Biphasic ventilatory response of adult cats to sustained hypoxia has central origin

Hypoxia stimulates ventilation, but when it is sustained, a decrease in the response is often seen. The mechanism of this depression or "roll off" is unclear. In this study we attempted to localize the responsible mechanism at one of three possible sites: the carotid bodies, the central nervous system (CNS), or the ventilatory apparatus. The ventilatory response to sustained hypoxia (PETO2, 40-50 Torr) was tested in 5 awake and 14 anesthetized adult cats. The roll off was found in both anesthetized and awake cats. Isocapnic hypoxia initially increased ventilation as well as phrenic and carotid sinus nerve activity in anesthetized cats (288 +/- 31, 269 +/- 31, 273 +/- 29% of control value, respectively). During the roll off, ventilation and phrenic nerve activity decreased similarly (to 230 +/- 26 and 222 +/- 28%, respectively after the roll off), but in contrast carotid sinus nerve activity remained unchanged (270 +/- 26%). Thus the ventilatory roll off was reflected in phrenic but not in carotid sinus nerve activity. We conclude that the cat represents a useful animal model of the roll off phenomenon and that the mechanism responsible for the secondary decrease in ventilation lays within the CNS.     

Effects of haloperidol and domperidone on ventilatory roll off during sustained hypoxia in cats.

In a previous work, we showed that the adult cat demonstrates a ventilatory decline during sustained hypoxia (the "roll off" phenomenon) and that the mechanism responsible for this secondary decrease in ventilation lies within the central nervous system (J. Appl. Physiol. 63: 1658-1664, 1987). In this study, we sought to determine whether central dopaminergic mechanisms could have a role in the roll off. We studied the effects of haloperidol, a peripheral and centrally acting dopamine receptor antagonist, on the ventilatory response to sustained isocapnic hypoxia (end-tidal PO2 40-50 Torr, 20-25 min) in awake cats. In vehicle control cats (n = 5), sustained hypoxia elicited a biphasic respiratory response, during which an initial ventilatory stimulation is followed by a 24 +/- 6% (P less than 0.01) reduction. In contrast, in haloperidol- (0.1 mg/kg) treated cats (n = 5) the ventilatory roll off was virtually abolished (-1 +/- 1%; P = NS). We also measured ventilatory, carotid sinus nerve (CSN) and phrenic nerve (PhN) responses to sustained isocapnic hypoxia in anesthetized animals (n = 6) to explore the influence of haloperidol on peripheral and central response during the roll off. Control responses to hypoxia showed an initial increase in ventilation, PhN, and CSN activity, followed by a subsequent decline in ventilation and PhN activity of 17 +/- 3 and 17 +/- 5%, respectively (P less than 0.05). In contrast, CSN activity remained unchanged during the roll off. Administration of haloperidol (1 mg/kg) reduced the initial increment in ventilation, while the initial increase in CSN activity was augmented.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of carotid body activity responsible for hypoxic ventilatory decline in awake humans

Long, W. Q., G. G. Giesbrecht, and N. R. Anthonisen. Ventilatory response to moderate hypoxia in awakechemodenervated cats. J. Appl. Physiol. 74(2): 805-810, 1993.In humans and cats the ventilatory response to 30 min ofmoderate hypoxia (arterial PO₂ 40-55Torr) is biphasic: ventilation increases sharply for the first 5 minand then declines. In humans there is evidence that the decline isdependent on the initial increase. We therefore examined ventilatoryresponses to moderate isocapnic hypoxia in awake cats with and withoutcarotid body denervation. Cats underwent denervation or a shamoperation. Then they were studied in a Drorbaugh-Fenn plethysmographwhile ventilation, arterial PO₂, and end-tidal PO₂ and PCO₂ weremeasured. Three sham-operated and four denervated cats were studiedwith room air as the control. Sham animals demonstrated a biphasicresponse: ventilation rose to 211% of control at 5 min and fell to114% of control at 25 min. Denervated animals showed neither theinitial increase nor the subsequent decrease in ventilation. Threesham-operated and three denervated cats were studied with 2%CO₂ added to the inspirate. Results were similar: intactcats showed a biphasic response to hypoxia, whereas denervated catsshowed neither an increase nor a decrease in ventilation. Preliminaryexperiments showed that hypoxia was not associated with changes inCO₂ output or systemic blood pressure in either denervatedor intact animals. We conclude that depression of ventilation does notoccur in awake denervated cats in response to moderate hypoxiaand that the decline in ventilation that occurs in intact cats is insome way dependent on peripheral chemoreceptor output.

