Mechanism of the ventilatory response to carbon monoxide.

The effects of carbon monoxide on ventilation were studied in unanesthetized goats. Responses to single breaths of 10-25% CO in O2, which rapidly raised carboxyhemoglobin (COHb) from 5 to 60%, were considered to reflect peripheral chemoreceptor-mediated reflexes whereas responses to continuous inhalation of 1% CO in O2, which slowly raised COHb from 0 to 60%, were considered to reflect both peripheral chemoreceptor and nonperipheral chemoreceptor mechanisms. In each of six goats, single breaths of CO failed to elicit any immediate ventilatory response. However, slow buildup of carboxyhemoglobinemia in the same animals always elicited ventilatory stimulation (from a mean of 7.43 to 16.02 liter/min, P less than 0.001) beginning 5-6 min after onset of 1% CO in O2 inhalation when COHb saturation reached 50-60%. In eight studies of six animals HCO3- concentration fell (from 21.3 to 15.8 meq/liter; P less than 0.001) and lactate concentration rose (from 2.5 to 4.2 meq/liter; P less than 0.05) in the cisternal cerebrospinal fluid during the CO-induced hyperpnea. Additional studies ruled out ventilatory stimulation from left heart failure or enhanced chemo-sensitivity to carbon dioxide. Although the delayed hyperpnea was associated with a hyperdynamic cardiovascular response to CO, blockade of these circulatory effects with propranolol (2 mg/kg) failed to abolish the delayed hyperpnea; however, the propranolol did unmask an element of ventilatory depression which preceded the hyperpnea. Conclusions were: (a) hyperventilation in response to CO inhalation is not mediated by the carotid bodies; (b) the delayed hyperpnea in response to CO inhalation is primarily due to brain-cerebrospinal fluid acidosis; (c) mobilization of body CO2 stores due to the circulatory response to CO may obscure an initial depression of ventilation by CO.

The effect of anemia on the ventilatory response to transient and steady-state hypoxia.

The effects of anemia upon the ventilatory responses to transient and steady-state hypoxia were studied in unanesthetized goats. Responses to transient hypoxia (inhalation of several breaths of nitrogen) were considered to reflect peripheral chemoreceptor and non-chemoreceptor influences of hypoxia upon ventilatory control. In all goats, severe anemia (hemoglobin 3.1-4.8 g/100ml) markedly heightened the responses to transient hypoxia (from a mean of 0.27 to a mean of 0.75 liter/min/percent fall in SaO2). This phenomenon was substantially reversed by alpha-adrenergic blockade (phenoxybenzamine, 5 mg/kg). In contrast, the ventilatory responses to steady-state hypoxia were unaffected by severe anemia. These data suggest that severe anemia enhances the peripheral chemoreceptor-mediated response to hypoxia through a mechanism involving the alpha-adrenergic system. It also appears that a ventilatory depressant effect of hypoxia which is not mediated by the peripheral chemoreceptors is also enhanced by severe anemia, thereby preventing an increase in the steady-state ventilatory response to hypoxia. Finally, experiments involving variation in oxygen affinity of hemoglobin suggested that O2 tension rather than O2 availability in arterial blood is the major determinant of peripheral chemoreceptor activity.

Prevention of collagen deposition following pulmonary oxygen toxicity in the rat by cis-4-hydroxy-L-proline.

Exposure of rats to high oxygen tensions causes increased collagen content of lungs and alveolar enlargement in 3-6 wk. We tested whether cis-hydroxyproline, a proline analogue that inhibits collagen synthesis, could prevent the collagen accumulation and alveolar enlargement. Rats were exposed to hyperoxia for 60 h and then to room air and hyperoxia for alternate 24-h periods for 11.5 d. Treated oxygen-exposed rats received 200 mg/kg cis-hydroxyproline twice daily over the 14-d exposure period. Control rats breathed room air. Examination of lungs on day 14 showed collagen content of oxygen-exposed lungs to be 48% greater than control (P < 0.05). The collagen content of the treated oxygen-exposed lungs was -12% of control (NS). Total lung volume was 16% greater than control in oxygen-exposed rats (P < 0.05) and 8% greater than control in treated oxygen-exposed rats (NS). Morphometric studies showed alveolar size was greater than control in oxygen-exposed rats (188+/-11 [SE] vs. 143+/-6 mumul [P < 0.05]). Oxygen-exposed, treated rats had a mean alveolar volume of 150+/-7 mumul. Lung pressure-volume curves were significantly shifted to the left of control in the oxygen-exposed rats, whereas the curves of the oxygen-exposed, treated group were identical to control. These data suggest that cis-hydroxyproline prevented the accumulation of collagen in the lungs in pulmonary oxygen toxicity. In addition, there was apparent protection from airspace dilatation and decreased lung elasticity, suggesting that alveolar enlargement after oxygen toxicity is linked to the deposition in lung tissue of new connective tissue fibers.

