Developmental plasticity of the hypoxic ventilatory response in rats induced by neonatal hypoxia.

Neonatal hypoxia alters the development of the hypoxic ventilatory response in rats and other mammals. Here we demonstrate that neonatal hypoxia impairs the hypoxic ventilatory response in adult male, but not adult female, rats. Rats were raised in 10% O(2) for the first postnatal week, beginning within 12 h after birth. Subsequently, ventilatory responses were assessed in 7- to 9-week-old unanaesthetized rats via whole-body plethysmography. In response to 12% O(2), male rats exposed to neonatal hypoxia increased ventilation less than untreated control rats (mean +/-s.e.m. 35.2 +/- 7.7%versus 67.4 +/- 9.1%, respectively; P= 0.01). In contrast, neonatal hypoxia had no lasting effect on hypoxic ventilatory responses in female rats (67.9 +/- 12.6%versus 61.2 +/- 11.7% increase in hypoxia-treated and control rats, respectively; P > 0.05). Normoxic ventilation was unaffected by neonatal hypoxia in either sex at 7-9 weeks of age (P > 0.05). Since we hypothesized that neonatal hypoxia alters the hypoxic ventilatory response at the level of peripheral chemoreceptors or the central neural integration of chemoafferent activity, integrated phrenic responses to isocapnic hypoxia were investigated in urethane-anaesthetized, paralysed and ventilated rats. Phrenic responses were unaffected by neonatal hypoxia in rats of either sex (P > 0.05), suggesting that neonatal hypoxia-induced plasticity occurs between the phrenic nerve and the generation of airflow (e.g. neuromuscular junction, respiratory muscles or respiratory mechanics) and is not due to persistent changes in hypoxic chemosensitivity or central neural integration. The basis of sex differences in this developmental plasticity is unknown.

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.

Life-long impairment of hypoxic phrenic responses in rats following 1 month of developmental hyperoxia.

Hypoxic ventilatory and phrenic responses are reduced in adult rats (3-5 months old) exposed to hyperoxia for the first month of life (hyperoxia treated). We previously reported that hypoxic phrenic responses were normal in a small sample of 14- to 15-month-old hyperoxia-treated rats, suggesting slow, spontaneous recovery. Subsequent attempts to identify the mechanism(s) underlying this spontaneous recovery of hypoxic phrenic responses led us to re-evaluate our earlier conclusion. Experiments were conducted in two groups of aged Sprague-Dawley rats (14-15 months old) which were anaesthetized, vagotomized, neuromuscularly blocked and ventilated: (1) a hyperoxia-treated group raised in 60 % O2 for the first 28 postnatal days; and (2) an age-matched control group raised in normoxia. Increases in minute phrenic activity and integrated phrenic nerve amplitude (integral Phr) during isocapnic hypoxia (arterial partial pressures of O2, 60, 50 and 40 +/- 1 mmHg) were greater in aged control (n = 15) than hyperoxia-treated rats (n = 11; P < or = 0.01). Phrenic burst frequency during hypoxia was not different between groups. To examine the central integration of carotid chemoafferent inputs, steady-state relationships between carotid sinus nerve (electrical) stimulation frequency and phrenic nerve activity were compared in aged control (n = 7) and hyperoxia-treated rats (n = 7). Minute phrenic activity, integral Phr and burst frequency were not different between groups at any stimulation frequency between 0.5 and 20 Hz. Carotid body chemoreceptor function was examined by recording whole carotid sinus nerve responses to cessation of ventilation or injection of cyanide in aged control and hyperoxia-treated rats. Electrical activity of the carotid sinus nerve did not change in five out of five hyperoxia-treated rats in response to stimuli that evoked robust increases in carotid sinus nerve activity in five out of five control rats. Estimates of carotid body volume were lower in aged hyperoxia-treated rats (4.4 (+/- 0.2) x 10(6) microm3) compared to controls (17.4 (+/- 1.6) x 10(6) microm3; P <0.01). We conclude that exposure to hyperoxia for the first month of life causes life-long impairment of carotid chemoreceptor function and, consequently, blunted phrenic responses to hypoxia.

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.

Responses of single-unit carotid body chemoreceptors in adult rats.

