Influence of the ventral surface of the medulla on tracheal responses to CO2

These studies investigated the role of the intermediate area of the ventral surface of the medulla (VMS) in the tracheal constriction produced by hypercapnia. Experiments were performed in chloralose-anesthetized, paralyzed, and artificially ventilated cats. Airway responses were assessed from pressure changes in a bypassed segment of the rostral cervical trachea. Hyperoxic hypercapnia increased tracheal pressure and phrenic nerve activity. Intravenous atropine pretreatment or vagotomy abolished the changes in tracheal pressure without affecting phrenic nerve discharge. Rapid cooling of the intermediate area reversed the tracheal constriction produced by hypercapnia. Graded cooling produced a progressive reduction in the changes in maximal tracheal pressure and phrenic nerve discharge responses caused by hypercapnia. Cooling the intermediate area to 20 degrees C significantly elevated the CO2 thresholds of both responses. These findings demonstrate that structures near the intermediate area of the VMS play a role in the neural cholinergic responses of the tracheal segment to CO2. It is possible that neurons or fibers in intermediate area influence the motor nuclei innervating the trachea. Alternatively, airway tone may be linked to respiratory motor activity so that medullary interventions that influence respiratory motor activity also alter bronchomotor tone.     

Hypoxia potentiates, oxygen attenuates deflation-induced reflex tracheal constriction

The reflex tracheomotor responses of in situ isolated segments of the extrathoracic trachea of anesthetized, paralyzed, and ventilated dogs were monitored. Reflex tracheal constriction was evoked by passive lung deflation. The purpose of this study was to determine whether the prevailing state of oxygenation altered the magnitude of this reflex. Compared with the magnitude of the response during normoxia [arterial O2 tension (PaO2) = 78 Torr], that during hypoxia (PaO2 = 44 Torr) was nearly threefold larger while that during hyperoxia (PaO2 greater than 250 Torr) was about 50% smaller. The isocapnic changes in oxygenation by themselves usually had no effect on tracheomotor tone. The deflation-induced reflex tracheal constriction was eliminated by complete denervation of the tracheal segment but usually only diminished by partial denervation. Bilateral vagotomies or bilateral carotid body denervation also usually decreased the magnitude of the reflex. It appears that the magnitude of this reflex is dependent on the prevailing state of oxygenation and that a pulmonary stretch receptor-carotid body chemoreceptor interaction accounts for the exaggerated reflex tracheal constriction during hypoxia and the attenuated response during hyperoxia.     

Influence of ventrolateral surface of medulla on reflex tracheal constriction

To assess the role of structures located superficially near the ventrolateral surface of the medulla on the reflex constriction of tracheal smooth muscle that occurs when airway and pulmonary receptors are stimulated mechanically or chemically, experiments were conducted in alpha-chloralose-anesthetized, paralyzed, and artificially ventilated cats. Pressure changes within a bypassed segment of the trachea were used as an index of alterations smooth muscle tone. The effects of focal cooling of the intermediate areas or topically applied lidocaine on the ventral surface of the medulla on the response of the trachea to mechanical and chemical stimulation of airway receptors were examined. Atropine abolished tracheal constriction induced by mechanical stimulation of the carina or aerosolized histamine, showing that the responses were mediated over vagal pathways. Moderate cooling of the intermediate area (20 degrees C) or local application of lidocaine significantly decreased the tracheal constrictive response to mechanical activation of airway receptors. Furthermore, when the trachea was constricted by histamine, cooling of the intermediate area significantly diminished the increased tracheal tone, whereas rewarming restored tracheal tone to the previous level. These findings suggest that under the conditions of the experiments the ventral surface of the medulla plays an important role in constriction of the trachea by inputs from intrapulmonary receptors and in the modulation of parasympathetic outflow to airway smooth muscle.     