The effects of abnormal sympathetic nervous function upon the ventilatory response to hypoxia.

THE VENTILATORY RESPONSE TO HYPOXIA WAS STUDIED IN TWO GROUPS OF SUBJECTS WITH ABNORMAL SYMPATHETIC NERVOUS CONTROL: (a) human subjects with familial dysautonomia (Riley-Day syndrome), and (b) unanesthetized goats treated with an alpha-adrenergic blocking agent (phenoxybenzamine). The ventilatory response to hypoxia was evaluated in two ways: (a) from the slope of the relationship between ventilation and alveolar P(Co2) ([unk]V(E)-P(ACo2) slope) during the rebreathing of hypoxic and hyperoxic gases, and (b) from the change in ventilation produced when hypoxia was abruptly relieved. The ventilatory and circulatory responses of the unanesthetized, phenoxybenzamine-treated goats were qualitatively similar to those of dysautonomic patients. In contrast to the sustained stimulation of ventilation produced by hypoxia in normal subjects, hypoxia either did not change, or decreased, the [unk]V(E)-P(ACo2) slope of dysautonomic patients and phenoxybenzamine-treated goats; CO(2)-free hypoxia produced a fleeting hyperventilation, which was followed by apnea when hypoxia was abruptly relieved. Unlike normal subjects, the dysautonomic patients and phenoxybenzamine-treated goats became hypotensive while hypoxic. The results indicate that peripheral chemoreceptor reflex responses to hypoxia are preserved in subjects in whom sympathetic nervous responses are impaired. However, the central nervous depression of ventilation by hypoxia is enhanced simultaneously. The inordinate central depression is attributed to the inability of the dysautonomic subjects and goats to maintain systemic blood pressure and, consequently, cerebral blood flow during hypoxia, thereby aggrevating central nervous hypoxia.

Correlation between ventilation and brain blood flow during sleep.

The relationships between brain blood flow (BBF) and ventilation (VI) were studied during sleep in 13 goats. Unilateral BBF was continuously measured with an electromagnetic flow probe; total and regional BBF were assessed by the radioactive microsphere technique in four animals. Interacting changes in VI and BBF occurred during both slow wave (SWS) and rapid eye movement (REM) sleep. During SWS, significant decreases in VI and increases in arterial PCO2 occurred compared to wakefulness. BBF during SWS correlated linearly with arterial CO2 tension (PaCO2); nd the relationship was similar to that for awake goats breathing CO2. During REM sleep, VI was significantly less than both the awake (W) and SWS states due principally to a decrease in tidal volume. BBF during REM sleep was significantly and substantially increased compared with both the W and SWS states; this increase was shared by all brain areas. The increase in BBF during REM sleep was greater than that predicted from changes in PaCO2. In five goats provided with chronic sagittal sinus fistulae, arteriovenous oxygen difference was measured in separate studies and found to be significantly lower during REM sleep compared with W; brain O2 consumption was similar in magnitude in the REM and W states. Thus, the high BBF of REM sleep was also unexplained by an increase of brain metabolic activity. We conclude that, during SWS, increases in BBF are explained by hypoventilation and hypercapnia. In contrast, during REM sleep, BBF is substantially in excess of that expected from PaCO2 or brain metabolism. It is postulated that this excess of BBF during REM sleep could reduce the central chemoreceptor pH relative to that present in SWS. The combination of reduction of sensitivity to CO2 and lower tissue PCO2 during REM sleep makes it likely that the output of the central chemoreceptors during this state is less than that during SWS and wakefulness. This may contribute to the low tidal volume and respiratory irregularities of this sleep period.

Control of breathing during methadone addiction.

