Site of central chemosensitivity in fetal sheep.

The heart rate, blood pressure, and respiratory response to topically applied cyanide on the ventrolateral medullary surface and upper spinal cord was studied on exteriorized sinaortic-denervated fetal lambs under pentobarbital anesthesia. On all sites tested cyanide produced a rapid increase in heart rate and blood pressure (P smaller than 0.05) which was most pronounced from the area adjacent to the nerve roots IX to XI (mean 32%). Respiratory efforts consisting of 1-8 gasps were induced in half the applications to the medulla but never when the pledgets were applied to the spinal cord. The mean delay to response was 43 s (range 13-102 s). After cautery of the chemosensitive areas, topical application of cyanide failed to stimulate gasping, whereas intravenous cyanide or cord clamping still produced a vigorous respiratory response. It is concluded that sympathetic stimulation of the heart and blood vessels can originate centrally in response to local histotoxic hypoxia of the ventral medulla and upper spinal cord. Furthermore, it is proposed that in the apneic fetus histotoxic hypoxia of the medulla initiates respiration possibly by stimulating a special gasping mechanism which is separate from the respiratory center responsible for rhythmic breathing after birth. The responsible neurons must be located at least 2 mm beneath the ventral medullary surface.     

Identification of a subsurface area in the ventral medulla sensitive to local changes in PCO2.

The exact location of the central respiratory chemoreceptors sensitive to changes in PCO2 has not yet been determined. To avoid the confounding effects of the cerebral circulation, we used the in vitro brain stem-spinal cord of neonatal rats (1-5 days old) to identify areas within 500 microns of the ventral surface of the medulla where changes in PCO2 evoked a sudden increase in the rate of respiratory neural activity. The preparation was superfused with mock cerebrospinal fluid (CSF) while maintained at constant temperature (26 +/- 1 degrees C) and pH (7.34). Respiratory frequency increased linearly with decreases in superfusate pH (r2 = 0.92, P less than 0.001), indicating that the respiratory circuitry for the detection of CO2 and stimulation of breathing was intact in this preparation. The search for central chemoreceptors was performed with a specially designed micropipette that allowed microejection of 2-10 nl of mock CSF equilibrated with different CO2-O2 gas mixtures. The pipette was advanced in 50- to 100-microns steps by use of a microdrive to a maximum depth of 500 microns from the surface of the ventral medulla. Depending on the location of the micropipette, ejection of CO2-acidified mock CSF at depths of 100-350 microns below the ventral surface of the medulla stimulated neural respiratory output. Using this response as an indication of the location of central respiratory chemoreceptors, we found that chemoreceptive elements were located in a column in the ventromedial medulla extending from the hypoglossal rootlets caudally to an area 0.75 mm caudal to VI nerve in the rostral medulla.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebral interstitial fluid acid-base status follows arterial acid-base perturbations

Cerebral interstitial fluid (ISF) pH of ventral medulla or thalamus, cisternal cerebrospinal fluid (CSF) pH, and arterial blood pH, PCO2, and [HCO-3] were measured in chloralose-urethan-anesthetized, gallamine-paralyzed New Zealand White rabbits during 30-min episodes of either HCl or NaHCO3 intravenous infusions. ISF pH was measured continuously with glass microelectrodes (1- to 2-microns tip diameter). Cisternal CSF pH was measured continuously with an indwelling pH probe (1-mm tip diameter). Both ventral medullary and thalamic ISF [H+] changed significantly, whereas arterial PCO2 remained constant. CSF [H+] did not change. We conclude from these data that 1) changes in blood acid-base conditions are rapidly reflected in cerebral ISF and 2) transient differences in [H+] and [HCO-3] can exist between cerebral ISF and CSF.     

