Hypoxic and hypercapnic ventilatory responses in aging male vs. aging female rats.

It is clear that sex hormones impact ventilation. While the effects of the menstrual cycle, pregnancy, testosterone, and progesterone on resting ventilation have been well documented, effects of sex hormones on the hypoxic (HVR) and hypercapnic ventilatory responses (HCVR) are inconclusive. In addition, in no study have systemic sex steroid hormone levels been measured. Age and sex differences in long-term facilitation in response to episodic hypoxia were found in anesthetized rats. The purpose of the present study was to assess the effects of sex and age [young, 3-4 mo; middle age, 12-13 mo; and old, >20 mo] on the HVR and the HCVR of awake rats relative to systemic hormone levels. Based on findings from long-term facilitation studies, we hypothesized that the HVR would be influenced by both sex and age. We found no age-related changes in the HVR or HCVR. However, female rats have a greater HVR than male rats at old age, and at middle age female rats have a greater HCVR than male rats. Additionally, we found no correlation between the minute ventilation/oxygen consumption and the progesterone-to-estrogen ratio during hypoxia or hypercapnia. However, changes in ventilatory responses with age were not similar between the sexes. Thus it is critical to take sex, age, estrous cycle stage, and systemic hormone levels into consideration when conducting and reporting studies on respiratory control.

25-hydroxycholecalciferol: direct effect on calcium transport.

The perfused small intestine from a vitamin D deficient rat exhibits about one-half the calcium transport of the intestine from a rat given vitamin D. These levels of calcium transport can be maintained for at least 4 hours. Addition of 2.5 micrograms of 25-hydroxycholecalciferol added to the vitamin D deficient intestine via the arterial blood perfusate induces a rise in calcium transport to +D levels within 2 hours. In contrast, 250 micrograms of vitamin D(3) given in the same manner has no effect on the calcium transport level overa 4-hour period. These data provide strong evidence that 25-hydroxycholecalci ferol represents the metabolically active form of vitamin D(3).

Sustained hypoxia-induced proliferation of carotid body type I cells in rats.

Sustained hypoxia (SH) has been shown to cause profound morphological and cellular changes in carotid body (CB). However, results regarding whether SH causes CB type I cell proliferation are conflicting. By using bromodeoxyuridine, a uridine analog that is stably incorporated into cells undergoing DNA synthesis, we have found that SH causes the type I cell proliferation in the CB; the proliferation occurs mainly during the first 1-3 days of hypoxic exposure. Moreover, the new cells survive for at least 1 mo after the return to normoxia. Also, SH does not cause any cell death in CB as examined by the terminal deoxynucleotidyl transferase-mediated dUTP-X nick-end labeling assay. Taken together, our results suggest that SH stimulates CB type I cell proliferation, which may produce long-lasting changes in CB morphology and function.

Serotonin and the control of ventilation in awake rats.

In awake, unrestrained, intact rats, reserpine, para-chlorophenylalanine, 6-fluorotryptophan, and para-chloroamphetamine depleted whole brain serotonin and produced a substantial and sustained hyperventilation as evidenced by a 5--9 torr drop in PaCO2. Administration of 5-hydroxytryptophan to rats treated with para-chlorophenylalanine partially alleviated the hyperventilation. No change in ventilation was observed after alpha-methyltyrosine. 5,7-Dihydroxytryptamine produced contradictory results. On the basis of these pharmacological studies, we propose that some serotonin-mediated nerve transmissions might function under physiological conditions to inhibit the central nervous system output which controls normal breathing.

The effect of hepatectomy on the synthesis of 25-hydroxyvitamin D3.

The metabolism of [3H]vitamin D3 in hepatectomized vitamin D-deficient rats has been studied. Hepatectomy drastically disrupts vitamin D3 metabolism as revealed by prolonged high levels of [3H] vitamin D3 in the plasma compartment even 12 h after dose in contrast to sham-operated controls. Some conversion of [3H] vitamin D3 to [3H]25-hydroxyvitamin D3 was detected in hepatectomized rats, but the amount was small in spite of the high circulating levels of [3H]vitamin D3. Since the liver initially takes up much of an administered dose in normal animals and the conversion of [3H]vitamin D3 to [3H]25-hydroxyvitamin D3 is small in hepatectomized rats in spite of high circulating [3H]-vitamin D3, it is concluded that the liver plays a major role in the metabolism of vitamin D3 to 25-hydroxy-vitamin D3.

