Intermittent hypoxia reduces cerebrovascular sensitivity to isocapnic hypoxia in humans

The purpose of this study was to determine the changes in human cerebrovascular function associated with intermittent poikilocapnic hypoxia (IH). Healthy men (n=8; 24+/-1 years) were exposed to IH for 10 days (12% O(2) for 5min followed by 5min of normoxia for 1h). During the hypoxic exposures, oxyhemoglobin saturation (SaO(2)) was 85% and the end-tidal partial pressure of CO(2) was permitted to fall as a result of hypoxic hyperventilation. Pre- and post-IH intervention subjects underwent a progressive isocapnic hypoxic test where ventilation, blood pressure, heart rate, and cerebral blood flow velocity (middle cerebral artery, transcranial Doppler) were measured to determine the ventilatory, cardiovascular and cerebrovascular sensitivities to isocapnic hypoxia. When compared to the pre-IH trial, cerebrovascular sensitivity to hypoxia significantly decreased (pre-IH=0.28+/-0.15; post-IH=0.16+/-0.14cms(-1)%SaO(2)(-1); P<0.05). No changes in ventilatory, blood pressure or heart rate sensitivity were observed (P>0.05). We have previously shown that the ability to oxygenate cerebral tissue measured using spatially resolved near infrared spectroscopy is significantly reduced following IH in healthy humans. Our collective findings indicate that intermittent hypoxia can blunt cerebrovascular regulation. Thus, it appears that intermittent hypoxia has direct cerebrovascular effects that can occur in the absence of changes to the ventilatory and neurovascular control systems.     

Cardiorespiratory and cerebrovascular responses to hyperoxic and hypoxic rebreathing: effects of acclimatization to high altitude

We examined the cardiorespiratory and cerebrovascular responses to hyperoxic and hypoxic rebreathing at low attitude and high altitude. We measured ventilation, middle cerebral artery blood flow velocity (MCAv) and arterial blood pressure in conditions of eucapnia, hypocapnia (voluntary hyperventilation) and during hyperoxic and hypoxic rebreathing firstly at low altitude (1400 m) then again at high altitude (3840 m) in five individuals, following 9 days at altitude >5000 m. High altitude was associated with elevations in the blood pressure response to hyperoxic rebreathing, whilst cerebrovascular reactivity was reduced and ventilatory sensitivity was unchanged. During hypoxic rebreathing, whilst ventilatory and blood pressure reactivity were increased (vs. low altitude and hyperoxic rebreathing), cerebrovascular reactivity was preserved. In conclusion, at high altitude there was an enhancement in peripheral but not central chemosensitivity to CO(2); and during hypoxic rebreathing, marked elevations in blood pressure may restore some of the reduction in cerebrovascular CO(2) reactivity, potentially reflecting a pressure-passive relationship in the brain offsetting sympathetic-induced cerebral vasoconstriction.     

Hypercapnic and hypoxic ventilatory responses during growth

Cross-sectional studies on hypercapnic and hypoxic ventilatory chemosensitivities were performed in 71 children ranging in age from 7 to 18 yrs. The subjects were classified into 6 successive 2-year age groups. CO2 ventilatory response was measured by rebreathing 5% CO2 in O2, a slight modification of the method originally proposed by Read. The results were evaluated when the CO2-ventilation feedback control system was supposed to have attained the open-loop condition. Hypoxic ventilatory response was measured by the isocapnic progressive hypoxia test. To obtain good reproducibility in the ventilatory response, end-tidal PCO2 was maintained at 5 mmHg higher than the resting condition throughout the test. Normalized ventilatory responses to CO2 by body surface area (S/BSA) progressively decreased from the 7-8 through the 11-12 yr groups, and then tended to decrease further in a more gradual manner with increasing age. This trend was very similar to the normalized CO2 output (VCO2/BSA), but did not parallel so closely the normalized O2 intake (VO2/BSA). When ventilatory and metabolic parameters were normalized by body weight (BW), or the lean body mass (LBM), qualitatively similar relationships between CO2 sensitivities and metabolic parameters were also obtained. Contrary to the hypercapnic response, hypoxic ventilatory chemosensitivities were not significantly different among the 6 different age groups. We concluded that normalized hypercapnic chemosensitivity decreased during growth and corresponded well with decreased CO2 output per unit body mass.     