Involvement of ventral medullary surface in respiratory responses induced by 2,4-dinitrophenol

We examined the contribution of the neural elements near the ventral medullary surface (VMS) to the respiratory response caused by 2,4-dinitrophenol (DNP). Two series of experiments were performed on 12 vagotomized and sinoaortic denervated cats. The first series examined the effect of focal cooling of the VMS on the respiratory response to DNP in four spontaneously breathing, anesthetized cats. When the VMS temperature was 37 degrees C, systemic administration of DNP increased minute ventilation under nearly isocapnic conditions, and focal cooling of the intermediate area of VMS to 20 degrees C attenuated the ventilatory augmentation caused by DNP. To eliminate the influence of anesthetics, a second group of experiments was performed on eight decerebrate, artificially ventilated cats while phrenic nerve activity was monitored as an index of respiration. AgNO3 (10%) was topically applied to the VMS until the respiratory response to inhaled CO2 was abolished. Apnea occurred in seven of eight cats after AgNO3, whereas in the remaining one animal, tidal phrenic activity decreased substantially. Systemic administration of DNP produced no respiratory excitation in any of the animals. On the other hand, rhythmic respiratory activity could be provoked by electrical stimulation of the mesencephalic locomotor area and carotid sinus nerve and by excitation of somatic afferents. Histological examination of the brain stem showed that the AgNO3 had penetrated no more than 350 microns from the ventral medullary surface. These results indicate superficial structures of the VMS are of potential importance in mediating the respiratory responses to hypermetabolism.     

Differential respiratory effects of HCO3- and CO2 applied on ventral medullary surface of rats

To estimate whether H+ is the unique stimulus of the medullary chemosensor, ventilatory effects of HCO3- and/or CO2 applied on the ventral medullary surface using an improved superfusion technique and of CO2 inhalation were compared in halothane-anesthetized spontaneously breathing rats. Superfusion with low [HCO3-]-acid mock cerebrospinal fluid (CSF) (normal Pco2) induced a significant increase in ventilation, with an accompanying reduction in endtidal Pco2 (PETco2). High [HCO3-]-alkaline CSF depressed ventilation. Changes in Pco2 of superfusing CSF, on the other hand, had no significant effect despite the similar changes in pH. Simultaneous decrease in [HCO3-] and Pco2 of mock CSF with normal pH also maintained stimulated respiration. CO2 inhalation during superfusion with various [HCO3-] solutions caused further increase in ventilation as PETco2 increased. The results suggest that the surface area of the rat ventral medulla contains HCO3- (or H+)-sensitive respiratory neural substrates which are, however, little affected by CO2 in the subarachnoid fluid. A CO2 (or CO2-induced H+)-sensitive chemosensor responsible for the increase in ventilation during CO2 inhalation may exist elsewhere functionally apart from the HCO3- (or H+)-sensitive sensor in the examined surface area.     

Substance P in the ventrolateral medulla oblongata regulates ventilatory responses.

Local injection of substance P (SP) into the ventral portion of the nucleus gigantocellularis, nucleus reticularis lateralis, and nucleus retrofacialis of the ventrolateral medulla oblongata (VLM) or direct application on the ventral surface of the medulla oblongata caused marked stimulation of tidal volume (VT) and/or minute ventilation (VE). The ventilatory response to hypoxia was significantly blunted after SP in the VLM but not in the dorsal medulla oblongata (DM) (nucleus tractus solitarius). The SP antagonist [D-Pro2,D-Trp7,9]SP almost completely inhibited this response when applied locally to a wide area of the superficial layer of the VLM but not of the DM. Unilateral or bilateral application of 0.3-1.5 nmol of the SP antagonist in the VLM (corpus trapezoideum and the caudal region extending from the rootlets of the nucleus hypoglossus to the first cervical segment) markedly attenuated the response to a 5% CO2 inhalation. The inhibition of the CO2 response was seen after [D-Pro2,D-Trp7,9]SP in the rostral areas of the medulla oblongata corresponding to the corpus trapezoideum and the caudal region extending from the rootlets of the nucleus hypoglossus to the first cervical segment of the cervical cord. Electric somatosensory-induced ventilatory stimulation could be depressed by approximately 70% by [D-Pro2,D-Trp7,9]SP locally applied on the surface of the VLM. We conclude that SP is involved in the hypoxic, hypercapnic, and somatosensory ventilatory responses in the rat. However, these respiratory reflexes are mediated via different neuronal pools in the medulla oblongata, mainly the VLM.     

Light and electronmicroscopic study of area M, the chemosensitive area of the ventral medulla oblongata

An electron and light microscopic study was performed to elucidate the structure of area M, an area on the ventral surface of the medulla oblongata which participates in the central respiratory control of the cat. We found no particular morphological barriers to fluid transport from the cerebrospinal fluid space towards the capillaries of this area. The astroglial contacts proved to be mostly gap junctions; furthermore, no tight junctions could be found here. Multipolar ganglion cells could be localized at a depth of 400-800 micron. These cells form numerous synaptic contacts with thin, unmyelinated axons running superficially, parallel to the pial surface in area M. Our findings support the contention that the ventral chemosensitive areas of the medulla oblongata are influenced by the chemical constitution of the cerebrospinal fluid.     