Chemical control of breathing was studied before and after the administration of the daily dose of methadone in 14 former heroin addicts who were enrolled in a methadone maintenance program and taking 60 to 100 mg/day. Two major groups were identified: group 1 in which subjects (n=6) had taken the drug for less than two months, and group 2 in which the subjects (n=6) had taken the drug from eight to 43 months. Prior to the daily dose of methadone, the levels of arterial carbon dioxide tension were significantly higher and ventilatory response to hypoxia significantly lower in group 1 than in group 2. Ventilatory responses to carbon dioxide (CO2) were also lower in group 1, but the difference was not statistically significant. Following the daily dose of methadone, the subjects in group 1 manifested significant reductions of ventilation and arterial oxygen tension, significant increases in arterial carbon dioxide tension and significant depressions of ventilatory responses to both CO2 and hypoxia in comparison to values before the administration of methadone. In contrast, subjects in group 2 manifested only a significant decrease in ventilatory responsiveness to hypoxia with no change in ventilation, arterial blood gas tensions or ventilatory responsiveness to CO2 following the daily dose. Two intermediate subjects (five and seven months) behaved as long-term subjects with regard to arterial carbon dioxide tension and CO2 responses but as short-term subjects with regard to responsiveness to hypoxia. Thus, during the first two months of methadone maintence, there is continual alveolar hypoventilation due to depression o both central (CO2) and peripheral (hypoxia) chemoreception. After five months, alveolar hypoventilation is abolished as the CO2-sensitive chemoreflex acquires full tolerance to methadone at the maintenance dose level. In contrast, tolerance of the hypoxia-sensitive chemoreflex is developed more slowly and is never complete.

Blunted respiratory drive in congenital myopathy.

Two patients with clinically mild congenital myopathies presented with chronic respiratory failure. Muscle weakness alone could not account for the respiratory insufficiency since static respiratory pressures were not markedly impaired, ventilation during exercise was normal, and daytime ventilation was normal if ventilatory assistance was provided at night. The ventilatory responses to inhaled carbon dioxide were very low, suggesting that impairment of the central nervous respiratory chemoreceptor contributed to hypoventilation. These patients and others described in the literature suggest that central depression of ventilation may occur more frequently than previously recognized in patients with muscular disorders. Patients with chronic respiratory failure due to central depression of respiratory drive can be effectively managed by assisted ventilation at night.

Chemosensitivity of medullary neurons in explant tissue cultures.

To determine whether cultured medulla contains chemosensitive neurons which are excited by CO2 and fixed acid and whether this function is specific to the ventral medulla, tissue explants of ventral and dorsal medulla were prepared from neonatal rats and incubated for two to three weeks. Cultures were superfused with artificial cerebrospinal fluid, maintained at 37 degrees C, and pH of the superfusate was varied either with PCO2 (14-71 Torr) at constant HCO3- (22 mM) or HCO3- (10-30 mM) at constant PCO2 (35 Torr). Spontaneous action potentials were recorded extracellularly in 51 ventral and 23 dorsal medullary neurons. Ventral medullary neurons exhibited a steady baseline firing frequency of 4 +/- 0.8 Hz. In contrast, dorsal medullary neurons exhibited two different patterns of spontaneous activity: 11 fired continuously (7.2 +/- 1.4 Hz) while 12 fired with a bursting pattern. Burst duration was 0.80 +/- 0.14 min and cycle time was 1.74 +/- 0.43 min. Decreasing pH with CO2 caused an increase in the activity of 10 of 27 ventral medullary neurons and two of six dorsal medullary neurons with a mean response of 7.5 Hz/pH unit. Varying pH by changing HCO3- had no effect on firing frequency. These results demonstrate that: (i) chemosensitive neurons are present in both ventral and dorsal medullary explant cultures; (ii) these cells only respond to changes in pH induced with CO2; and (iii) about half of the dorsal medullary neurons fire spontaneously with a regular bursting pattern of activity.

Enhanced responses to aerosolized bronchodilator therapy in asthma using respiratory maneuvers.

To determine if respiratory maneuvers may enhance the response to inhaled bronchodilator drugs, we evaluated the bronchodilator responses when isoproterenol was: inhaled as a bolus high (80 percent VC) compared to low (20 percent VC) lung volumes, and inhaled as a single 800 microgram dose compared to four 200 microgram doses given 20 min apart. Nine asthmatic subjects inhaled isoproterenol sequentially at high and low lung volumes on two separate days; 15 others inhaled single doses of 200, 400, 600, and 800 microgram isoproterenol on four separate days. FEV1, specific conductance (Gaw/VL), Vmax50%, and the slope of phase 3 of the single-breath nitrogen test (deltaN2/L) were measured 10 min after each dose. FEV1 and Gaw/VL increased and deltaN2/L decreased more following inhalation at high compared to low lung volume (P less than 0.05). Gaw/VL increased more in the group given 800 microgram in divided doses than the group given a single dose (P less than 0.05). These findings suggest that the bronchodilator response to isoproterenol may be enhanced by inhaling the drug in divided doses sequentially and by delivering the drug near maximal inspiration. An enhanced response after the latter maneuver may be due to more uniform distribution of the drug to airway receptor sites.