Effects of antigen on tracheal circulation and smooth muscle in sheep of different ages

The effects of Ascaris suum antigen on tracheal circulation and tracheal smooth muscle tone were compared in two groups of sheep: the first group was 1 yr old (14 sheep) and the second 5 yr old (8 sheep). Cranial tracheal arteries of anesthetized and paralyzed sheep were perfused at constant flow with monitoring of perfusion pressure. Tracheal smooth muscle tone was assessed by measuring changes in the external diameter of the cranial trachea. Close-arterial injection of antigen (1-20 micrograms) in young sheep produced dose-dependent vasodilation (6.1-15.5% fall in perfusion pressure) and smooth muscle contraction (0.06-0.28 mm reduction in tracheal diam). In old sheep, antigen (1-20 micrograms) produced vasoconstriction (4.1-16.8%) but no smooth muscle response. The smooth muscle contraction in young sheep was blocked by mepyramine (2 mg/kg iv) suggesting mediation by release of histamine. The vasodilation in young sheep and the vasoconstriction in old sheep were reduced by indomethacin (5 mg/kg iv), and the residual response was further reduced by FPL 55712 (2 mg/kg iv), suggesting mediation by both cyclooxygenase products and leukotrienes. Thus antigen given in the tracheal vasculature releases a mixture of inflammatory mediators. This mixture of mediators or their actions on the tracheal vasculature and smooth muscle may depend on the age of the sheep.     

Nasal and tracheal responses to chemical and somatic afferent stimulation in anesthetized cats

Respiratory chemical and reflex interventions have been shown to affect nasal resistance or tracheal tone, respectively. In the present study, nasal caliber (assessed from pressure at a constant flow) and tracheal tone (assessed from pressure in a fluid-filled balloon within an isolated tracheal segment) were monitored simultaneously in anesthetized, paralyzed, artificially ventilated (inspired O2 fraction = 100%) cats. We examined the effect of CO2 inhalation and sciatic nerve stimulation as well as the application of nicotine (6 X 10(-4) mol/l) or lidocaine (2% solution) to the intermediate area of the ventral medullary surface (VMS). CO2 and VMS nicotine resulted in a significant increase in tracheal pressure [147 +/- 73 and 91 +/- 86% (SD), respectively]; and a significant reduction in nasal pressure (-35 +/- 10 and -20 +/- 13%, respectively). In contrast, sciatic nerve stimulation resulted in a significant fall in both tracheal (-50 +/- 36%) and nasal pressure (-21 +/- 13%). Application of 2 or 4% lidocaine to the VMS reduced tracheal pressure but did not significantly affect nasal pressure. After VMS lidocaine, nasal and tracheal responses to CO2, sciatic nerve stimulation, or VMS nicotine, when present, were negligible. These results suggest a role for the VMS in the regulation and coordination of nasal and tracheal caliber responses.     

Effect of cardiogenic oscillations on gas mixing during tracheal insufflation of oxygen

In a previous study using tracheal insufflation of O2 (TRIO) at a rate of 2 l/min, we showed that anesthetized paralyzed dogs could be adequately oxygenated for up to 5 h, albeit with hypercapnia (mean arterial PCO2 approximately 160 Torr). To examine the contribution of cardiogenic oscillations in producing this gas exchange, we studied seven anesthetized paralyzed dogs weighing between 19.6 and 25.5 kg and quantified gas transport by analyzing continuous N2-washout curves in vivo and postmortem. We found that cardiogenic oscillations increase gas mixing roughly fourfold and that this value was independent of insufflation flow rate (0.2-10.0 l/min). Our results lend indirect evidence that, with regard to gas exchange, there are two mechanistically different zones in the lung during TRIO. One zone, located in the more peripheral areas of the lung, is dominated by the effects of cardiac oscillations and molecular diffusion and accounts for the increase in gas mixing found in the alive vs. dead dog. A second zone, close to the insufflated jet of O2, uses convective streaming to produce greater gas mixing at higher flows.     

Muscarinic excitation-contraction coupling mechanisms in tracheal and bronchial smooth muscles.

We investigated the mechanisms underlying muscarinic excitation-contraction coupling in canine airway smooth muscle using organ bath, fura 2 fluorimetric, and patch-clamp techniques. Cyclopiazonic acid (CPA) augmented the responses to submaximal muscarinic stimulation in both tracheal (TSM) and bronchial smooth muscles (BSM), consistent with disruption of the barrier function of the sarcoplasmic reticulum. During maximal stimulation, however, CPA evoked substantial relaxation in TSM but not BSM. CPA reversal of carbachol tone persisted in the presence of tetraethylammoium or high KCl, suggesting that hyperpolarization is not involved; CPA relaxations were absent in tissues preconstricted with KCl alone or by permeabilization with beta-escin, ruling out a nonspecific effect on the contractile apparatus. Peak contractions were sensitive to inhibitors of tyrosine kinase (genistein) or Rho kinase (Y-27632). Sustained responses were dependent on Ca(2+) influx in TSM but not BSM; this influx was sensitive to Ni(2+) but not La(3+). In conclusion, there are several mechanisms underlying excitation-contraction coupling in airway smooth muscle, the relative importance of which varies depending on tissue and degree of stimulation.     