Involvement of cholinergic mechanisms in the central control of respiration in the cane toad, Bufo marinus

Chemical substrates, central sites and central mechanisms underlying the regulation of breathing in lower vertebrates have not been well characterized. The present study was undertaken to determine the effect of pH changes and cholinergic agents on the central control of respiration in the cane toad, Bufo marinus. Adult toads were anesthetized, catheterized and unidirectionally ventilated before exposing the brainstem. An airtight buccal cannula was also inserted through the tympanum to record buccal pressure. The animal was decerebrated, anesthetic removed and the responses to pH changes of solutions bathing the ventral surface of the medulla (VSM) were tested by superfusing the VSM with mock cerebrospinal fluid (mCSF) of pH 7.8-normal, 7.2-acidic and 8.4-basic. The acidic solution increased respiratory activity, the basic solution decreased activity and the normal solution had no effect. In addition, cholinergeric agents (acetylcholine-ACh, physostigmine-Phy, nicotine-Nic, and atropine-Atr) dissolved in mCSF were applied bilaterally onto the VSM using filter paper pledgets. ACh, Phy and Nic increased episodic breathing frequency by 14.3+/-9.7, 9.4+/-5.4 and 29.1+/-11.8 %, respectively, whereas, Atr caused a decrease (-26.6+/-16.6%). These agents had no effect on blood pressure. It is therefore, concluded that the VSM is pH sensitive and a cholinergic mechanism is involved in the central modulation of respiration in Bufo.     

Effect of hypocapnia on ventral medullary blood flow and pH during hypoxia in cats

Ventral medullary blood flow was measured in 33 chloralose-urethan anesthetized cats during 60 min of isocapnia-hypoxia, mild hypocapnia-hypoxia, or severe hypocapnia-hypoxia. In an additional group of six animals we measured ventral medullary extracellular fluid (ECF) pH during mild hypocapnia-hypoxia. The increase in blood flow during hypoxia was reduced by mild hypocapnia and eliminated by severe hypocapnia. With the exception of an initial decrease in ECF [H+], which occurred during the first 10 min of mild hypocapnia-hypoxia, ECF [H+] increased progressively throughout the exposure and recovery periods and was significantly elevated from the control value by the first 10 min of the recovery period. The results suggest that hypocapnia affects the hypoxic cerebrovascular response of the ventral medulla and that this phenomenon could affect the regulation of ventral medullary ECF [H+].     

pH-regulated chloride secretion in fetal lung epithelia

The fetal lung actively transports chloride across the airway epithelium. ClC-2, a pH-activated chloride channel, is highly expressed in the fetal lung and is located on the apical surface of the developing respiratory epithelium. Our goal was to determine whether acidic pH could stimulate chloride secretion in fetal rat distal lung epithelial cells mounted in Ussing chambers. A series of acidic solutions stimulated equivalent short-circuit current (I(eq)) from a baseline of 28 +/- 4.8 (pH 7.4) to 70 +/- 5 (pH 6.2), 114 +/- 12.8 (pH 5.0), and 164 +/- 19.2 (pH 3.8) microA/cm(2). These changes in I(eq) were inhibited by 1 mM cadmium chloride and did not result in large changes in [(3)H]mannitol paracellular flux. Immunofluorescent detection by confocal microscopy revealed that ClC-2 is expressed along the luminal surface of polarized fetal distal lung epithelial cells. These data suggest that the acidic environment of the fetal lung fluid could activate chloride channels contributing to fetal lung fluid production and that the changes in I(eq) seen in these Ussing studies may be due to stimulation of ClC-2.     