Chronic intermittent hypoxia alters NE reactivity and mechanics of skeletal muscle resistance arteries.

Although arterial dilator reactivity is severely impaired during exposure of animals to chronic intermittent hypoxia (CIH), few studies have characterized vasoconstrictor responsiveness in resistance arteries of this model of sleep-disordered breathing. Sprague-Dawley rats were exposed to CIH (10% inspired O2 fraction for 1 min at 4-min intervals; 12 h/day) for 14 days. Control rats were housed under normoxic conditions. Diameters of isolated gracilis muscle resistance arteries (GA; 120-150 microm) were measured by television microscopy before and during exposure to norepinephrine (NE) and angiotensin II (ANG II) and at various intraluminal pressures between 20 and 140 mmHg in normal and Ca2+-free physiological salt solution. There was no difference in the ability of GA to constrict in response to ANG II (P = 0.42; not significant; 10(-10)-10(-7) M). However, resting tone, myogenic activation, and vasoconstrictor responses to NE (P < 0.001; 10(-9)-10(-6) M) were reduced in CIH vs. controls. Treatment of rats with the superoxide scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (tempol; 1 mM) in the drinking water restored myogenic responses and NE-induced constrictions of CIH rats, suggesting that elevated superoxide production during exposure to CIH attenuates vasoconstrictor responsiveness to NE and myogenic activation in skeletal muscle resistance arteries. CIH also leads to an increased stiffness and reduced vessel wall distensibility that were not correctable with oral tempol treatment.

Recovery of phrenic activity and ventilation after cervical spinal hemisection in rats.

We tested two hypotheses: 1) that the spontaneous enhancement of phrenic motor output below a C2 spinal hemisection (C2HS) is associated with plasticity in ventrolateral spinal inputs to phrenic motoneurons; and 2) that phrenic motor recovery in anesthetized rats after C2HS correlates with increased capacity to generate inspiratory volume during hypercapnia in unanesthetized rats. At 2 and 4 wk post-C2HS, ipsilateral phrenic nerve activity was recorded in anesthetized, paralyzed, vagotomized, and ventilated rats. Electrical stimulation of the ventrolateral funiculus contralateral to C2HS was used to activate crossed spinal synaptic pathway phrenic motoneurons. Inspiratory phrenic burst amplitudes ipsilateral to C2HS were larger in the 4- vs. 2-wk groups (P<0.05); however, no differences in spinally evoked compound phrenic action potentials could be detected. In unanesthetized rats, inspiratory volume and frequency were quantified using barometric plethysmography at inspired CO2 fractions between 0.0 and 0.07 (inspired O2 fraction 0.21, balance N2) before and 2, 3, and 5 wk post-C2HS. Inspiratory volume was diminished, and frequency enhanced, at 0.0 inspired CO2 fraction (P<0.05) 2-wk post-C2HS; further changes were not observed in the 3- and 5-wk groups. Inspiratory frequency during hypercapnia was unaffected by C2HS. Hypercapnic inspiratory volumes were similarly attenuated at all time points post-C2HS (P<0.05), thereby decreasing hypercapnic minute ventilation (P<0.05). Thus increases in ipsilateral phrenic activity during 4 wk post-C2HS have little impact on the capacity to generate inspiratory volume in unanesthetized rats. Enhanced crossed phrenic activity post-C2HS may reflect plasticity associated with spinal axons not activated by our ventrolateral spinal stimulation.

Immunological identification and effects of 3-methylcholanthrene and phenobarbital on rat pulmonary cytochrome P-450.

Rabbit antibodies to the phenobarbital (PB) inducible rat liver microsomal cytochrome P-450s b and e and to 3-methylcholanthrene (MC) inducible P-450c were used to examine the expression of these isozymes in rat lungs. Western blots of total lung microsomes demonstrated that about 40 pmol P-450b/mg protein (and no detectable P-450e) were present in lungs from control or MC treated rats and that pretreatment with PB caused a small but significant (P less than 0.05) increase in the expression of P-450b. Microsomes from control and PB treated lung contained minimal levels of P-450c, and MC induced this isozyme to 185 pmol/mg. Immunocytochemistry was used to demonstrate immunoreactivity to these isozymes in specific cell types. Neither P-450b nor P-450c was detectable in endothelial cells from control or PB treated lungs, but MC increased immunoreactivity to P-450c in pulmonary endothelial cells. Type II alveolar cells showed distinct immunoreactivity to P-450b and weak immunoreactivity to P-450c in control or PB treated rats. Individual Clara cells stained for either P-450c or P-450b in control, MC treated, and PB treated rats, and colocalization was observed in some cells. An increase in type II alveolar cell and Clara cell immunoreactivity to P-450c was observed after MC induction. Mast cells, identified by metachromatic Giemsa staining, appeared to react nonspecifically with both antisera. In conclusion, P-450c is highly inducible by MC in rat lung (detected in microsomes by Western blot), specifically in endothelial cells, Clara cells, and alveolar type II cells (as visualized by immunocytochemistry); and P-450b is present in rat lung microsomes, and immunoreactivity to this isozyme is localized in alveolar type II and Clara cells.