     

Effect of a synthetic progestin on ventilatory response to hypoxia in anesthetized rats

Effects on ventilatory responses to progressive isocapnic hypoxia of a synthetic potent progestin, chlormadinone acetate (CMA), were determined in the halothane-anesthetized male rat. Ventilation during the breathing of hyperoxic gas was largely unaffected by treatment with CMA when carotid chemoreceptor afferents were kept intact. The sensitivity to hypoxia evaluated by hyperbolic regression analysis of the response curve did not differ between the control and CMA groups. The reduction of ventilation after bilateral section of the carotid sinus nerve (CSN) in hyperoxia was less severe in CMA-treated than in untreated animals. Furthermore, the CMA-treated rats showed a larger increase in ventilation during the hypoxia test and a lower PO2 break point for ventilatory depression. Inhibition of hypoxic ventilatory depression by CMA persisted even after the denervation of CSN. We conclude that exogenous progestin likely protects regulatory mechanism(s) for respiration against hypoxic depression through a stimulating action independent of carotid chemoreceptor afferents and without a change in the sensitivity of the ventilatory response to hypoxia.     

Effect of aortic balloon inflation on ventilation and brain stem blood flow in piglets

Increases in brain stem blood flow (BBF) during hypoxia may decrease tissue PCO2/[H+], causing minute ventilation (VE) to decrease. To determine whether an increase in BBF, isolated from changes in arterial PO2 and PCO2, can affect respiration, we obstructed the thoracic aorta with a balloon in 31 intact and 24 peripherally chemobarodenervated, anesthetized, spontaneously breathing newborn piglets. Continuous measurements of cardiorespiratory variables were made before and during 2 min of aortic obstruction. Radiolabeled microspheres were used to measure BBF before and approximately 30 s after balloon inflation in eight intact and five denervated animals. After balloon inflation, there was a rapid increase in mean blood pressure in both the intact and denervated animals, followed within 10 s by a decrease in tidal volume and VE. In the intact animals, the decrease in VE after acute hypertension can be ascribed to a baroreceptor-mediated reflex. After peripheral chemobarodenervation, however, acute hypertension continued to produce a decrease in VE, which cannot be explained by baroreceptor stimulation. In these denervated animals, aortic balloon inflation was associated with an increase in BBF (13.1 +/- 2.7%; P less than 0.05). We speculate that the increase in BBF during hypoxia may contribute to the decrease in ventilation observed after carotid body denervation.     

Role of the carotid bodies in chemosensory ventilatory responses in the anesthetized mouse.

We examined the effects of carotid body denervation on ventilatory responses to normoxia (21% O2 in N2 for 240 s), hypoxic hypoxia (10 and 15% O2 in N2 for 90 and 120 s, respectively), and hyperoxic hypercapnia (5% CO2 in O2 for 240 s) in the spontaneously breathing urethane-anesthetized mouse. Respiratory measurements were made with a whole body, single-chamber plethysmograph before and after cutting both carotid sinus nerves. Baseline measurements in air showed that carotid body denervation was accompanied by lower minute ventilation with a reduction in respiratory frequency. On the basis of measurements with an open-circuit system, no significant differences in O2 consumption or CO2 production before and after chemodenervation were found. During both levels of hypoxia, animals with intact sinus nerves had increased respiratory frequency, tidal volume, and minute ventilation; however, after chemodenervation, animals experienced a drop in respiratory frequency and ventilatory depression. Tidal volume responses during 15% hypoxia were similar before and after carotid body denervation; during 10% hypoxia in chemodenervated animals, there was a sudden increase in tidal volume with an increase in the rate of inspiration, suggesting that gasping occurred. During hyperoxic hypercapnia, ventilatory responses were lower with a smaller tidal volume after chemodenervation than before. We conclude that the carotid bodies are essential for maintaining ventilation during eupnea, hypoxia, and hypercapnia in the anesthetized mouse.     

Nonperipheral chemoreceptor stimulation of ventilation by cyanide.