Chemical control of tracheal vascular resistance in dogs

With anesthetized dogs we have measured upper tracheal vascular resistance on both sides of the trachea simultaneously by perfusing the cranial tracheal arteries and measuring inflow pressures at constant flows. The ratio of pressure to flow gave vascular resistance (Rtv). Lung airflow, blood pressure (BP), heart rate, and pressure in a cervical tracheal balloon (Ptr) were also measured. In paralyzed dogs, systemic hypoxia due to artificial ventilation with 10% O2-90% N2 increased Rtv by +8.1 +/- 1.0% (SE), Ptr by +76 +/- 22.8%, and BP by +18.9 +/- 24%. After bilateral cervical vagosympathectomy the increases in Rtv and BP were present (+8.8 +/- 0.9 and +22.3 +/- 0.3%, respectively). After carotid body denervation Rtv, Ptr, and BP increased (+6.4 +/- 1.3, +58.6 +/- 31.6, and +14.6 +/- 3.3%, respectively). After vagotomy Rtv and BP increased (+14.1 +/- 1.7 and +22.4 +/- 10.1%, respectively). Tracheal perfusion with hypoxic blood caused a small vasodilation (-2.2 +/- 1.1%). Systemic hypercapnia due to artificial ventilation with 8% CO2-92% air increased Rtv by +16.7 +/- 3.8%, Ptr by +67 +/- 2.0%, and BP by +12.9 +/- 9.9%. Tracheal perfusion with hypercapnic blood caused a small vasodilation (-2.5 +/- 1.2%). Stimulation of the carotid body chemoreceptors with KCN caused a small increase in Rtv (+1.2 +/- 0.5%) and increases in Ptr (+49.8 +/- 13.6%) and BP (+11.1 +/- 2.1%). Systemic hypoxia and hypercapnia caused tracheal vasoconstriction mainly by an action on the central nervous system.     

Differential response of dog and pig tracheal smooth muscle to the acetylcholinesterase inhibitor soman

The effect of the acetylcholinesterase inhibitor soman on tracheal smooth muscle (TSM) from the dog and pig was studied. In response to soman, tracheal ring preparations contract more and the resting tension for TSM preparations is higher for the dog compared with the pig. Tension induced by electrical field stimulation (EFS) and the half-time of EFS-train induced contractions have a similar dependence on soman exposure in both dog and pig TSM. These results suggest that the basal acetylcholine secretion or leakage within the TSM nerve terminal is probably higher for the dog compared with the pig.     

Neuronal histamine release elicited by hyperthermia mediates tracheal dilation and pressor response

Whether brain histaminergic neurons contribute to the regulation of tracheal tone and peripheral vascular tone under hyperthermia was investigated in anesthetized rabbits. Histamine release from the rostral ventrolateral medulla (RVLM), the raphe nuclei, and the solitary nucleus of the medulla oblongata was significantly increased by hyperthermia. The increased histamine was significantly suppressed by 10(-6) M tetrodotoxin microdialyzed in each area. Tracheal pressure and mean arterial pressure were significantly decreased and increased by hyperthermia, respectively. An H(1)-receptor antagonist, 5 x 10(-6) M (+)-chlorpheniramine, bilaterally microdialyzed in the RVLM significantly enhanced histamine release in the RVLM as well as significantly suppressed tracheal dilation and pressor response caused by hyperthermia. These data indicate that histamine release in the medulla oblongata is enhanced by hyperthermia. The enhanced histamine is the neuronal origin and the cause of tracheal dilation and pressor response at least via H(1) receptors in the RVLM. Brain histaminergic neurons play important roles in tracheal tone and peripheral vascular tone via H(1) receptors in the RVLM and homeostasis on body temperature.     