Chronic intermittent hypoxia elicits serotonin-dependent plasticity in the central neural control of breathing.

We tested the hypothesis that chronic intermittent hypoxia (CIH) elicits plasticity in the central neural control of breathing via serotonin-dependent effects on the integration of carotid chemoafferent inputs. Adult rats were exposed to 1 week of nocturnal CIH (11-12% O(2)/air at 5 min intervals; 12 hr/night). CIH and untreated rats were then anesthetized, paralyzed, vagotomized, and artificially ventilated. Time-dependent hypoxic responses were assessed in the phrenic neurogram during and after three 5 min episodes of isocapnic hypoxia. Integrated phrenic amplitude (integralPhr) responses during hypoxia were greater after CIH at arterial oxygen pressures (PaO(2)) between 25 and 45 mmHg (p < 0.05), but not at higher PaO(2) levels. CIH did not affect hypoxic phrenic burst frequency responses, although the post-hypoxia frequency decline that is typical in rats was abolished. integralPhr and frequency responses to electrical stimulation of the carotid sinus nerve were enhanced by CIH (p < 0.05). Serotonin-dependent long-term facilitation (LTF) of integralPhr was enhanced after CIH at 15, 30, and 60 min after episodic hypoxia (p < 0.05). Pretreatment with the serotonin receptor antagonists methysergide (4 mg/kg, i.v.) and ketanserin (2 mg/kg, i.v.) reversed CIH-induced augmentation of the short-term hypoxic phrenic response and restored the post-hypoxia frequency decline in CIH rats. Whereas methysergide abolished CIH-enhanced phrenic LTF, the selective 5-HT(2) antagonist ketanserin only partially reversed this effect. The results suggest that CIH elicits unique forms of serotonin-dependent plasticity in the central neural control of breathing. Enhanced LTF after CIH may involve an upregulation of a non-5-HT(2) serotonin receptor subtype or subtypes.

Physiological dead space increases during initial hours of chronic hypoxemia with or without hypocapnia.

A whole body plethysmograph was used to determine the minute ventilation-to-CO2 production ratio (VE/VCO2) of intact unrestrained unanesthetized adult male Sprague-Dawley rats during 7 days of hypoxemia (arterial PO2 approximately 50 Torr). In one set of rats, normocapnia (arterial PCO2 approximately 40 Torr) was maintained. Arterial blood gases and acid-base status were determined, and arterial PCO2 was used to calculate alveolar ventilation-to-VCO2 ratio (VA/VCO2) in all situations when inhaled CO2 was not elevated. In normoxia VE/VCO2 = 25 +/- 1 (mean +/- 95% confidence limits); after 12 h of hypoxemia, VE/VCO2 was maximal, 61 +/- 5 in hypoxemic hypocapnia and 200 +/- 55 in hypoxemic normocapnia. Between 2 and 7 days of hypoxemia, VE/VCO2 had plateaued, 42 +/- 3 in hypoxemic hypocapnia and 95 +/- 19 in hypoxemic normocapnia. Dead space-to-tidal volume ratio (VD/VT) = (VE/VCO2 - VA/VCO2)/(VE/VCO2), and in normoxia VD/VT = 0.17 +/- 0.04. In hypoxemic hypocapnia, VD/VT measured between 1 and 5 h was 0.38 +/- 0.04. It remained elevated at 0.29 +/- 0.04 after 24 h, but after 4-7 days in hypoxemic hypocapnia, VD/VT had recovered to 0.15 +/- 0.03. It is postulated that the disproportionate increase in VE/VCO2 observed during the first 24 h of exposure to hypoxemic normocapnia (compared with elevated steady-state plateau levels maintained from 2 to 7 days sojourn) reflects an immediate transient increase of physiological dead space on exposure to hypoxemia.