1. Our goal was to describe the in situ responses in rats of single-unit carotid body chemoreceptors to changes in arterial PO2 and PCO2. We identified single-unit carotid chemoreceptor activity in male, adult Sprague-Dawley rats by their rapid responses to i.v. NaCN (20 microg) and transient (10 s) asphyxia. 2. Single-unit chemoreceptor responses to isocapnic changes in oxygenation within the arterial oxygen pressure range 34-114 mmHg were described by the power function: f(dis) = 74010(Pa,O2)-2.5; (r2 = 0.6), where f(dis) is the discharge frequency (spikes s-1), P(a,O2) is the arterial oxygen partial pressure (mmHg) and r2 is the correlation coefficient. 3. The responses to iso-oxic changes in CO2, assumed to be linear, had a slope of 0.089 spikes s-1 (mmHg Pa,CO2)-1 (r2 = 0.7). 4. We conclude that carotid body chemoreceptors in adult rats have responses to changes in Pa,O2 and Pa,CO2 similar to those of other species.

Parasympathetic innervation of canine tracheal smooth muscle.

To investigate whether efferent parasympathetic fibers to the tracheal smooth muscle course through the pararecurrent nerve rather than the recurrent or the superior laryngeal nerve, we stimulated all three nerves in anesthetized dogs. We also recorded the pararecurrent nerve activity response to bronchoconstrictor stimuli and compared it with pressure changes inside a saline-filled cuff of an endotracheal tube. Electrical stimulation (30 s, 100 Hz, 0.1 ms, 10 mA) increased tracheal cuff pressure by 21.0 +/- 3.2 and 1.3 +/- 0.7 cmH(2)O for the pararecurrent and the recurrent laryngeal nerve, respectively. Stimulation of the superior laryngeal nerve increased tracheal cuff pressure before, but not after, sectioning of the ramus anastomoticus, which connects it to the pararecurrent nerve. Intravenous administration of sodium cyanide increased pararecurrent nerve activity by 208 +/- 51% and tracheal cuff pressure by 14.4 +/- 3.5 cmH(2)O. Elevation of end-tidal PCO(2) to 50 Torr increased pararecurrent nerve activity by 49 +/- 19% and tracheal cuff pressure by 8.4 +/- 3.6 cmH(2)O. Further elevation to 60 Torr increased pararecurrent nerve activity by 101 +/- 33% and tracheal cuff pressure by 11.3 +/- 2.9 cmH(2)O. These results lead us to the conclusion that parasympathetic efferent fibers reach the smooth muscle of the canine trachea via the pararecurrent nerve.

Endogenous excitatory drive to the respiratory system in rapid eye movement sleep in cats.

A putative endogenous excitatory drive to the respiratory system in rapid eye movement (REM) sleep may explain many characteristics of breathing in that state, e.g. its irregularity and variable ventilatory responses to chemical stimuli. This drive is hypothetical, and determinations of its existence and character are complicated by control of the respiratory system by the oscillator and its feedback mechanisms. In the present study, endogenous drive was studied during apnoea caused by mechanical hyperventilation. We reasoned that if there was a REM-dependent drive to the respiratory system, then respiratory activity should emerge out of the background apnoea as a manifestation of the drive. Diaphragmatic muscle or medullary respiratory neuronal activity was studied in five intact, unanaesthetized adult cats who were either mechanically hyperventilated or breathed spontaneously in more than 100 REM sleep periods. Diaphragmatic activity emerged out of a background apnoea caused by mechanical hyperventilation an average of 34 s after the onset of REM sleep. Emergent activity occurred in 60 % of 10 s epochs in REM sleep and the amount of activity per unit time averaged approximately 40 % of eupnoeic activity. The activity occurred in episodes and was poorly related to pontogeniculo-occipital waves. At low CO2 levels, this activity was non-rhythmic. At higher CO2 levels (less than 0.5 % below eupnoeic end-tidal percentage CO2 levels in non-REM (NREM) sleep), activity became rhythmic. Medullary respiratory neurons were recorded in one of the five animals. Nineteen of twenty-seven medullary respiratory neurons were excited in REM sleep during apnoea. Excited neurons included inspiratory, expiratory and phase-spanning neurons. Excitation began about 43 s after the onset of REM sleep. Activity increased from an average of 6 impulses s-1 in NREM sleep to 15.5 impulses s-1 in REM sleep. Neuronal activity was non-rhythmic at low CO2 levels and became rhythmic when levels were less than 0.5 % below eupnoeic end-tidal levels in NREM sleep. The level of CO2 at which rhythmic neuronal activity developed corresponded to eupnoeic end-tidal CO2 levels in REM sleep. These results demonstrate an endogenous excitatory drive to the respiratory system in REM sleep and account for rapid and irregular breathing and the lower set-point to CO2 in that state.