家兔延髓腹侧防御反应相关神经元

实验在25只乌拉坦(700m/kg)、氯醛糖(35mg/kg)麻醉,肌肉麻痹,人工呼吸的家兔上进行。第一组16只家兔中,单或双脉冲刺激下丘脑和中脑防御反应区,在延髓腹侧记录刺激所兴奋的单位。大部分单位分布于网状巨细胞核腹侧α部。52％的单位有自发放电活动。用阈下强度同时刺激下丘脑和中脑,97％单位有兴奋反应,提示家兔下丘脑和中脑防御反应区在延髓腹侧有聚合投射。第二组9只家兔中,在延髓腹表面单侧应用甘氨酸滤纸片或电凝损毁时,血压轻度下降,刺激下丘脑和中脑防御反应区引起的升压反应也部分被阻断。双侧应用甘氨酸或损毁,血压下降到脊动物水平,升压反应几乎完全被阻断。上述结果提示家兔延髓腹侧神经元在维持正常血压水平和在中继防御反应传出通路中起重要作用。     

Effects on respiratory pattern of focal cooling in the medulla of the dog

Studies in cats have shown that, in addition to respiratory neuron groups in the dorsomedial (DRG) and ventrolateral (VRG) medulla, neural structures in the most ventral medullary regions are important for the maintenance of respiratory rhythm. The purpose of this study was to determine whether a similar superficially located ventral region was present in the dog and to assess the role of each of the other regions in the canine medulla important in the control of breathing, in 20 anesthetized, vagotomized, and artificially ventilated dogs, a cryoprobe was used to cool selected regions of the medulla to 15-20 degrees C. Respiratory output was determined from phrenic nerve or diaphragm electrical activity. Cooling in or near the nucleus of the solitary tract altered timing and produced little change in the amplitude or rate of rise of inspiratory activity; lengthening of inspiratory time was the most common timing effect observed. Cooling in ventrolateral regions affected the amplitude and rate of rise of respiratory activity. Depression of neural tidal volume and apnea could be produced by unilateral cooling in two ventrolateral regions: 1) near the nucleus ambiguus and nucleus para-ambiguus and 2) just beneath the ventral medullary surface. These findings indicate that in the dog dorsomedial neural structures influence respiratory timing, whereas more ventral structures are important to respiratory drive.     

Enhanced baroreflex-mediated inhibition of respiration after muscimol dialysis in the rostroventral medulla.

The rostral ventral medulla (RVM) may be important in the control of cardiorespiratory interactions. We hypothesized that inhibition of the RVM would enhance inhibition of breathing associated with transient blood pressure elevations. In 25 piglets 3-16 days of age, we studied the effect of acutely increasing blood pressure, by systemic infusion of phenylephrine, on respiratory activity before and after inhibition of neural activity in the RVM by dialysis of 10 mM muscimol, a GABA(A)-receptor agonist. Muscimol dialysis through probes that were placed along the ventral medullary surface from approximately 1 mm rostral to the facial nucleus to approximately 0.5 mm caudal to the facial nucleus augmented the respiratory inhibition associated with acute increases in blood pressure. No similar enhancement of respiratory inhibition after phenylephrine treatment was seen in six control animals that did not receive muscimol dialysis. We conclude that the piglet RVM participates in cardiorespiratory interactions and that dysfunction of homologous regions in the human infant could lead to cardiorespiratory instability and may be involved in the pathogenesis of sudden infant death syndrome.     

Ontogeny of central CO2 chemoreception: chemosensitivity in the ventral medulla of developing bullfrogs

Sites of central CO2 chemosensitivity were investigated in isolated brain stems from Rana catesbeiana tadpoles and frogs. Respiratory neurograms were made from cranial nerve (CN) 7 and spinal nerve 2. Superfusion of the brain stem with hypercapnic artificial cerebrospinal fluid elicited increased fictive lung ventilation. The effect of focal perfusion of hypercapnic artificial cerebrospinal fluid on discrete areas of the ventral medulla was assessed. Sites of chemosensitivity, which are active continuously throughout development, were identified adjacent to CN 5 and CN 10 on the ventral surface of the medulla. In early- and middle-stage tadpoles and frogs, unilateral stimulation within either site was sufficient to elicit the hypercapnic response, but simultaneous stimulation within both sites was required in late-stage tadpoles. The chemosensitive sites were individually disrupted by unilateral application of 1 mg/ml protease, and the sensitivity to bath application or focal perfusion of hypercapnia was reassessed. Protease lesions at CN 10 abolished the entire hypercapnic response, but lesions at CN 5 affected only the hypercapnic response originating from the CN 5 site. Neurons within the chemosensitive sites were also destroyed by unilateral application of 1 mM kainic acid, and the sensitivity to bath or focal application of hypercapnia was reassessed. Kainic acid lesions within either site abolished the hypercapnic response. Using a vital dye, we determined that kainic acid destroyed neurons by only within 100 microm of the ventral medullary surface. Thus, regardless of developmental stage, neurons necessary for CO2 sensitivity are located in the ventral medulla adjacent to CN 5 and 10.     