Influence of CPAP on reflex responses to tracheal irritation in anesthetized humans

We investigated the effects of lung inflation during continuous positive airway pressure breathing (CPAP) on airway defensive reflexes in 10 enflurane-anesthetized spontaneously breathing humans. The airway defensive reflexes were induced by instillation into the trachea of 0.5 ml of distilled water at two different levels of end-expiratory pressure (0 and 10 cmH2O CPAP). The tracheal irritation at an end-expiratory pressure of 0 cmH2O caused a variety of reflex responses including apnea, spasmodic panting, expiration reflex, cough reflex, an increase in heart rate, and an increase in blood pressure. Lung inflation during CPAP of 10 cmH2O did not exert any influence on these reflex responses in terms of the types, latencies, and durations of reflex responses although the intensity of the expiration reflex and cough reflex was augmented by lung inflation. Our results suggest that the pulmonary stretch receptors do not play an important role in the mechanisms of airway defensive reflexes in humans.     

Maturation of respiratory reflex responses in the piglet

Stimulation of chemo-, irritant, and pulmonary C-fiber receptors reflexly constricts airway smooth muscle and alters ventilation in mature animals. These reflex responses of airway smooth muscle have, however, not been clearly characterized during early development. In this study we compared the maturation of reflex pathways regulating airway smooth muscle tone and ventilation in anesthetized, paralyzed, and artificially ventilated 2- to 3- and 10-wk-old piglets. Tracheal smooth muscle tension was measured from an open tracheal segment by use of a force transducer, and phrenic nerve activity was measured from a proximal cut end of the phrenic nerve. Inhalation of 7% CO2 caused a transient increase in tracheal tension in both age groups, whereas hypoxia caused no airway smooth muscle response in either group. The phrenic responses to 7% CO2 and 12% O2 were comparable in both age groups. Lung deflation and capsaicin (20 micrograms/kg iv) administration did not alter tracheal tension in the younger piglets but caused tracheal tension to increase by 87 +/- 28 and 31 +/- 10%, respectively, in the older animals (both P less than 0.05). In contrast, phrenic response to both stimuli was comparable between ages: deflation increased phrenic activity while capsaicin induced neural apnea. Laryngeal stimulation did not increase tracheal tension but induced neural apnea in both age groups. These data demonstrate that between 2 and 10 wk of life, piglets exhibit developmental changes in the reflex responses of airway smooth muscle situated in the larger airways in response to irritant and C-fiber but not chemoreceptor stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of substance P in hypercapnic excitation of carotid chemoreceptors

Experiments were performed on 17 anesthetized, paralyzed, and artificially ventilated cats to evaluate the importance of substance P-like peptide (SP) on the carotid body responses to CO2. Single or paucifiber carotid chemoreceptor activity was recorded from the peripheral end of the cut carotid sinus nerve. In eight of the cats the influence of SP on hyperoxic hypercapnic responses was studied. While the animals breathed 100% O2, intracarotid infusion of SP (1 microgram.kg-1.min-1, 3 min) increased chemoreceptor activity by +4.8 +/- 0.3 impulses/s. After SP infusion, inhalation of CO2 in O2 caused a rapid increase in activity that reached a peak and then adapted to a lower level, whereas similar levels of CO2 before SP caused only a gradual increase in carotid body discharge rate without any overshoot in response. Furthermore SP significantly increased the magnitude and slope of the CO2 response. In the other nine cats the effect of intracarotid infusion of an SP antagonist, [D-Pro2,D-Trp7,9] SP (10-15 micrograms.kg-1.min-1), on carotid body responses to 1) hyperoxic hypercapnia (7% CO2-93% O2), 2) isocapnic hypoxia (11% O2-89% N2), and 3) hypoxic hypercapnia (11% O2-7% CO2-82% N2) was examined. SP antagonist had no effect on carotid body response to hyperoxic hypercapnia but significantly attenuated the chemoreceptor excitation caused by isocapnic hypoxia and hypoxic hypercapnia. These results suggest that 1) SP may play an important role in carotid body responses to hypoxia but not to CO2, and 2) the mechanisms of stimulation of the carotid body by hypercapnia and by hypoxia differ.     