To assess the ventilatory responses elicited by changes of tissue hypoxia, sodium cyanide (0.12 mg/kg-min for 10 min) was infused into the upper abdominal aorta of anesthetized dogs. These infusions produced decreases in oxygen consumption, increases in arterial lactate concentration, and increases in arterial lactate/pyruvate ratio. Coincident with these metabolic changes of hypoxia, minute ventilation (VE) increased 228 +/- SE 36% and arterial PCO2 decreased 21 +/- SE 2 mmHg; therefore, pH increased both in arterial blood in and cisternal cerebrospinal fluid. Following infusion of cyanide into the abdominal aorta, small quantities of cyanide (48 +/- SE 14 mumol/liter) appeared in carotid arterial blood. To evaluate the possibility that the observed increases in VE were due to stimulation of peripheral arterial chemoreceptors by the recirculating cyanide, the carotid and aortic chemoreceptors were denervated in four dogs. Nonetheless, after intra-aortic infusion of sodium cyanide (1.2 mg/kg), ventilation in these chemodenervated animals again increased considerably (154 +/- SE 36%). In order to explore the possibility that cyanide infusion can stimulate ventilation by an extracranial mechanism, heads of vagotomized dogs (including the carotid bodies) were perfused entirely by donor dogs. The intra-aortic infusion of sodium cyanide (0.9 mg/kg) into these head-perfused animals still caused large increases in VE (163 +/- SE 19%). It is concluded that intra-aortic cyanide infusions stimulate VE by an extracranial mechanism other than the carotid and aortic chemoreceptors.     

Interaction of hypoxic and hypercapnic stimuli on breathing pattern in the newborn rat

We aimed to investigate whether newborn rats respond to acute hypoxia with a biphasic pattern as other newborn species, the characteristics of their ventilatory response to hypercapnia, and the ventilatory response to combined hypoxic and hypercapnic stimuli. First, we established that newborn unanesthetized rats (2-4 days old) exposed to 10% O2 respond as other species. Their ventilation (VE), measured by flow plethysmography, immediately increased by 30%, then dropped and remained around normoxic values within 5 min. The drop was due to a decrease in tidal volume, while frequency remained elevated. Hence, alveolar ventilation was about 10% below normoxic value. At the same time O2 consumption, measured manometrically, dropped (-23%), possibly indicating a mechanism to protect vital organs. Ten percent CO2 in O2 breathing determined a substantial increase in VE (+47%), indicating that the respiratory pump is capable of a marked sustained hyperventilation. When CO2 was added to the hypoxic mixture, VE increased by about 85%, significantly more than without the concurrent hypoxic stimulus. Thus, even during the drop in VE of the biphasic response to hypoxia, the respiratory control system can respond with excitation to a further increase in chemical drive. Analysis of the breathing patterns suggests that in the newborn rat in hypoxia the inspiratory drive is decreased but the inspiratory on-switch mechanism is stimulated, hypercapnia increases ventilation mainly through an increase in respiratory drive, and moderate asphyxia induces the most powerful ventilatory response by combining the stimulatory action of hypercapnia and hypoxia.     

Interindividual variation in hypoxic ventilatory response: potential role of carotid body

There is considerable interindividual variation in ventilatory response to hypoxia in humans but the mechanism remains unknown. To examine the potential contribution of variable peripheral chemorecptor function to variation in hypoxic ventilatory response (HVR), we compared the peripheral chemoreceptor and ventilatory response to hypoxia in 51 anesthetized cats. We found large interindividual differences in HVR spanning a sevenfold range. In 23 cats studied on two separate days, ventilatory measurements were correlated (r = 0.54, P less than 0.01), suggesting stable interindividual differences. Measurements during wakefulness and in anesthesia in nine cats showed that although anesthesia lowered the absolute HVR it had no influence on the range or the rank of the magnitude of the response of individuals in the group. We observed a positive correlation between ventilatory and carotid sinus nerve (CSN) responses to hypoxia measured during anesthesia in 51 cats (r = 0.63, P less than 0.001). To assess the translation of peripheral chemoreceptor activity into expiratory minute ventilation (VE) we used an index relating the increase of VE to the increase of CSN activity for a given hypoxic stimulus (delta VE/delta CSN). Comparison of this index for cats with lowest (n = 5, HVR A = 7.0 +/- 0.8) and cats with highest (n = 5, HVR A = 53.2 +/- 4.9) ventilatory responses showed similar efficiency of central translation (0.72 +/- 0.06 and 0.70 +/- 0.08, respectively). These results indicate that interindividual variation in HVR is associated with comparable variation in hypoxic sensitivity of carotid bodies. Thus differences in peripheral chemoreceptor sensitivity may contribute to interindividual variability of HVR.     