Critical developmental period for hyperoxia-induced blunting of hypoxic phrenic responses in rats.

Hypoxic ventilatory and phrenic responses are reduced in adult rats reared in hyperoxia (60% O(2)) for the first month of life but not after hyperoxia as adults. In this study, we identified the developmental window for susceptibility to hyperoxia. Phrenic nerve responses to hypoxia were recorded in anesthetized, vagotomized, paralyzed, and ventilated Sprague-Dawley rats (aged 3-4 mo) exposed to 60% O(2) for the first, second, third, or fourth postnatal week. Responses were compared with control rats and with rats exposed to 60% O(2) for the first month of life. Phrenic minute activity (burst amplitude x frequency) increased less during isocapnic hypoxia (arterial PO(2) = 60, 50, and 40 Torr) in rats exposed to hyperoxia for the first or second week, or the first month, of life (P < 0.01 vs. control). Functional impairment caused by 1 wk of hyperoxia diminished with increasing age of exposure (P = 0.005). Adult hypoxic phrenic responses are impaired by 1 wk of hyperoxia during the first and second postnatal weeks in rats, indicating a developmental window coincident with carotid chemoreceptor maturation.

Carotid body excision significantly changes ventilatory control in awake rats.

We determined the effects of carotid body excision (CBX) on eupneic ventilation and the ventilatory responses to acute hypoxia, hyperoxia, and chronic hypoxia in unanesthetized rats. Arterial PCO2 (PaCO2) and calculated minute alveolar ventilation to minute metabolic CO2 production (VA/VCO2) ratio were used to determine the ventilatory responses. The effects of CBX and sham operation were compared with intact controls (PaCO2 = 40.0 +/- 0.1 Torr, mean +/- 95% confidence limits, and VA/VCO2 = 21.6 +/- 0.1). CBX rats showed 1) chronic hypoventilation with respiratory acidosis, which was maintained for at least 75 days after surgery (PaCO2 = 48.4 +/- 1.1 Torr and VA/VCO2 = 17.9 +/- 0.4), 2) hyperventilation in response to acute hyperoxia vs. hypoventilation in intact rats, 3) an attenuated increase in VA/VCO2 in acute hypoxemia (arterial PO2 approximately equal to 49 Torr), which was 31% of the 8.7 +/- 0.3 increase in VA/VCO2 observed in control rats, 4) no ventilatory acclimatization between 1 and 24 h hypoxia, whereas intact rats had a further 7.5 +/- 1.5 increase in VA/VCO2, 5) a decreased PaCO2 upon acute restoration of normoxia after 24 h hypoxia in contrast to an increased PaCO2 in controls. We conclude that in rats carotid body chemoreceptors are essential to maintain normal eupneic ventilation and to the process of ventilatory acclimatization to chronic hypoxia.

Selected contribution: chronic intermittent hypoxia enhances respiratory long-term facilitation in geriatric female rats.

Age and the estrus cycle affect time-dependent respiratory responses to episodic hypoxia in female rats. Respiratory long-term facilitation (LTF) is enhanced in middle-aged vs. young female rats (72). We tested the hypothesis that phrenic and hypoglossal (XII) LTF are diminished in acyclic geriatric rats when fluctuating sex hormone levels no longer establish conditions that enhance LTF. Chronic intermittent hypoxia (CIH) enhances LTF (41); thus we further predicted that CIH would restore LTF in geriatric female rats. LTF was measured in young (3-4 mo) and geriatric (20-22 mo) female Sasco Sprague-Dawley rats and in a group of geriatric rats exposed to 1 wk of nocturnal CIH (11 vs. 21% O2 at 5-min intervals, 12 h/night). In anesthetized, paralyzed, vagotomized, and ventilated rats, time-dependent hypoxic phrenic and XII responses were assessed. The short-term hypoxic response was measured during the first of three 5-min episodes of isocapnic hypoxia (arterial Po2 35-45 Torr). LTF was assessed 15, 30, and 60 min postepisodic hypoxia. Phrenic and XII short-term hypoxic response was not different among groups, regardless of CIH treatment (P > 0.05). LTF in geriatric female rats was smaller than previously reported for middle-aged rats but comparable to that in young female rats. CIH augmented phrenic and XII LTF to levels similar to those of middle-aged female rats without CIH (P < 0.05). The magnitude of phrenic and XII LTF in all groups was inversely related to the ratio of progesterone to estradiol serum levels (P < 0.05). Thus CIH and sex hormones influence the magnitude of LTF in geriatric female rats.