Obstructive sleep apnea following bilateral carotid body resection.

A patient who had undergone bilateral carotid body resection five years earlier for palliation of chronic airflow obstruction was found to have severe obstructive sleep apnea. He presented with hypercapnic respiratory failure, which improved after tracheostomy. A physiologic mechanism is proposed to explain this association. Previously reported studies of anesthetized animals suggest that loss of peripheral chemoreceptor activity could selectively decrease neural output to the genioglossus, the main protrusor muscle of the tongue, predisposing the upper airway to inspiratory occlusion.

Sleep deprivation decreases ventilatory response to CO2 but not load compensation.

Because sleep is known to reduce ventilatory drive, and sleep deprivation is a common accompaniment to ventilatory failure, we tested ventilatory response to carbon dioxide (delta V1/delta PCO2) and response to an inspiratory flow resistive load (change in delta P100/delta PCO2 with load) after both a normal night of sleep and after 24 hours of sleep deprivation in 13 healthy volunteers. Sleep deprivation was associated with a significant decrease in delta V1/delta PCO2 from 2.51 +/- .36 to 2.09 +/- .34 L/min/mm Hg (p less than 0.02). However, load compensation was preserved during sleep deprivation. Since many acutely-ill patients are sleep deprived, an associated reduction of ventilatory drive may play a role in progressive respiratory insufficiency.

Ventilatory response to isocapnic hypoxia in parents of victims of sudden infant death syndrome.

Ventilatory response to progressive isocapnic hypoxia was measured in 14 parents of victims of sudden infant death syndrome (SIDS) and 12 matched control parents. Controls had a value for a measure of ventilatory responsiveness (parameter A) of 200.8 +/- 46.4, while SIDS parents had a significantly lower value of 64.4 +/- 16.2 (P less than 0.01). Since degree of hypoxic ventilatory drive is a hereditary characteristic, it is concluded that a relatively low ventilatory responsiveness to hypoxia might have been present in the SIDS victims.

Variable extrathoracic airflow obstruction and chronic laryngotracheitis in Gulf War veterans.

STUDY OBJECTIVES: To study the flow-volume loop for evidence of variable extrathoracic airflow obstruction in Persian Gulf War veterans. DESIGN: Retrospective case-control, single-center study. SETTING: The pulmonary division of an academic health-care center. SUBJECTS: A convenience sample of the Persian Gulf Registry. MEASUREMENTS AND INTERVENTIONS: (1) Midvital capacity ratio (ratio of maximum forced midexpiratory to maximum forced midinspiratory flow). This ratio is the criterion standard for the diagnosis of variable extrathoracic airflow obstruction. (2) Evaluation of the anatomy and function of the extrathoracic airway by fiberoptic bronchoscopy. (3) Further investigation into the airway abnormality by histologic evaluation of tracheal biopsy samples in Gulf War veterans only. RESULTS: Midvital capacity was > 1.0 in 32 of 37 Gulf War veterans compared with only 11 of 38 control subjects. The mean (+/-SD) value was 1.37+/-0.4 among Gulf War veterans and 0.88+/-0.3 among control subjects (p=0.0000005). FVC and its ratio to FEV1 were normal in all these subjects. Bronchoscopy showed inflamed larynx and trachea in all (n=17) Gulf War veterans. Histologic study showed chronic inflammation of the trachea in everyone (n=12) who had an adequate biopsy sample. CONCLUSION: Physicians should be made aware of the presence of chronic inflammation of the upper airways and inspiratory airflow limitation in a number of Gulf War veterans.

Opioids and breathing.

This review summarizes recent developments on the effects of opiate drugs and the various endogenous opioid peptides on breathing. These developments include demonstration of receptors and site-specific effects of application of opioids in the pons and medulla, demonstration of variable tolerance of respiratory responses in addicted individuals as well as their offspring, and demonstration of an endogenous opioid influence on breathing in early neonatal life and in certain physiological settings and disease states. The validity and limitations of using naloxone as a tool to uncover postulated endogenous opioid influences are also discussed as well as the potential problems imposed by the various settings in which this opiate antagonist drug is used. It is concluded that some parallelism exists between the role of endogenous opioids in pain modulation and their role in respiration especially in adults. Although more studies are needed especially with regard to defining specific effects of the various opioid receptors and ligands, it is felt that the effects of endogenous opioids on the control of breathing will probably be one of modulating the responses to drugs or nociceptive respiratory stimuli through inhibitory pathways.