Effect of hypoxia on ventilatory and arousal responses to CO2 during NREM sleep with and without flurazepam in young adults

We examined the ventilatory response to CO2 at two levels of oxygenation during wakefulness and sleep in healthy young adults before and after the ingestion of a single dose of 30 mg flurazepam. Progressive hypercapnia was produced at two levels of arterial O2 saturation (greater than 99 and 87%) by having subjects re-breathe from a tight-fitting face mask and a reservoir bag containing gas mixtures with two different O2 concentrations. Ventilation was measured with an inductive plethysmograph. O2 saturation was measured with an ear oximeter. Sleep was monitored using standard techniques by recording the electroencephalogram, eye movements, and chin electromyogram. During wakefulness, hypoxia increased the slope of the ventilatory response to CO2 and shifted the response slightly to the left. NREM sleep lowered the slope of the CO2 response under both hyperoxic and hypoxic conditions. The slope of the hyperoxic CO2 response curve was not affected by flurazepam during wakefulness or sleep. After administration of flurazepam to the subjects, the shift of the CO2 response curve to the left produced by hypoxia (additive effect) during NREM sleep was slightly less as compared to control, but hypoxia still increased the slope of the CO2 ventilatory response. During hypoxic hypercapnia, the PCO2 at arousal from sleep was significantly lower than during hyperoxic hypercapnia, but the level of ventilation at arousal during hypercapnia was similar in the control condition and after flurazepam. We conclude that (a) both natural and flurazepam-induced sleep depress ventilatory responses to hyperoxic and hypoxic hypercapnia and alter, in a complex fashion, the effects of hypoxia and hypercapnia on ventilation; and (b) hypoxia and hypercapnia interact as arousal stimuli in both natural and flurazepam-induced sleep.     

Relative peripheral and central chemosensory responses to metabolic alkalosis

We investigated the relative contribution of peripheral and central chemosensory mechanisms to ventilatory responses to metabolic alkalosis in anesthetized cats by simultaneously measuring steady-state carotid body chemosensory activity and ventilation. The effects of graded steady-state levels of metabolic alkalosis at constant levels of arterial O2 and CO2 partial pressure (PaO2 and PaCO2, respectively) were studied first. Then the responses to isocapnic hypoxia and hyperoxic hypercapnia before and after the induction of a given level of metabolic alkalosis were studied. From the relationship between the carotid chemosensory activity and ventilation, the contribution of the two chemosensory mechanisms was estimated. The depression of ventilation that could not be accounted for by a decrease in the carotid chemosensory activity is attributed to the central effect. We found that metabolic alkalosis decreased both carotid chemosensory activity and ventilation at all levels of PaO2 or PaCO2. The ventilatory effect of alkalosis increased during hypoxia due to suppression of both peripheral chemosensory input and its interaction with the central CO2-H+ drive. During hyperoxia the central effect of alkalosis was predominant, although the peripheral effect increased with hypercapnia. We conclude that acute metabolic alkalosis suppresses both peripheral and central chemosensory drives, and its ventilatory effect grows larger with decreasing PaO2.     

Carotid sinus nerve responses and ventilatory acclimatization to hypoxia in adult rats following 2 weeks of postnatal hyperoxia