Ventilatory response of intact cats to carbon monoxide hypoxia

Adult intact conscious or anesthetized cats have been exposed to either hypoxia or low concentrations of CO in air. In addition, the ventilatory response to CO2 was studied in air, hypoxic hypoxia, and CO hypoxia. The results show that 1) in conscious cats, low concentrations of CO (0.15%) induce a slight decrease in ventilation and higher concentrations of CO (0.20%) induce first a small decrease in ventilation and then a characteristic tachypnea similar to the hypoxic tachypnea described in carotid-denervated cats; 2) in anesthetized cats, CO hypoxia induces only mild changes in ventilation; and 3) the ventilatory response to CO2 is increased in CO hypoxia in both conscious and anesthetized animals but differs from the increase observed during hypoxia. It is concluded that the initial decrease in ventilation may be caused by some brain stem depression of the respiratory centers with CO hypoxia, whereas the tachypnea originates probably at some suprapontine level. Conversely, the possible central acidosis may account for the potentiation of the ventilatory response to CO2 observed in either conscious or anesthetized animals.     

Influence of pregnancy on ventilatory and carotid body neural output responsiveness to hypoxia in cats

Pregnancy increases ventilation and ventilatory sensitivity to hypoxia and hypercapnia. To determine the role of the carotid body in the increased hypoxic ventilatory response, we measured ventilation and carotid body neural output (CBNO) during progressive isocapnic hypoxia in 15 anesthetized near-term pregnant cats and 15 nonpregnant females. The pregnant compared with nonpregnant cats had greater room-air ventilation [1.48 +/- 0.24 vs. 0.45 +/- 0.05 (SE) l/min BTPS, P less than 0.01], O2 consumption (29 +/- 2 vs. 19 +/- 1 ml/min STPD, P less than 0.01), and lower end-tidal PCO2 (30 +/- 1 vs. 35 +/- 1 Torr, P less than 0.01). Lower end-tidal CO2 tensions were also observed in seven awake pregnant compared with seven awake nonpregnant cats (28 +/- 1 vs. 31 +/- 1 Torr, P less than 0.05). The ventilatory response to hypoxia as measured by the shape of parameter A was twofold greater (38 +/- 5 vs. 17 +/- 3, P less than 0.01) in the anesthetized pregnant compared with nonpregnant cats, and the CBNO response to hypoxia was also increased twofold (58 +/- 11 vs. 29 +/- 5, P less than 0.05). The increased CBNO response to hypoxia in the pregnant compared with the nonpregnant cats persisted after cutting the carotid sinus nerve while recording from the distal end, indicating that the increased hypoxic sensitivity was not due to descending central neural influences. We concluded that greater carotid body sensitivity to hypoxia contributed to the increased hypoxic ventilatory responsiveness observed in pregnant cats.     

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.     

Diphasic ventilatory response to hypoxia in newborn lambs

The ventilatory response of newborn lambs to hypoxemia was evaluated in two groups of seven awake lambs studied at 2 and 7 days of life. Minute ventilation (VE) and airway occlusion pressure (P0.1) were monitored as the animals were exposed in sequence to room air, 12% O2 (15 min), 7% O2 (15 min), and room air. On 12 and 7% O2, 2-day-old lambs experienced a brisk hyperventilation followed by a VE depression, previously described in newborns of other species (diphasic response). The 7-day-old lambs had a clear diphasic VE response only on 7% O2 breathing. In the 2-day-old lambs, at the time of the relative VE depression to 12% O2, the respiratory centers showed a persisting responsiveness to further hypoxia; switching to 7% O2 caused a brisk increase in VE and P0.1 of 70 and 130%, respectively, which was followed again by a VE depression. The magnitude of the immediate VE response to hypoxia, taken as an index of the chemoreceptor strength, was inversely related to the magnitude of the VE depression (R = 0.81, P less than 0.001). It was concluded that 1) lambs as well as other neonates have an age-related diphasic VE response to hypoxia; 2) at the time of the VE depression, the respiratory centers maintain their responsiveness to further acute hypoxia; and 3) the weakness of the chemoreceptors in the newborn is a major determinant of the diphasic response.     