Hypoxic excitation in neurons cultured from the rostral ventrolateral medulla of the neonatal rat.

Neurons within cardiorespiratory regions of the rostral ventrolateral medulla (RVLM) have been shown to be excited by local hypoxia. To determine the electrophysiological properties of these excitatory responses to hypoxia, we developed a primary dissociated cell culture system to examine the intrinsic response of RVLM neurons to hypoxia. Neonatal rat neurons plated on medullary astrocyte monolayers were studied using the whole cell perforated patch-clamp technique. Sodium cyanide (NaCN, 0.5-10 mM) was used, and membrane potential (V(m)), firing frequency, and input resistance were examined. In 11 of 19 neurons, NaCN produced a V(m) depolarization, an increase in firing frequency, and a decrease in input resistance, suggesting the opening of a cation channel. The hypoxic depolarization had a linear dose response and was dependent on baseline V(m), with a greater response at more hyperpolarized V(m). In 8 of 19 neurons, NaCN produced a V(m) hyperpolarization, decrease in firing frequency, and variable changes in input resistance. The V(m) hyperpolarization exhibited an all-or-none dose response and was independent of baseline V(m). These differential responses to NaCN were retained after synaptic blockade with low Ca(2+)-high Mg(2+) or TTX. Thus hypoxic excitation 1) is maintained in cell culture, 2) is an intrinsic response, and 3) is likely due to the increase in a cation current. These hypoxia-excited neurons are likely candidates to function as central oxygen sensors.

Role of brain lactic acidosis in hypoxic depression of respiration.

The role of lactic acidosis of progressive brain hypoxia (PBH) as both a central chemoreceptor stimulant and a general respiratory depressant was assessed by preventing lactate formation both locally and globally with dichloroacetate (DCA). Phrenic nerve activity (PN) and ventral medullary pH (Vm pH) responses to PBH (1% CO-40% O2-balance N2) were determined in anesthetized, paralyzed, peripherally chemodenervated, vagotomized cats while fraction of end-tidal CO2 (FETCO2) and mean arterial blood pressure (MABP) were maintained constant. Topical DCA near the central chemoreceptors prevented the progressive Vm acidosis of PBH and was associated with a slightly greater depression of PN for any given level of brain hypoxia [75 +/- 12% base-line mock cerebrospinal fluid compared with 63 +/- 11% base-line topical DCA at O2 content of arterial blood (CaO2) of 7.5 ml O2/dl]. Systemic DCA also prevented the progressive acidosis of PBH and significantly altered the profile of depression with PBH. Before DCA, PBH produced a progressive reduction in PN after reducing CaO2 by 20%. After DCA, PN was not significantly depressed until CaO2 was reduced to very low levels, whereupon there was a sharp decline in PN. Before DCA, reducing CaO2 to 6 ml O2/dl reduced PN by 41 +/- 16%, whereas after DCA there was no significant reduction in PN (4 +/- 5%). We conclude that 1) lactic acidosis near the central chemosensitive regions does produce a small stimulation of respiration during PBH but that 2) the overwhelming response to central lactic acidosis of PBH is respiratory depression.

Effects of respiratory afferent stimulation on phrenic neurogram during hypoxic gasping in the cat.

Previous studies suggested that phrenic motor output is largely refractory to afferent stimuli during gasping. We tested this concept by electrically stimulating the carotid sinus nerve (CSN) or the superior laryngeal nerve (SLN) of anesthetized peripherally chemodenervated vagotomized ventilated cats during eupnea or gasping induced by hypoxia. During eupnea, phrenic neurogram amplitude (PNA) increased by 110% during 30 s of supramaximal CSN stimulation, but burst frequency did not change. Progressive hypoxia caused gasping after arterial O2 content was reduced by 75%. During gasping, CSN stimulation caused premature onset of gasp in 12 of 13 trials, shortened intergasp interval [6.3 +/- 0.9 vs. 14.8 +/- 2.5 (SE) s], and resulted in a small (20%) but significant increase in PNA. Intensity of SLN stimulation was adjusted to abolish phrenic activity during the 30-s eupneic stimulation period. During gasping, SLN stimulation of the same intensity tended to delay onset of the next gasp, increased intergasp interval (16.9 +/- 1.9 vs. 13.3 +/- 1.2 s), and reduced PNA by 32%. Thus the respiratory burst pattern formation circuitry responds to afferent stimuli during gasping, albeit in a manner different from the eupneic response. These observations suggest that gasping is the output of a modified eupneic burst pattern formation circuit.