Effects of modulation of cholinergic transmission of activity of the medullary respiratory generator of newborn rats:in vitro study

Periodic phasic activity (respiratory discharges) was recorded from the spinal ventral rootsC ₄−C ₅ in the experiments on isolated medullo-spinal preparations of 1- to 3-day-old rats. Applications of acetylcholine (ACh) in different concentrations and modifications of pH were tested under normal conditions and after treatment with cholinoblockers, atropine and benzohexonium, and an acetylcholinesterase blocker, physostigmine. ACh intensified periodic respiratory activity in a concentration-dependent manner, and the duration of postactivatory depression showed similar dependence. ACh-induced effects were facilitated after pH of the superfusing solution had been decreased. Atropine decreased the frequency of respiratory discharges and suppressed responses to ACh applications and pH modification. Contrastingly, benzohexonium and, especially, physostigmine in concentrations, exerting no significant independent influence on the frequency of respiratory activity, increased sensitivity of preparations and facilitated responses to ACh applications and pH decrease. Involvement of cholinergic neuronal mechanisms, localized in the chemosensitive region of the ventral surface of the medulla, in generation of periodic activity by the medullary respiratory generator is discussed.     

Local effects of substance P on respiratory regulation in the rat medulla oblongata.

The effect of substance P (SP) and the SP antagonist [D-Pro2,D-Trp7,9]-SP on basal ventilation was investigated in halothane-anesthetized rats. Microinjections of SP (0.4-1.5 nmol) into the ventrolateral medulla oblongata (VLM), (nuclei gigantocellularis, facialis, ambiguus, and reticularis lateralis) or into the dorsomedial medulla oblongata (DM, nucleus tractus solitarius) and its ventral surroundings dose dependently increased tidal volume (VT) and/or minute ventilation. In sensitive areas, the ventilatory stimulation was initiated within minutes, peaked around 8-10 min, and slowly returned to normal over 30-45 min after the injection. In the VLM sites, the increase in VT was generally accompanied by a decrease in respiratory frequency (f), whereas in the DM, f increased in parallel with VT. Furthermore, within the VLM, the respiratory response patterns differed with the definite location of the SP injection. A shortening of inspiratory time was observed in the ventromedial part, the ventrolateral portion of the nucleus paragigantocellularis and ventral to the nucleus facialis. In contrast, a lengthening of expiratory time was seen when SP was injected or applied more laterally along the ventral portion of nucleus facialis and near or directly on the ventral medullary surface. Application of [D-Pro2, D-Trp7,9]SP before or after SP completely antagonized the excitatory effects of SP on ventilation. The SP antagonist administered into the VLM decreased the ventilatory response to hypoxic breathing but caused no change during hyperoxic conditions.     

Effects of phrenic nerve section on the respiratory system of fetal lambs

We investigated the effects of phrenic nerve section (PNS) on the respiratory system of fetal lambs. Seven ewes, three of which had twin fetuses, were given a general anesthetic. The thoracic phrenic nerves were cut in two singleton fetuses and in one fetus in each set of twins (116-121 days); two singleton fetuses and one fetus in each set of twins underwent the same procedure except for PNS. Fetal arterial blood pressure, heart rate, and arterial pH and blood gas tensions were the same in both groups. Phrenic nerve section eliminated fetal breathing movements and decreased airway fluid volume, lung weight, and total lung DNA (P less than 0.05). However, PNS did not affect production of tracheal fluid or percent dry weight of the lungs. Furthermore, PNS did not affect the concentration of saturated phosphatidylcholine in the lung or its flux in tracheal fluid. We conclude that PNS in fetal lambs retards lung growth but does not affect tracheal fluid production or formation and release of surfactant.     

Neurokinin-1 receptor-expressing neurons in the ventral medulla are essential for normal central and peripheral chemoreception in the conscious rat.