5-HT5a receptors in the carotid body chemoreception pathway of rat.

By using a specific antibody, 5-HT5a receptor-like immunoreactivity was revealed in the chemoreceptive, oxygen sensitive, carotid body (CB) type I cells, and neurons of the petrosal ganglion (PG) and the superior cervical ganglion (SCG) in rat. mRNA encoding for the 5-HTa receptor was also detected in these tissues by RT-PCR, and confirmed with DNA sequencing. The present study provides direct evidence that 5-HT5a receptors are expressed in the CB, PG and SCG, which all likely play fundamental roles in arterial chemoreception.

Slow recovery of impaired phrenic responses to hypoxia following perinatal hyperoxia in rats.

1. Previous studies demonstrated that both ventilatory and phrenic nerve responses to acute hypoxia are greatly attenuated in adult rats (3-5 months old) previously exposed to 1 month of perinatal hyperoxia (60 % O2; perinatal treated rats). The present study tested the hypothesis that this functional impairment recovers spontaneously with advancing age in perinatal treated rats. 2. Hypoxia-induced chemoreflexes were examined by measuring integrated phrenic responses to strictly controlled isocapnic hypoxia in urethane-anaesthetized, vagotomized, paralysed and ventilated rats at different ages. 3. At 50 mmHg Pa,O2 (arterial O2 partial pressure), the hypoxia-induced increase in minute phrenic activity was significantly attenuated in both 3- to 5-month-old (166 +/- 15% of baseline) and 6-month-old (130 +/- 17%) perinatal treated rats, relative to 3- to 6-month-old, untreated control rats (279 +/- 28%; both P < 0.05). However, at 40 mmHg Pa,O2, the hypoxic minute phrenic activity response was attenuated only in 3- to 5-month-old (154 +/- 33%), but not 6-month-old (232 +/- 33%) perinatal treated rats versus control rats (293 +/- 30%). 4. The minute phrenic activity response to hypoxia was not significantly different between geriatric perinatal treated rats (14-15 months) and untreated geriatric control rats at either 50 mmHg (treated: 250 +/- 20% versus control: 274 +/- 23%) or 40 mmHg Pa,O2 (treated: 292 +/- 19% versus control: 315 +/- 36%). 5. These data suggest that partial spontaneous recovery may occur in 6-month-old perinatal treated rats and that full recovery occurs by 15 months of age.

Chemoafferent degeneration and carotid body hypoplasia following chronic hyperoxia in newborn rats.

1. To define the role of environmental oxygen in regulating postnatal maturation of the carotid body afferent pathway, light and electron microscopic methods were used to compare chemoafferent neurone survival and carotid body development in newborn rats reared from birth in normoxia (21 % O2) or chronic hyperoxia (60 % O2). 2. Four weeks of chronic hyperoxia resulted in a significant 41 % decrease in the number of unmyelinated axons in the carotid sinus nerve, compared with age-matched normoxic controls. In contrast, the number of myelinated axons was unaffected by hyperoxic exposure. 3. Chemoafferent neurones, located in the glossopharyngeal petrosal ganglion, already exhibited degenerative changes following 1 week of hyperoxia from birth, indicating that even a relatively short hyperoxic exposure was sufficient to derange normal chemoafferent development. In contrast, no such changes were observed in the vagal nodose ganglion, demonstrating that the effect of high oxygen levels was specific to sensory neurones in the carotid body afferent pathway. Moreover, petrosal ganglion neurones were sensitive to hyperoxic exposure only during the early postnatal period. 4. Chemoafferent degeneration in chronically hyperoxic animals was accompanied by marked hypoplasia of the carotid body. In view of previous findings from our laboratory that chemoafferent neurones require trophic support from the carotid body for survival after birth, we propose that chemoafferent degeneration following chronic hyperoxia is due specifically to the loss of target tissue in the carotid body.