Biphasic ventilatory response to hypoxia in unanesthetized rats

To determine the role of postinspiratory inspiratory activity of the diaphragm in the biphasic ventilatory response to hypoxia in unanesthetized rats, we examined diaphragmatic activity at its peak (DI), at the end of expiration (DE), and ventilation in adult unanesthetized rats during poikilocapnic hypoxia (10 % O2) sustained for 20 min. Hypoxia induced an initial increase in ventilation followed by a consistent decline. Tidal volume (VT), frequency of breathing (fR), DI and DE at first increased, then VT and DE decreased, while fR and DI remained enhanced. Phasic activation of the diaphragm (DI-DE) increased significantly at 10, 15 and 20 min of hypoxia. These results indicate that 1) the ventilatory response of unanesthetized rats to sustained hypoxia has a typical biphasic character and 2) the increased end-expiratory activity of the diaphragm limits its phasic inspiratory activation, but this increase cannot explain the secondary decline in tidal volume and ventilation.     

Neonatal caffeine induces sex-specific developmental plasticity of the hypoxic respiratory chemoreflex in adult rats

Caffeine is widely used to treat apneas of prematurity during the neonatal period; however, the potential consequences of administering a neonatal caffeine treatment (NCT) during a critical period for respiratory control development are unknown. The present study therefore determined whether NCT in rats alters the hypoxic respiratory chemoreflex measured at adulthood. Newborn rats received either caffeine (15 mg/kg) or water (control) each day from postnatal day 3 to 12. The ventilatory response to a hypoxic challenge (inspired O(2) fraction = 0.12) was first evaluated in awake adult female and male rats using whole body plethysmography. Results showed that NCT increased the initial phase of the breathing frequency response to hypoxia in males only. This result was confirmed in anesthetized and artificially ventilated adult male rats where NCT also increased the phrenic burst frequency response to hypoxia. RT-PCR assessment of mRNA encoding for adenosine A(1A) and A(2A) receptors, dopamine D(2) receptors, and tyrosine hydroxylase in the rat carotid bodies showed that NCT enhanced mRNA expression levels of adenosine A(2A), dopamine D(2) receptors, and tyrosine hydroxylase of males but not females. Subsequent experiments on awake male rats showed that injection of the adenosine A(2A) receptor antagonist ZM2413855 (1 mg/kg ip) before ventilatory measurements abolished, in NCT rats, the enhanced respiratory frequency response observed during the early phase of hypoxia. We propose that NCT elicits a sex-specific increase in the hypoxic respiratory chemoreflex, which is related, at least partially, to an enhancement in adenosine A(2A) receptors in the rat carotid body.     

Effect of hypoxic episode number and severity on ventilatory long-term facilitation in awake rats.

Episodic hypoxia induces a persistent augmentation of respiratory activity, termed long-term facilitation (LTF). Phrenic LTF saturates in anesthetized animals such that additional episodes of stimulation cause no further increase in LTF magnitude. The present study tested the hypothesis that 1) ventilatory LTF also saturates in awake rats and 2) more severe hypoxia and hypoxic episodes increase the effectiveness of eliciting ventilatory LTF. Minute ventilation was measured in awake, male Sprague-Dawley rats by plethysmography. LTF was elicited by five episodes of 10% O(2) poikilocapnic hypoxia (magnitude: 17.3 +/- 2.8% above baseline, between 15 and 45 min posthypoxia, duration: 45 min) but not 12 or 8% O(2). LTF was also elicited by 10, 20, and 72 episodes of 12% O(2) (19.1 +/- 2.2, 18.9 +/- 1.8, and 19.8 +/- 1.6%; 45, 60, and 75 min, respectively) but not by three or five episodes. These results show that there is a certain range of hypoxia that induces ventilatory LTF and that additional hypoxic episodes may increase the duration but not the magnitude of this response.     

Dopamine and ventilatory effects of hypoxia and almitrine in chronically hypoxic rats

We hypothesized that the temporary blunted ventilatory response to hypoxia seen in chronically hypoxic rats could be related to the increased amount of dopamine found in their carotid bodies. Rats, kept 2-3 wk in 10% O2, showed reduced nonisocapnic ventilatory responses to 21-12% inspiratory O2 fraction compared with control rats. Stimulus-response curves to almitrine, which simulates the action of hypoxia on the carotid body, were also depressed in chronically hypoxic rats. Responses to hypoxia and almitrine were significantly correlated in the two groups of rats. Dopamine depressed ventilation during normoxia, hypoxia, and almitrine stimulation in both groups, an action abolished by the dopamine-2 antagonist domperidone. Domperidone slightly increased responses to hypoxia and almitrine in control rats but had a greater enhancing effect in chronically hypoxic rats, such that there was no longer a difference between the responses of the two groups.     