Adult rats have decreased carotid body volume and reduced carotid sinus nerve, phrenic nerve, and ventilatory responses to acute hypoxic stimulation after exposure to postnatal hyperoxia (60% O2, PNH) during the first 4 weeks of life. Moreover, sustained hypoxic exposure (12%, 7 days) partially reverses functional impairment of the acute hypoxic phrenic nerve response in these rats. Similarly, 2 weeks of PNH results in the same phenomena as above except that ventilatory responses to acute hypoxia have not been measured in awake rats. Thus, we hypothesized that 2-week PNH-treated rats would also exhibit blunted chemoafferent responses to acute hypoxia, but would exhibit ventilatory acclimatization to sustained hypoxia. Rats were born into, and exposed to PNH for 2 weeks, followed by chronic room-air exposure. At 3-4 months of age, two studies were performed to assess: (1) carotid sinus nerve responses to asphyxia and sodium cyanide in anesthetized rats and (2) ventilatory and blood gas responses in awake rats before (d0), during (d1 and d7), and 1 day following (d8) sustained hypoxia. Carotid sinus nerve responses to i.v. NaCN and asphyxia (10 s) were significantly reduced in PNH-treated versus control rats; however, neither the acute hypoxic ventilatory response nor the time course or magnitude of ventilatory acclimatization differed between PNH and control rats despite similar levels of PaO2 . Although carotid body volume was reduced in PNH rats, carotid body volumes increased during sustained hypoxia in both PNH and control rats. We conclude that normal acute and chronic ventilatory responses are related to retained (though impaired) carotid body chemoafferent function combined with central neural mechanisms which may include brainstem hypoxia-sensitive neurons and/or brainstem integrative plasticity relating both central and peripheral inputs.     

Pronounced depression by propofol on carotid body response to CO2 and K+-induced carotid body activation

Propofol is a commonly used anesthetic agent, and it attenuates hypoxic ventilatory response in humans. Propofol reduce in vivo and in vitro carotid body responses to hypoxia as well as to nicotine in experimental animals. In the present study we examined the effects of propofol on carotid body responses to hypercapnia and K(+)-induced carotid body activation and compared these effects with hypoxia in an in vitro rabbit carotid body preparation. Hypoxia, hypercapnia and potassium increased the carotid sinus nerve activity and propofol attenuated the chemoreceptor responses to all three stimuli. However, the magnitude of propofol-induced attenuation was greater for hypercapnic and K(+)-induced carotid body activation compared to the hypoxic response. These observations suggest that propofol-induced attenuation of the hypoxic response is partly secondary to depression of chemoreceptor response to hypercapnia inhibiting the synergistic interactions between O(2) and CO(2) and may involve CO(2)/H(+) sensitive K(+) channels.     

Ventilation- and carotid chemoreceptor discharge-response to hypoxia during induced hypothermia in halothane anesthetized rat

It has been hypothesized that respiratory "gain" to hypoxic stimulus is not depressed in hypothermic animals though ventilation and that metabolic O(2) demand (Vo(2)) decreases with reduction in body temperature. The present study addressed this hypothesis by quantitative analysis of ventilatory and carotid chemoreceptor responsiveness to hypoxia during induced hypothermia in halothane anesthetized and spontaneously breathing rats. Rectal temperature was lowered from 37 degrees C (normothermia) to 30 and 25 degrees C by cooling body surface at comparable anesthetic depth without inducing shivering. Ventilation (V(E)), V(O2), PaO(2) and carotid chemoreceptor afferent discharges were measured during hyperoxic and hypoxic gas breathing. PaO(2) values at the same Fi(O2) (range 0. 35-0.08) decreased progressively as rectal temperature decreased. Both the V(E)/V(O2)- and chemoreceptor discharge-response curves shifted toward a lower PaO(2) range with a slight increase in the response slopes during hypothermia. The results indicated that the sensitivity of carotid chemoreceptor and ventilatory responses to hypoxia did not decrease at reduced body temperature. It is concluded that carotid chemoreceptor mediated regulation of ventilation is tightly coupled to changes in PaO(2 )range in halothane anesthetized rats during induced hypothermia.     