Activity of medullary respiratory neurons during ventilator-induced apnea in sleep and wakefulness.

Mechanical ventilation of cats in sleep and wakefulness causes apnea, often within two to three cycles of the ventilator. We recorded 137 medullary respiratory neurons in four adult cats during eupnea and during apnea caused by mechanical ventilation. We hypothesized that the residual activity of respiratory neurons during apnea might reveal its cause(s). The results showed that residual activity depended on 1) the amount of nonrespiratory inputs to the cell (cells with more nonrespiratory inputs had greater amounts of residual activity); 2) the cell type (expiratory cells had more residual activity than inspiratory cells); and 3) the state of consciousness (more residual activity in wakefulness and rapid-eye-movement sleep than in non-rapid-eye-movement sleep). None of the cells showed an activation during ventilation that could explain the apnea. Residual activity of approximately one-half of the cells was modulated in phase with the ventilator. The strength of this modulation was quantified by using an effect-size statistic and was found to be weak. The patterns of modulation did not support the idea that mechanoreceptors excite some respiratory cells that, in turn, inhibit others. Indeed, most cells, inspiratory and expiratory, discharged during the deflation-inflation transition of ventilation. Residual activity failed to reveal the cause of apnea but showed that during apnea respiratory neurons act as if they were disinhibited and disfacilitated.

Phrenic responses to isocapnic hypoxia in adult rats following perinatal hyperoxia.

The purpose of this study was to test the hypothesis that carotid body-mediated, phrenic nerve responses to hypoxia are attenuated in adult rats that had been previously exposed to perinatal hyperoxia (one month of 60% O2; perinatal treated rats.) Integrated phrenic nerve responses to strictly controlled isocapnic hypoxia were measured in urethane-anesthetized, vagotomized, paralyzed and ventilated adult rats 2-5 months after perinatal hyperoxia, before and after bilateral carotid denervation. In untreated control rats, phrenic burst frequency, peak amplitude of integrated phrenic activity and minute phrenic activity increased 21 +/- 3 bursts/min (mean +/- SE), 158 +/- 20% and 279 +/- 34%, respectively, during hypoxia (50 Torr PaO2). In contrast, phrenic nerve activity increased to a significantly lesser degree in perinatal treated rats (frequency, 12 +/- 2 bursts/min; amplitude, 87 +/- 13%; minute activity, 150 +/- 19%; all P < 0.05). Hypoxic phrenic responses were abolished by carotid degeneration in both rat groups. In rats exposed to hyperoxia as adults, hypoxic phrenic responses were not attenuated versus untreated control rats. The data indicate that carotid body-mediated, isocapnic hypoxic chemoreflexes are impaired in perinatal treated rats, an effect unique to development. These effects cannot be accounted for by differences in blood gases (O2 or CO2) or pulmonary mechanics.

Integrated phrenic responses to carotid afferent stimulation in adult rats following perinatal hyperoxia.

1. Hypoxic ventilatory responses are greatly attenuated in adult rats exposed to moderate hyperoxia (60% O2) during the first month of life (perinatal treated rats). The present study was designed to test the hypothesis that perinatal hyperoxia impairs central integration of carotid chemoreceptor afferent inputs, thereby diminishing the hypoxic ventilatory response. 2. Time-dependent phrenic nerve responses to electrical stimulation of the carotid sinus nerve (CSN) and steady-state relationships between CSN stimulation frequency and phrenic nerve output were compared in control and perinatal treated rats. The rats were urethane anaesthetized, vagotomized, paralysed and artificially ventilated. End-tidal CO2 was monitored and maintained at isocapnic levels; arterial blood gases were determined. 3. Two stimulation protocols were used: (1) three 2 min episodes of CSN stimulation (20 Hz, 0.2 ms duration, 3 x threshold), separated by 5 min intervals; and (2) nine 45 s episodes of CSN stimulation with stimulus frequencies ranging from 0.5 to 20 Hz (0.2 ms duration, 3 x threshold), separated by 4 min intervals. 4. The mean threshold currents to elicit phrenic responses were similar between groups. Burst frequency (f, burst min-1), peak amplitude of integrated phrenic activity (integral of Phr), and minute phrenic activity (integral of Phr x f) during and after CSN stimulation were not distinguishable between groups in either protocol at any time or at any stimulus intensity (P > 0.05). 5. Perinatal hyperoxia does not alter temporal or steady-state phrenic responses to CSN stimulation, suggesting that the central integration of carotid chemoreceptor afferent inputs is not impaired in perinatal treated rats. It is speculated that carotid chemoreceptors per se are impaired in perinatal treated rats.

