngeal nerve (SLN), vagus, and ICN were obtained, EAA receptor antagonists were injected into the medial aspects of the NTS. Injections of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or 6,7-dinitro-quinoxaline-2,3-dione (DNQX), EAA receptor antagonists; (+/-)-2-amino-5-phosphonopentanoic acid (AP5), an NMDA antagonist; or 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX), a non-NMDA antagonist, ipsilateral to the vagus abolished the termination response. The SLN-elicited response persisted after AP5 injection but was abolished by NBQX injections. The ICN-elicited response persisted after bilateral injections of CNQX/DNQX or procaine. We conclude that the inspiratory termination elicited by ICN stimulation is independent of the regions medial to the NTS. Inspiratory termination elicited by vagal or SLN stimulation requires non-NMDA-mediated EAA neurotransmission within medial aspects of the NTS, but the vagally elicited response also requires NMDA receptors.

Excitatory amino acid neurotransmission in superior laryngeal nerve-evoked inspiratory termination.

Superior laryngeal nerve (SLN) stimulation elicits a transient inhibition of inspiration (single shocks) or inspiratory termination (stimulus trains). The neural pathways mediating these responses are unknown, but the medial nucleus tractus solitarius (mNTS) has been implicated in the termination reflex. This study tested the hypothesis that SLN-evoked inspiratory termination requires excitatory amino acid (EAA) neurotransmission in medial aspects of the NTS. Experiments were conducted in decerebrate, vagotomized, and paralyzed adult cats. Inspiratory motor output was recorded from the phrenic nerve. After control responses to SLN stimulation were recorded, a unilateral injection of the EAA antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX, 10 mM) was made into the mNTS. The transient inhibitions were not altered by DNQX. Inspiratory termination elicited by stimulation of the SLN contralateral to the injection persisted after DNQX (n = 4). Stimulation of the ipsilateral SLN no longer elicited termination (5 of 9 animals) or did so only at greatly elevated thresholds (4 of 9). We conclude that EAA neurotransmission in the mNTS is not required in the transient reflex but is necessary for the production of the SLN-evoked inspiratory termination.

Pontine-evoked inspiratory inhibitions after antagonism of NMDA, GABAA, or glycine receptor.

Single-shock stimulation of the pontine respiratory group (PRG) produces a transient short-latency inhibition of inspiratory motor activity. Stimulus trains delivered to the PRG can elicit a premature termination of inspiration. This study examined the involvement of N-methyl-D-aspartate (NMDA), gamma-aminobutyrateA (GABAA), or glycine receptors in these inhibitory responses. Experiments were conducted in decerebrate, paralyzed, and ventilated cats. Control responses to PRG stimulation were obtained from recordings of the left phrenic nerve activity. After systemic injection of MK-801, bicuculline, or strychnine (antagonists to NMDA, GABAA, or glycine receptors, respectively), responses to stimulation were again recorded. Inspiratory termination elicited by the PRG stimulation persisted after antagonism of NMDA, GABAA, or glycine receptors. The onset latency and duration of the transient inhibition were not changed after administration of bicuculline, but MK-801 administration did significantly prolong the duration of the transient inhibition. Strychnine significantly prolonged both the onset latency and the duration. These data suggest that none of the three receptor types is required in the inspiratory termination response elicited by electrical stimulation of the PRG region and that NMDA, GABAA, or glycine receptor-mediated neurotransmission is not solely responsible for the transient inhibitory response. However, the prolonged onset and duration of the transient inhibition after strychnine administration suggest that glycine does normally participate in this response.

Response of roosters to resistive loads at constant chemical drive to breathe.

This study investigated the role of mechanoreceptors in the respiratory responses to resistive loading in roosters. Adult roosters were unidirectionally ventilated (maintaining a constant chemical drive to breathe). Electrical circuits assessed the respiratory muscle pressure (Pmus) and controlled the relationship between Pmus and the respiratory volume changes. Respiratory volume changes similar to those achieved by flow-resistive unloading or loading were produced by the circuits, imposing a 'virtual' resistance (Rv). When Rv was doubled (decreased rate of volume change, n = 6), tidal volume (VT, measured by whole body plethysmography) decreased significantly (28%), while thoracic volume (VRIP, measured by respiratory inductance plethysmography) did not change. When RV was quadrupled (n = 4) VT and VRIP decreased significantly (53% and 24%, respectively). Changing RV to one half the normal value (n = 5) did not affect these parameters. Inspiratory time and Pmus were not significantly altered at any RV. It is concluded that, at constant chemical drive, mechanoreceptors play a minimal role in maintaining tidal volume during impeded breathing in roosters. Comparative differences which may explain these results are discussed.