Level and duration of developmental hyperoxia influence impairment of hypoxic phrenic responses in rats.

Developmental hyperoxia (1-4 wk of 60% O2) causes long-lasting impairment of hypoxic phrenic responses in rats. We hypothesized that shorter or less severe hyperoxic exposures would produce similar changes. Hypoxic phrenic responses were measured in 3- to 5-mo-old, urethane-anesthetized rats exposed to 60% O2 for postnatal day 1 or week 1 or to 30% O2 for postnatal week 1. Whereas 1 day of 60% O2 had no lasting effects (P > 0.05 vs. control), both 1 wk of 60% O2 and 1 wk of 30% O2 decreased adult hypoxic phrenic responses (P < 0.05 vs. control), although the effects of 30% O2 were smaller. Hypoxic ventilatory responses (expressed as the ratio of minute ventilation to metabolic CO2 production) were also reduced in unanesthetized rats (5-10 mo old) exposed to 1 wk of 60% O2 during development (P < 0.05). An age-dependent increase toward normal hypoxic phrenic responses was observed in rats exposed to 1 wk of 60% O2 (P < 0.05), suggesting a degree of spontaneous recovery not observed after 1 mo of 60% O2. These data indicate that long-lasting effects of developmental hyperoxia depend on the level and duration of hyperoxic exposure.

Ventilatory long-term facilitation in unanesthetized rats.

We tested the hypothesis that unanesthetized rats exhibit ventilatory long-term facilitation (LTF) after intermittent, but not continuous, hypoxia. Minute ventilation (VE) and carbon dioxide production (VCO(2)) were measured in unanesthetized, unrestrained male Sprague-Dawley rats via barometric plethysmography before, during, and after exposure to continuous or intermittent hypoxia. Hypoxia was either isocapnic [inspired O(2) fraction (FI(O(2))) = 0.08--0.09 and inspired CO(2) fraction (FI(CO(2))) = 0.04] or poikilocapnic (FI(O(2)) = 0.11 and FI(CO(2)) = 0.00). Sixty minutes after intermittent hypoxia, VE or VE/VCO(2) was significantly greater than baseline in both isocapnic and poikilocapnic conditions. In contrast, 60 min after continuous hypoxia, VE and VE/VCO(2) were not significantly different from baseline values. These data demonstrate ventilatory LTF after intermittent hypoxia in unanesthetized rats. Ventilatory LTF appeared similar in its magnitude (after accounting for CO(2) feedback), time course, and dependence on intermittent hypoxia to phrenic LTF previously observed in anesthetized, vagotomized, paralyzed rats.

Adult carotid chemoafferent responses to hypoxia after 1, 2, and 4 wk of postnatal hyperoxia.

Exposing newborn rats to postnatal hyperoxia (60% O2) for 1-4 wk attenuates the ventilatory and phrenic nerve responses to acute hypoxia in adult rats. The goal of this research was to increase our understanding of the carotid chemoreceptor afferent neural input in this depressed response with different durations of postnatal hyperoxic exposure. Rats were exposed from a few days before birth to 1, 2, or 4 wk of 60% O2 and studied after 3-5 mo in normoxia. The rats were anesthetized with urethane. Whole carotid sinus nerve (CSN) responses to NaCN (40 microg/kg iv), 10 s of asphyxia and acute isocapnic hypoxia (arterial Po2 45 Torr) were determined. Mean CSN responses to stimuli after postnatal hyperoxia were reduced compared with controls. Responses in rats exposed to 1 wk of postnatal hyperoxia were less affected than those exposed to 2 and 4 wk of hyperoxia, which were equivalent to each other. These studies illustrate the importance of normoxia during the first 2 wk of life in development of carotid chemoreceptor afferent function.

Invited review: Intermittent hypoxia and respiratory plasticity.