Developmental plasticity of the hypoxic ventilatory response.

This paper will describe recent studies concerning the existence of developmental plasticity in the hypoxic ventilatory control system and the locus of the functional impairment following perinatal sensory suppression. Suppression of peripheral arterial chemoreceptor activity was achieved by exposing rats to hyperoxia (60% O2) for the first month of life; all measurements were conducted 2-5 months after the exposure (perinatal treated rats). Hypoxic (but not hypercapnic) ventilatory responses were severely attenuated in awake perinatal treated rats, but not in rats exposed to hyperoxia as adults, indicating that the persistent effect is unique to development and is not the nonspecific result of O2 toxicity. Impairments of the hypoxic ventilatory response due to changes in pulmonary mechanics, gas exchange or central integration of carotid chemoafferent inputs were all ruled out as primary causal factors. However, a persistent impairment of carotid chemotransduction in perinatal treated rats was apparent. These studies suggest that the hypoxic ventilatory response is susceptible to developmental plasticity, and that a carotid chemoreceptor deficit is the primary cause. These findings may have important clinical implications for patients subjected to excessive O2 therapy during neonatal intensive care.

Attenuation of the hypoxic ventilatory response in adult rats following one month of perinatal hyperoxia.

1. This study was designed to test the hypothesis that perinatal suppression of peripheral arterial chemoreceptor inputs attenuates the hypoxic ventilatory response in adult rats. Perinatal suppression of peripheral chemoreceptor activity was achieved by exposing rats to hyperoxia throughout the first month of life. 2. Late-gestation pregnant rats were housed in a 60% O2 environment, exposing the pups to hyperoxia from several days prior to birth until they were returned to normoxia on postnatal day 28. These perinatally treated rats were then reared to adulthood (3-5 months old) in normoxia. In addition to the mother rats, adult male rats were also exposed to hyperoxia, creating an adult-treated control group. Two to four months after the hyperoxic exposure, treated rats were compared with untreated male rats of similar age. 3. A whole-body, flow-through plethysmograph was used to measure hypoxic and hypercapnic ventilatory responses of the unanaesthetized adult rats. In moderate hypoxia (arterial oxygen partial pressure, Pa,O2 approximately 48 mmHg). VE (minute ventilation) and the ratio VE/VCO2 (ventilation relative to CO2 production) increased by 16.7 +/- 4.0 and 35.4 +/- 3.4%, respectively, in perinatal-treated rats (means +/- S.E.M.), but increased more in untreated control rats (51.4 +/- 2.8 and 83.1 +/- 4.3%; both P < 10(-6)). 4. In contrast to the impaired hypoxic ventilatory response, ventilatory responses to hypercapnia (5% CO2) were similar between untreated control and perinatal-treated rats. 5. Impaired hypoxic responsiveness was unique to the perinatal-treated rats since hypoxic ventilatory responses were not attenuated in adult-treated rats. 6. The results indicate that ventilatory responses to hypoxaemia are greatly attenuated in adult rats that had experienced hyperoxia during their first month of life, and suggest that normal hypoxic ventilatory control mechanisms are susceptible to developmental plasticity.

Negative pressure-induced deformation of the upper airway causes central apnea in awake and sleeping dogs.