Ca2+]i changes in guinea pig tracheal smooth muscle cells in culture: effects of Na+ and ouabain

The objective of this work was to confirm that the contractile effects of ouabain and Na(+)-free solutions in guinea pig tracheal rings are associated with increments in the cytosolic free Ca2+ concentration ([Ca2+]i) in cultured tracheal smooth muscle (TSM) cells. Cultured cells were alpha-actin positive. Histamine (50 microM) and Na(+)-free solution elicited a transient increase in [Ca2+]i, while the responses to thapsigargin (1 microM) and ouabain (1 mM) were long lasting. However, carbachol (10, 200, and 500 mM) and high K(+)-solution produced no effect on [Ca2+]i, suggesting that cultured guinea pig TSM cells display a phenotype change but maintain some of the tracheal rings physiological properties. The transient rise in [Ca2+]i in response to the absence of extracellular Na+ and the effect of ouabain may indicate the participation of the Na(+)/Ca2+ exchanger (NCX) in the regulation of [Ca2+]i.     

Endogenous AA metabolites and their possible role in tracheal smooth muscle tone in guinea pigs

The effects of endogenous arachidonic acid (AA) metabolites on inherent tone and histamine-induced constriction were studied in guinea pig tracheal smooth muscle. Inhibitors of either cyclooxygenase (indomethacin) or lipoxygenase (AA 861) significantly diminished the inherent tone of the muscle. Antagonists of prostaglandins (SC 19220) or leukotrienes (FPL 55712) also diminished the inherent tone, whereas an inhibitor of thromboxane synthase (OKY 046) had no significant effect. These results show that the metabolites of the lipoxygenase pathway as well as prostaglandins also participate in the maintenance of inherent tone. To reexamine the previously reported augmentation of histamine constriction induced by the inhibitors and the antagonists, we compared the active tension of the muscle measured from the maximum relaxed level as the base line to eliminate the fluctuation of inherent tone. Such comparison revealed that the inhibitors and the antagonists have no augmentative effect on either the maximum response to histamine or the concentration required to produce 50% of maximum active tension and that there is functional synergism between the exogenously added histamine and the endogenously produced AA metabolites. Therefore the zero active tension is useful as a base line to compare the contractile response of a drug-treated preparation with that of a nontreated preparation.     

Interaction between histamine and vagal stimulation on tracheal smooth muscle in dogs

We examined the interaction between histamine and vagal efferent activity on airway smooth muscle reactivity in 11 anesthetized vagotomized dogs using an isolated closed segment of the intrathoracic trachea filled with Tyrode solution under an isovolumetric condition. Intratracheal pressure change was measured as an index of tracheal smooth muscle tone. The administration into the tracheal segment of histamine (0.1 or 1.0 mg/ml) in six dogs and methacholine chloride (0.001 or 0.01 mg/ml) in the other five dogs elevated intratracheal pressure by about 5 cmH2O. The electrical stimulation of the peripheral ends of both of the cut cervical vagus nerves in the presence of histamine produced significantly greater responses than the additive responses of these two stimuli applied individually (two-way analysis of variance, P less than 0.025). However, the combined effects of vagal stimulation and methacholine were not significantly different from the additive responses of these two stimuli applied individually. The average values of intratracheal pressure elevated by the combined effects of vagal stimulation and histamine were significantly higher than those obtained by the combination of vagal stimulation and methacholine (two-way analysis of variance, P less than 0.01). This suggests that histamine potentiates tracheal smooth muscle reactivity to electrical vagal stimulation, which may contribute to the hyperreactivity observed in patients with asthma.     

Functional anatomy of the vagal innervation of the cervical trachea of the dog.

The canine cervical trachea has been used for numerous studies regarding the neural control of tracheal smooth muscle. The purpose of the present study was to determine whether there is lateral dominance by either the left or right vagal innervation of the canine cervical trachea. In anesthetized dogs, pressure in the cuff of the endotracheal tube was used as an index of smooth muscle tone in the trachea. After establishment of tracheal tone, as indicated by increased cuff pressure, either the right or left vagus nerve was sectioned followed by section of the contralateral vagus. Sectioning the right vagus first resulted in total loss of tone in the cervical trachea, whereas sectioning the left vagus first produced either a partial or no decrease in tracheal tone. After bilateral section of the vagi, cuff pressure was recorded during electrical stimulation of the rostral end of the right or left vagus. At the maximum current strength used, stimulation of the left vagus produced tracheal constriction that averaged 28.5% of the response to stimulation of the right vagus (9.0 +/- 1.8 and 31.6 +/- 2.5 mmHg, respectively). In conclusion, the musculature of cervical trachea in the dog appears to be predominantly controlled by vagal efferents in the right vagus nerve.     

Influence of ventrolateral surface of medulla on tracheal gland secretion.