Effects of dopamine on chemoreflexes in breathing

The effects of intravenous infusion of dopamine (20 microgram.min) on the steady-state ventilatory and carotid chemoreceptor responses to successive levels of isocapnic hypoxia and hyperoxic hypercapnia were investigated in cats anesthetized with alpha-chloralose. Dopamine infusion was followed by a maximal decrease in ventilation in about 20 s. Thereafter, the effect diminished and stabilized. Termination of dopamine infusion was promptly followed by an increase in ventilation. These ventilatory responses were smaller than the corresponding carotid chemoreceptor responses. The steady-state effect of dopamine infusion was to diminish ventilation at all levels of arterial O2 tension, the decrease being greater during hypoxia than that during hyperoxia. Bilateral section of the carotid sinus nerves significantly diminished but did not abolish the inhibitory effect of dopamine on ventilation during hyperoxia. Thus the ventilatory depression due to dopamine infusion is not entirely due to its effect on the carotid chemoreceptors. Dopamine decreased ventilatory responses to successive levels of hypercapnia by the same magnitude without changing the slope of the response curves. The steady-state relationship between chemoreceptor activity and ventilation shows that the ventilatory equivalent for carotid chemoreceptor activity is increased during dopamine infusion because of its greater inhibitory effect on carotid chemoreceptor activity than on ventilation with the decrease of arterial O2 tension.     

Ventilatory responses to specific CNS hypoxia in sleeping dogs.

Our study was concerned with the effect of brain hypoxia on cardiorespiratory control in the sleeping dog. Eleven unanesthetized dogs were studied; seven were prepared for vascular isolation and extracorporeal perfusion of the carotid body to assess the effects of systemic [and, therefore, central nervous system (CNS)] hypoxia (arterial PO(2) = 52, 45, and 38 Torr) in the presence of a normocapnic, normoxic, and normohydric carotid body during non-rapid eye movement sleep. A lack of ventilatory response to systemic boluses of sodium cyanide during carotid body perfusion demonstrated isolation of the perfused carotid body and lack of other significant peripheral chemosensitivity. Four additional dogs were carotid body denervated and exposed to whole body hypoxia for comparison. In the sleeping dog with an intact and perfused carotid body exposed to specific CNS hypoxia, we found the following. 1) CNS hypoxia for 5-25 min resulted in modest but significant hyperventilation and hypocapnia (minute ventilation increased 29 +/- 7% at arterial PO(2) = 38 Torr); carotid body-denervated dogs showed no ventilatory response to hypoxia. 2) The hyperventilation was caused by increased breathing frequency. 3) The hyperventilatory response developed rapidly (<30 s). 4) Most dogs maintained hyperventilation for up to 25 min of hypoxic exposure. 5) There were no significant changes in blood pressure or heart rate. We conclude that specific CNS hypoxia, in the presence of an intact carotid body maintained normoxic and normocapnic, does not depress and usually stimulates breathing during non-rapid eye movement sleep. The rapidity of the response suggests a chemoreflex meditated by hypoxia-sensitive respiratory-related neurons in the CNS.     

Ventilatory response to sustained hypoxia after pretreatment with aminophylline

During sustained hypoxia the decline in ventilation that occurs in normal adult humans may be related to central accumulation of a neurochemical with net inhibitory effect. Recent investigations have shown that the putative neurotransmitter adenosine can effect a prolonged respiratory inhibition. Therefore we evaluated the possible role of adenosine in the hypoxia ventilatory decline by employing aminophylline as an adenosine blocker. We evaluated the ventilatory response to 25 min of sustained hypoxia (80% arterial O2 saturation), in eight young adults after pretreatment with either intravenous saline or aminophylline. With a mean serum aminophylline level of 15.7 mg/l, over 25 min of sustained hypoxia, peak hypoxic ventilation decreased by only 12.8% compared with 24.8% with saline, a significant difference. However, the ventilatory decline during sustained hypoxia was not abolished by the aminophylline pretreatment. Unlike the usual tidal volume-dependent attenuation of hypoxic ventilation exhibited after saline, after aminophylline the ventilatory decline was achieved predominantly through alterations in respiratory timing. Thus aminophylline pretreatment did alleviate the hypoxic ventilatory decline, although the associated alterations in breathing pattern were uncharacteristic. We conclude that adenosine may play a contributing role in the hypoxic ventilatory decline.