Protocol to measure acute cerebrovascular and ventilatory responses to isocapnic hypoxia in humans

This study describes a protocol to determine acute cerebrovascular and ventilatory (AHVR) responses to hypoxia. Thirteen subjects undertook a protocol twice, 5 days apart. The protocol started with 8 min of eucapnic euoxia (end-tidal P(CO2) (PET(CO2)= 1.5 Torr) above rest; end-tidal P(O2) (PET(O2)) = 88 Torr) followed by six descending 90 s hypoxic steps (PET(O2) = 75.2, 64.0, 57.0, 52.0, 48.2, 45.0 Torr). Then, PET(O2) was elevated to 300 Torr for 10 min while PET(O2) remained at eucapnia (5 min) then raised by 7.5 Torr (5 min). Peak blood flow velocity in the middle cerebral artery (MCA) and regional cerebral oxygen saturation (Sr(O2)) were measured with transcranial Doppler ultrasound and near-infrared spectroscopy, respectively, and indices of acute hypoxic sensitivity were calculated (AHR(CBF) and AHRSr(O2)). Values for AHR(CBF), AHRSr(O2) and AHVR were 0.43 cm s(-1) % desaturation(-1), 0.80% % desaturation(-1) and 1.24l min(-1) % desaturation(-1), respectively. Coefficients of variation for AHR(CBF), AHRSr(O2) and AHVR were small (range = 8.0-15.2%). This protocol appears suitable to quantify cerebrovascular and ventilatory responses to acute isocapnic hypoxia.     

The effects of hypo- and hyperglycaemia on the hypoxic ventilatory response in humans

Animal and tissue studies have indicated that the carotid bodies are sensitive to glucose concentrations within the physiological range. This glucose sensitivity may modulate the ventilatory response to hypoxia, with hyperglycaemia suppressing the hypoxic response and hypoglycaemia stimulating it. This study was designed to determine whether hypo- and hyperglycaemia modulate the hypoxic ventilatory response in humans. In 11 normal research participants, glucose levels were clamped at 2.8 and 11.2 mmol l⁻¹ for 30 min. At the start and end of each clamp, blood was drawn for hormone measurement and the isocapnic hypoxic ventilatory response was measured. Because generation of reactive oxygen species may be a common pathway for the interaction between glucose and oxygen levels, the experiments were repeated with and without pretreatment for 1 week with vitamins C and E. Hypoglycaemia caused an increase in the counter-regulatory hormones, a 54% increase in isocapnic ventilation, and a 108% increase in the hypoxic ventilatory response. By contrast, hyperglycaemia resulted in small but significant increases in both ventilation and the hypoxic ventilatory response. Antioxidant vitamin pretreatment altered neither response. In conclusion, the stimulant effect of hypoglycaemia on the hypoxic ventilatory response is consistent with a direct effect on the carotid body, but an indirect effect through the activation of the counter-regulatory response cannot be excluded. The mechanisms behind the mild stimulating effect of hyperglycaemia remain to be elucidated.     

Effect of hypoxia and hyperoxia on cardiorespiratory responses during exercise in man

To clarify the role of the carotid body in the mechanism governing exercise hyperpnea, the effect of hypoxia and hyperoxia on ventilation and cardiac output was studied in four healthy men. The VE increased 10.7% in hypoxia and decreased 10.1% in hyperoxia from normoxia as judged from the steady-state values during exercise. On the contrary, Q showed only a slight reduction of -3.2% in hyperoxia. The hypoxic hyperpnea and hyperoxic hypopnea led to a concomitant alteration in PETCO2. An overshoot following the onset of exercise was observed during the first 30s of VE response in hypoxia, which damped progressively in normoxia and hyperoxia. No remarkable difference was observed in the early transient responses of Q between hypoxia and hyperoxia. The discrepancy in the dynamics between VE and Q led to a phasic deviation in PETCO2; an isocapnic transition from the control to stimulus period in normoxia, hypocapnic in hypoxia and hypercapnic in hyperoxia. The time constant representing the kinetics of VE and that for VCO2 prolonged significantly in hyperoxia. These results support the cardiodynamic consequence of exercise hyperpnea, i.e., the carotid body is the first to respond to the increase in CO2 flow into the lungs.     