Airway secretion can be modified reflexly as well as locally. Previous studies indicate that neurons in a circumscribed region near the ventral surface of the medulla (VMS) can substantially modify airway tone and reflex responses to vagal inputs. In the present studies we assessed the importance of these neurons on tracheal gland secretion. We examined the changes in the number of hillocks of secretion appearing from submucosal glands in an exposed field of tracheal epithelium (1.2 cm2) coated with tantalum dust before and after interventions on the VMS. Experiments were performed in alpha-chloralose-anesthetized dogs paralyzed and ventilated with 40% O2. Stimulation of nicotinergic receptors by application of a pledget containing nicotine in 11 dogs caused a significant elevation in tracheal gland secretion in the subsequent 60 s, compared with a control period in which buffered saline was applied. Prior application of lidocaine or hexamethonium bromide to the VMS blocked the effect of topically applied nicotine. The central effects of nicotine were diminished by atropine methylnitrate given intravenously. In addition, lidocaine application to the VMS or focal cooling of intermediate areas to between 20 and 15 degrees C significantly decreased secretion rates reflexly produced by capsaicin-induced stimulation of pulmonary C-fiber receptors and by mechanical stimulation of the carina and larynx. These findings suggest that the ventral medulla contains cells near its surface that influence tracheal fluid secretion and modulate reflex responses of airway submucosal glands, probably by altering the level of general excitation within the central respiratory integrating circuits.     

Tracheal smooth muscle responses to substance P and neurokinin A in the piglet.

The tachykinins substance P (SP) and neurokinin A (NKA) have been shown to induce airway smooth muscle contraction in mature animals, and the enzyme neutral endopeptidase (NEP) modulates this effect. We evaluated maturation of SP- and NKA-induced tracheal smooth muscle contraction and modulation of their effects by NEP in anesthetized, paralyzed, and artificially ventilated piglets less than 4 days, 2-3 wk, and 10 wk of age. Tracheal smooth muscle tension was measured in vivo from an open tracheal segment by use of a force transducer. Intravenous SP caused a dose-dependent increase in tracheal tension in all three age groups; however, the response in less than 4-day-old piglets was significantly weaker than in 2- to 3- and 10-wk-old piglets. NKA caused a dose-dependent increase in tracheal tension only in 2- to 3- and 10-wk-old piglets. The response of tracheal tension to NKA was weaker than the response to SP in all age groups. Atropine (2 mg/kg) significantly diminished the responses of tracheal tension to SP and NKA, indicating a cholinergic contribution to these responses at all ages. Intravenous thiorphan, a known NEP inhibitor, potentiated the effects of SP only in 2- to 3- and 10-wk-old piglets and did not affect the response of tracheal tension to NKA at any age. Biochemical analyses demonstrated a significant increase in tracheal NEP activity in comparably aged piglets over the first 10 wk of life.(ABSTRACT TRUNCATED AT 250 WORDS)     

Responses of ganglioglomerular nerve activity to respiratory stimuli in the cat

We studied the responses of the ganglioglomerular nerve (GGN) efferents to brief periods of hypoxia and hypercapnia and to several levels of steady-state arterial PO2 and PCO2 and to intravascular injection of cyanide in thirteen anesthetized cats. The cats breathed spontaneously. A branch of the GGN which was cut close to the carotid body was divided into several filaments, and the activity of each filament was tested until clean and identifiable action potentials were obtained. The GGN efferent activity, breath-by-breath inspiratory volume, tracheal PO2 and PCO2 and arterial blood pressure were recorded simultaneously. We found that the GGN contained spontaneously active fibers which showed a range of responses to the respiratory stimuli. Fifty-eight percent of the filaments with dominant cardiovascular rhythm showed the least response to blood gas stimuli. Forty-two percent showed clear responses to hypoxia and hypercapnia. These responses developed slowly with the onset of the stimulus but decreased promptly with the withdrawal of the stimulus. These GGN efferents were also promptly stimulated by sodium cyanide. The steady-state response curve to hypoxia was hyperbolic and to hypercapnia it was linear. Some of these fibers showed stronger respiratory rhythms than others. The responses of these GGN efferents were associated with the respiratory responses to hypoxia and hypercapnia. For the same respiratory drive, however, the steady-state hypoxic stimulus elicited a greater GGN response than did hypercapnia.