We investigated the effects of negative pressure (NP) in the isolated upper airway (UA) in three unanesthetized dogs. The UA was isolated, and the dogs breathed through an endotracheal tube while wearing a fitted fiberglass snout mask. NP (-2 to -32 cmH2O) was applied in a square wave below the larynx or at the snout at end expiration and was held until inspiratory effort during wakefulness, non-rapid-eye-movement (NREM) sleep, and rapid-eye-movement (REM) sleep. During all states of consciousness, NP applied to the UA prolonged expiratory time (TE) 1) below a threshold of -8 to -10 cmH2O, which coincided with closure of the oro- and/or velopharynx; and 2) in a progressive fashion at more negative pressures than threshold, up to a mean apneic length of 324% of the control value (or 13.9 s) at -30 cmH2O. TE prolongation was less during REM sleep at a given NP (P < 0.05). Augmented tonic genioglossal electromyographic activity also occurred with the applied NP during wakefulness and NREM sleep but not with REM sleep. NP (-20 to -32 cmH2O) applied as a brief pulse (300-500 ms) during NREM sleep caused transient airway occlusion, terminated the breath during inspiration, and prolonged TE when applied at end expiration. Central apneas always persisted beyond the termination of the UA closure. TE prolongation in response to NP persisted in the presence of a topical anesthetic nebulized through the UA sufficient to abolish the laryngeal gag reflexes. We conclude that UA closure and deformation will cause significant TE prolongation during all states of consciousness and activation of the genioglossus muscle during wakefulness and NREM sleep but not during REM sleep.

Circumsinus branch: a convenient source of baro- and chemoreceptor activity in dogs.

We found a branch of the carotid sinus nerve in 44 of 48 dogs. We propose that this branch be referred to as the "circumsinus" branch of the carotid sinus nerve. Both chemoreceptor and baroreceptor activity were detected in this branch during electrophysiological recording efforts utilizing classic nerve recording techniques. Its convenient location permits whole nerve or single unit recording without having to transect, dissect, or even expose the carotid sinus nerve. Carotid baroreceptor and chemoreceptor activity can be monitored with most of the carotid bifurcation's neural pathways intact.

Response of the goat carotid body to acute and prolonged hypercapnia.

The effect of prolonged hypercapnia on carotid chemoreceptor discharge frequency has not been elucidated. In addition, the effect of acute hypercapnia on chemoreceptor discharge has not been determined in the goat, a species commonly used for ventilatory control studies. Therefore, we determined the effects of acute and prolonged normoxic-hypercapnia on single fiber output of the carotid body of chloralose anesthetized goats. The animals were paralyzed and artificially ventilated. The average acute response curve for 12 single fibers was linear over the range of 30-80 Torr PaCO2 with a mean slope of 0.115 +/- 0.057 (SD) imp.sec-1.Torr-1 PaCO2. Elevated discharge frequency was maintained during prolonged (up to 240 min, n = 11) steady-state hypercapnia (X PaCO2 = 85 Torr). No systematic time-dependent changes in afferent discharge frequency occurred during the period. The findings obtained during sustained hypercapnia are in contrast to the time-dependent increase in carotid body activity seen previously in our laboratory with prolonged normocapnic-hypoxia of up to 240 min duration.

Carotid chemoreceptor activity during acute and sustained hypoxia in goats.

The role of carotid body chemoreceptors in ventilatory acclimatization to hypoxia, i.e., the progressive, time-dependent increase in ventilation during the first several hours or days of hypoxic exposure, is not well understood. The purpose of this investigation was to characterize the effects of acute and prolonged (up to 4 h) hypoxia on carotid body chemoreceptor discharge frequency in anesthetized goats. The goat was chosen for study because of its well-documented and rapid acclimatization to hypoxia. The response of the goat carotid body to acute progressive isocapnic hypoxia was similar to other species, i.e., a hyperbolic increase in discharge as arterial PO2 (PaO2) decreased. The response of 35 single chemoreceptor fibers to an isocapnic [arterial PCO2 (PaCO2) 38-40 Torr)] decrease in PaO2 of from 100 +/- 1.7 to 40.7 +/- 0.5 (SE) Torr was an increase in mean discharge frequency from 1.7 +/- 0.2 to 5.8 +/- 0.4 impulses. During sustained isocapnic steady-state hypoxia (PaO2 39.8 +/- 0.5 Torr, PaCO2, 38.4 +/- 0.4 Torr) chemoreceptor afferent discharge frequency remained constant for the first hour of hypoxic exposure. Thereafter, single-fiber chemoreceptor afferents exhibited a progressive, time-related increase in discharge (1.3 +/- 0.2 impulses.s-1.h-1, P less than 0.01) during sustained hypoxia of up to 4-h duration. These data suggest that increased carotid chemoreceptor activity contributes to ventilatory acclimatization to hypoxia.

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.