Intermittent hypoxia elicits long-term facilitation (LTF), a persistent augmentation (hours) of respiratory motor output. Considerable recent progress has been made toward an understanding of the mechanisms and manifestations of this potentially important model of respiratory plasticity. LTF is elicited by intermittent but not sustained hypoxia, indicating profound pattern sensitivity in its underlying mechanism. During intermittent hypoxia, episodic spinal serotonin receptor activation initiates cell signaling events, increasing spinal protein synthesis. One associated protein is brain-derived neurotrophic factor, a neurotrophin implicated in several forms of synaptic plasticity. Our working hypothesis is that increased brain-derived neurotrophic factor enhances glutamatergic synaptic currents in phrenic motoneurons, increasing their responsiveness to bulbospinal inspiratory inputs. LTF is heterogeneous among respiratory outputs, differs among experimental preparations, and is influenced by age, gender, and genetics. Furthermore, LTF is enhanced following chronic intermittent hypoxia, indicating a degree of metaplasticity. Although the physiological relevance of LTF remains unclear, it may reflect a general mechanism whereby intermittent serotonin receptor activation elicits respiratory plasticity, adapting system performance to the ever-changing requirements of life.

Increased spinal monoamine concentrations after chronic thoracic dorsal rhizotomy in goats.

In goats, bilateral thoracic dorsal rhizotomy (TDR) causes severe ventilatory failure during exercise, followed by progressive functional recovery. We investigated spinal neurochemical changes associated with TDR and/or functional recovery by measuring spinal concentrations of the monoamines serotonin (5-HT), norepinephrine, and dopamine via HPLC. Changes in 5-HT and calcitonin gene-related peptide were visualized with immunohistochemistry. Goat spinal cords were compared 4-15 mo after TDR from T(2) to T(12) (n = 7) with sham-operated (n = 4) or unoperated controls (n = 4). TDR increased the concentration of cervical 5-HT (C(5)-C(6); 122% change), caudal thoracic norepinephrine (T(7)-T(11); 53% change), and rostral thoracic dopamine (T(3)-T(6); 234% change). TDR increased 5-HT-immunoreactive terminal density (dorsal and ventral horns) and nearly eliminated calcitonin gene-related peptide immunoreactivity in the superficial laminae of the dorsal horn in rostral thoracic segments; both effects became less pronounced in caudal thoracic segments. Thus TDR elevates monoamine concentrations in discrete spinal regions, including possible compensatory changes in descending serotonergic inputs to spinal segments not directly affected by TDR (i.e., cervical) but associated with functionally related motor nuclei (i.e., phrenic nucleus).

Carotid body amine levels in goats exposed to hypoxia or hypercapnia.

The carotid body (CB) contains large amounts of several monoamines. There is considerable evidence that carotid body (CB) chemoreceptor function may be regulated by one or several of these monoamines. In order to test whether conditions stimulating the CB might change the CB content of these monoamines, we measured the norepinephrine, dopamine, 5-hydroxyindoleacetic acid, and 5-hydroxytryptamine content of carotid bodies collected from goats exposed to 4 h of either normoxic-normocapnic, hypoxic-normocapnic, or normoxic-hypercapnic gas mixtures. We found that there were no consistent changes in the levels of these amines associated with exposure to the test gases. These findings would not support the hypothesis that changes in these amine levels in the CB are responsible for the time-dependent changes in carotid chemoreceptor activity in goats exposed to 4 h of hypoxia.

Separate effects of low carbon dioxide and low oxygen content on rat brain monoamine metabolism during hypoxemia.

Awake, adult male rats (some with chronically indwelling femoral artery catheters) were exposed for up to 7 days to one of three environments: a) normoxia (PIO2 = 155 Torr), b) hypoxic hypocapnia (PIO2 = 90 Torr), and c) hypoxic normocapnia (PIO2 = 73 Torr, PICO2 = 32 Torr), and arterial blood gas and acid-base status were documented. After 1 hour to 7 days, rats were sacrificed, and the time courses of the brain levels and turnovers of norepinephrine (NE), dopamine (DA) and serotonin (5-hydroxytryptamine or 5HT) were determined in each condition. The transient decrease in monoamine levels seen on exposure to acute hypoxia was absent if normocapnia was maintained; 7 days hypoxia with or without hypocapnia resulted in increased monoamine levels. Normocapnia also prevented an immediate, sustained decrease in 5HT turnover and a delayed decrease in DA turnover which were observed in hypoxic hypocapnia. A delayed increase in 5HT turnover appeared to be due to hypoxia independent of PaCO2. Therefore, the initial, transient loss of mental acuity and some ventilatory adaptations observed during prolonged hypoxia may be a result of the decrease in PaCO2 rather than the decreased oxygen concentration.