Neurokinin-1 receptor immunoreactive (NK1R-ir) neurons and processes are widely distributed within the medulla, prominently at central chemoreceptor sites. Focal lesions of NK1R-ir neurons in the medullary raphe or the retrotrapezoid nucleus partially reduced the CO(2) response in conscious rats. We ask if NK1R-ir cells and processes over a wide region of the ventral medulla are essential for central and peripheral chemoreception by cisterna magna injection of SSP-SAP, a high-affinity version of substance P-saporin. After 22 days, NK1R-ir cell loss was -79% in the retrotrapezoid nucleus and -65% in the A5 region, which lie close to the ventral surface, and -38% in the medullary raphe and -49% in the pre-B?tzinger complex/rostral ventral respiratory group, which lie deeper. Dorsal chemoreceptor sites, the caudal nucleus tractus solitarius and the A6 region, were unaffected. At 8 and 22 days, these lesions produced 1) hypoventilation during air breathing in wakefulness ( approximately 8%) and in non-rapid eye movement (NREM) ( approximately 9%) and rapid eye movement ( approximately 14%) sleep, as measured over a 4-h period; 2) a substantially reduced ventilatory response to 7% CO(2) by 61% in wakefulness and 46-57% in NREM sleep; and 3) a decreased ventilatory response to 12% O(2) by 40% in wakefulness and 35% in NREM sleep at 8 days, with partial recovery by 22 days. NK1R-ir neurons in the ventral medulla are essential for normal central chemoreception, provide a drive to breathe, and modulate the peripheral chemoreceptor responses. These effects are not state dependent.     

Differential effects of CO2 and H+ as central stimuli of respiration in the cat

Effects of H+ and CO2 as independent stimuli of central respiratory chemoreceptors were studied in anesthetized cats in which pH and PCO2 on the ventral surface of the medulla (pHe and PeCO2) could be monitored in response to intravenous acid infusion or CO2 inhalation or to a combination of CO2 inhalation and base infusion that allowed PeCO2 to vary at constant pHe. Respiratory responses to these changes were monitored by measuring tidal volume (VT), respiratory frequency (f), and total ventilation. Respiratory acidosis stimulated ventilation by increasing both VT and f. Mild metabolic acidosis (decrease in pHe less than 0.05) exerted similar effects, but more severe metabolic acidosis failed to produce further stimulation. Increasing or decreasing PeCO2 at constant pHe caused pronounced increases or decreases in respiration mediated both by VT and f. For the same change in PeCO2 the respiratory effects were, however, less pronounced when pHe was kept constant than when pHe was allowed to change with PeCO2. The results suggest that both CO2 and H+ exert independent effects on respiration via central chemoreceptors.     

Naloxone reduces ventilatory depression of brain hypoxia

To assess whether endogenous opioids participate in respiratory depression due to brain hypoxia, we determined the ventilatory response to progressive carboxyhemoglobinemia (1% CO, 40% O2) before and after administration of naloxone (NLX, 0.1 mg/kg iv). Minute ventilation (VI) and ventral medullary surface pH (Vm pH) were measured in six anesthetized, peripherally chemodenervated cats. NLX consistently increased base-line hyperoxic VI from 618 +/- 99 to 729 +/- 126 ml/min (P less than 0.05). Although NLX did not alter the Vm pH response to CO [initial alkalosis, Vm pH +0.011 +/- 0.003 pH units, followed by acidosis, Vm pH -0.082 +/- 0.036 at carboxyhemoglobin (HbCO) 55%], NLX attenuated the amount of ventilatory depression; increasing HbCO to 55% decreased VI to 66 +/- 6% of base line before NLX and to 81 +/- 9% of base line after NLX (P less than 0.05). The difference in response after NLX was primarily the result of a linear increase in tidal volume (VT) with decreasing Vm pH (delta VT = 60.3 ml/-pH unit) which was absent before NLX. To assess whether the site of action of the endogenous opioid effect was the central chemosensors, the ventilatory and Vm pH response to progressive HbCO was determined in three additional cats before and after topical application of NLX (3 X 10(-4) M) to the ventral medullary surface. The effect of topical NLX was similar to systemic NLX; significant attenuation of the reduction in VI with increasing HbCO. We conclude that 1) endogenous opioids mediate a portion of the depression of ventilation due to acute brain hypoxia, and 2) this effect is probably at the central chemosensitive regions.