Endogenous nitric oxide required for an integrative respiratory function in the cat brain.

1. The involvement of nitric oxide (NO) in the respiratory function of the pons was examined by microinjecting NO synthase-related drugs into discrete regions of the pontine respiratory group (PRG) in decerebrate and decerebellate cats. 2. Microinjection of N omega-nitro-L-arginine (L-NNA, inhibitor of NO synthase), but not D-NNA (the inactive enantiomer), significantly prolonged the duration of inspiration in all 10 cats when lung inflation was withheld. 3. The prolongation of inspiration produced by L-NNA was partially reversed in three cats by microinjections of L-arginine (NO synthase substrate) at the same sites. 4. We conclude that endogenous production of NO from L-arginine in the PRG region is involved in the normal function of the pontine pneumotaxic mechanism. These findings provide the first conclusive evidence that endogenous NO formation is involved in the mechanisms associated with respiratory rhythm generation.

Effects of intravenous bicuculline and strychnine on inspiratory inhibitory responses in the cat.

Single shock stimulation of the superior laryngeal nerve (SLN), intercostal nerve (ICN), phrenic nerve (PN) or within the medullary respiratory groups (DRG-VRG) produces a transient, short-latency attenuation of inspiratory motor activity. Trains of stimuli delivered to SLN and ICN cause premature termination of inspiration. This study examined involvement of glycine and GABAA receptors in these reflex inhibitions. Experiments were conducted in decerebrate, vagotomized, and paralyzed cats. Control responses of left PN activity to threshold single shock stimulation of SLN, PN, ICN and the DRG-VRG were recorded and the thresholds for SLN- and ICN-evoked inspiratory termination were determined. Five min after intravenous injection of bicuculline (1 mg/kg) or strychnine (50 micrograms/kg), the responses to stimulation were again recorded. This procedure was reiterated until the cumulative dose elicited marked convulsions. Neither drug affected the inspiratory terminating reflexes. Systemic bicuculline had no effect on transient inspiratory inhibition. However strychnine prolonged the onset latency and the duration of all four inhibitory responses. Since the degree of transient inhibition was not lessened (only delayed), it appears that these inspiratory inhibitory reflexes do not rely exclusively on actions of glycine or GABAA receptors.

Blockade of N-methyl-D-aspartate receptors has no effect on certain inspiratory reflexes.

Previous studies have indicated that excitatory amino acids are involved in many afferent pathways. This study investigated the effects of intravenous MK-801 [an N-methyl-D-aspartate (NMDA) receptor-associated channel blocker] on several well-known respiratory reflexes elicited by afferent stimulation of the superior laryngeal (SLN), the intercostal (ICN), and the phrenic (PN) nerves. Control responses to stimulation were obtained from recordings of phrenic nerve activity in decerebrate, paralyzed cats. Inspiratory termination elicited by the delivery of stimulus trains to either the SLN or the ICN persisted after MK-801. The onset latency or duration of the short-latency excitations produced by SLN or ICN stimulation were unchanged. The transient inhibitions produced by SLN, ICN, PN, or medullary stimulation showed no significant changes in threshold, onset latency, or duration. Withholding lung inflation produced apneusis after administration of MK-801, indicating a central effect of the drug. Higher doses of MK-801 did not alter the parameters of these reflexes. These data indicate that NMDA-dependent neurotransmission is not required for the production of these reflexes.

Lesions of the rostral dorsolateral pons have no effect on afferent-evoked inhibition of inspiration.

This study investigated a possible role of the rostral dorsolateral pons (including nucleus parabrachialis medialis and Kölliker-Fuse nucleus) in mediating several inspiratory inhibitions. These inhibitions included the transient inhibition of phrenic inspiratory motor output produced by stimulation of the superior laryngeal nerve (SLN), the intercostal nerve (ICN) or the phrenic nerve (PN), as well as the inspiratory termination produced by trains of stimuli delivered to the SLN or ICN. In decerebrate, paralyzed, and artificially ventilated cats, the inhibitions produced by stimulation of these nerves were observed before and after lesioning (either radiofrequency, n = 8, or electrolytic, n = 9) the dorsolateral pons. Delivery of stimulus trains to the SLN or the ICN continued to elicit inspiratory termination following pontine lesions with no significant change in the threshold. There were no significant effects of bilateral dorsolateral pontine lesions on the threshold, onset latency, or duration of the short-latency, transient inhibitions produced by SLN, ICN or PN stimulation. From these data, we conclude that the rostral dorsolateral pons is not required in the production of any of these inhibitory reflexes.