CO(2)/H(+) chemoreception in the cat pre-Bötzinger complex in vivo.

We examined the effects of focal tissue acidosis in the pre-Bötzinger complex (pre-BötC; the proposed locus of respiratory rhythm generation) on phrenic nerve discharge in chloralose-anesthetized, vagotomized, paralyzed, mechanically ventilated cats. Focal tissue acidosis was produced by unilateral microinjection of 10-20 nl of the carbonic anhydrase inhibitors acetazolamide (AZ; 50 microM) or methazolamide (MZ; 50 microM). Microinjection of AZ and MZ into 14 sites in the pre-BötC reversibly increased the peak amplitude of integrated phrenic nerve discharge and, in some sites, produced augmented bursts (i.e., eupneic breath ending with a high-amplitude, short-duration burst). Microinjection of AZ and MZ into this region also reversibly increased the frequency of eupneic phrenic bursts in seven sites and produced premature bursts (i.e., doublets) in five sites. Phrenic nerve discharge increased within 5-15 min of microinjection of either agent; however, the time to the peak increase and the time to recovery were less with AZ than with MZ, consistent with the different pharmacological properties of AZ and MZ. In contrast to other CO(2)/H(+) brain stem respiratory chemosensitive sites demonstrated in vivo, which have only shown increases in amplitude of integrated phrenic nerve activity, focal tissue acidosis in the pre-BötC increases frequency of phrenic bursts and produces premature (i.e., doublet) bursts. These data indicate that the pre-BötC has the potential to play a role in the modulation of respiratory rhythm and pattern elicited by increased CO(2)/H(+) and lend additional support to the concept that the proposed locus for respiratory rhythm generation has intrinsic chemosensitivity.

Correlation between ventilation and brain blood flow during hypoxic sleep.

Ventilation and brain blood flow (BBF) were simultaneously measured during carbon monoxide (CO) inhalation in awake and sleeping goats up to HbCO levels of 40%. Unilateral BBF, which was continuously measured with an electromagnetic flow probe placed around the internal maxillary artery, progressively increased with CO inhalation in the awake and both sleep stages. The increase in BBF with CO inhalation during rapid-eye-movement (REM) sleep (delta BBF/delta arterial O2 saturation = 1.34 +/- 0.27 ml X min-1 X %-1) was significantly greater than that manifested during wakefulness (0.87 +/- 0.14) or slow-wave sleep (0.92 +/- 0.13). Ventilation was depressed by CO inhalation during both sleep stages but was unchanged from base-line values in awake goats. In contrast to slow-wave (non-REM) sleep, the ventilatory depression of REM sleep was primarily due to a reduction in tidal volume. Since tidal volume is more closely linked to central chemoreceptor function, we believe that these data suggest a possible role of the increased cerebral perfusion during hypoxic REM sleep. Induction of relative tissue alkalosis at the vicinity of the medullary chemoreceptor may contribute to the ventilatory depression exhibited during this sleep period.

Hypoxia does not increase CSF or plasma beta-endorphin activity.

The ability of moderate (30-50 Torr arterial PO2) and severe (less than 30 Torr arterial PO2) hypoxia to generate endogenous opioids that modulate ventilation was studied in unanesthetized goats. Ventilation and its components, arterial blood gas tensions and pH, and plasma and cerebrospinal fluid (CSF) beta-endorphin activity were measured before and after 4 h of sustained moderate or severe hypoxia. Ventilation, as expected, increased with hypoxia. There were no significant changes in either plasma or CSF beta-endorphin activity after sustained hypoxia. To rule out elaboration of endogenous opioids other than beta-endorphin after hypoxia, naloxone or saline was administered to five of the seven goats exposed to 4 h of severe hypoxia, and their ventilatory responses were compared for 30 additional min of hypoxic breathing. No significant differences in ventilation occurred in the two treatment groups during this time period. We conclude that, unlike increases in airway resistance, moderate and severe hypoxia do not cause the elaboration of endogenous opioids that modify respiratory output in unanesthetized adult goats. The apparent ability of hypoxia to cause elaboration of endogenous opioids in the neonate may represent a maturational phenomenon.