Multi-organ system model of O2 and CO2 transport during isocapnic and poikilocapnic hypoxia

A multi-organ systems model of O(2) and CO(2) transport is developed to analyze the control of ventilation and blood flow during hypoxia. Among the aspects of the control processes that this model addressed are possible mechanisms responsible for the second phase of the ventilatory hypoxic response to mild hypoxia, i.e., hypoxic ventilatory decline (HVD). Species mass transport processes are described by compartmental mass balances in brain, heart, skeletal muscle, and "other tissues" connected in parallel via the circulation. In pulmonary and systemic capillaries and in the vasculature connecting the systemic tissues, species transport processes are represented by a one-dimensional, convection-dispersion model. The effects of bicarbonate acid-base buffering, hemoglobin, and myoglobin on the transport processes are included. The model incorporates feedback control mechanisms through a cardiorespiratory control system in which peripheral and central chemoreceptors sense O(2) and CO(2) partial pressures. Model simulations of the ventilatory responses to isocapnic and poikilocapnic hypoxia show two phases with distinct dynamics. A fast phase is discernable immediately after switching from normoxic to hypoxic conditions, while a delayed slow phase (HVD) typically becomes manifested after several minutes. Model simulations allow quantitative evaluation of several proposed mechanisms to account for HVD. Under isocapnic hypoxia, simulations indicate that an increase in brain blood flow has no effect on HVD, but that HVD can be entirely described by central ventilatory depression (CVD). Under poikilocapnic hypoxia, the hypocapnia caused by hypoxic hyperventilation has no effect on HVD.     

Ventilatory responses and carotid body function in adult rats perinatally exposed to hyperoxia

Hypoxia increases the release of neurotransmitters from chemoreceptor cells of the carotid body (CB) and the activity in the carotid sinus nerve (CSN) sensory fibers, elevating ventilatory drive. According to previous reports, perinatal hyperoxia causes CSN hypotrophy and varied diminishment of CB function and the hypoxic ventilatory response. The present study aimed to characterize the presumptive hyperoxic damage. Hyperoxic rats were born and reared for 28 days in 55%–60% O₂; subsequent growth (to 3.5–4.5 months) was in a normal atmosphere. Hyperoxic and control rats (born and reared in a normal atmosphere) responded with a similar increase in ventilatory frequency to hypoxia and hypercapnia. In comparison with the controls, hyperoxic CBs showed (1) half the size, but comparable percentage area positive to tyrosine hydroxylase (chemoreceptor cells) in histological sections; (2) a twofold increase in dopamine (DA) concentration, but a 50% reduction in DA synthesis rate; (3) a 75% reduction in hypoxia-evoked DA release, but normal high [K⁺]₀-evoked release; (4) a 75% reduction in the number of hypoxia-sensitive CSN fibers (although responding units displayed a nearly normal hypoxic response); and (5) a smaller percentage of chemoreceptor cells that increased [Ca²⁺]₁ in hypoxia, although responses were within the normal range. We conclude that perinatal hyperoxia causes atrophy of the CB–CSN complex, resulting in a smaller number of chemoreceptor cells and fibers. Additionally, hyperoxia damages O₂-sensing, but not exocytotic, machinery in most surviving chemoreceptor cells. Although hyperoxic CBs contain substantially smaller numbers of chemoreceptor cells/sensory fibers responsive to hypoxia they appear sufficient to evoke normal increases in ventilatory frequency.     

Differential sensitivity to hypoxic inhibition of respiratory processes in the anesthetized rat

To estimate the sensitivity to hypoxic inhibition of various regulatory processes for respiration, changes in breathing pattern during hypoxic ventilatory depression (HVD) were analyzed in the halothane-anesthetized spontaneously breathing rat using a "progressive isocapnic hypoxia test." In the carotid sinus nerve (CSN) intact rats, ventilatory augmentation was followed by depression due to reduction in respiratory frequency (f) at end-tidal PO2 (PETO2) levels below 50-60 mmHg despite increased afferent activities from the carotid chemoreceptors. After CSN section, ventilation was progressively depressed at PETO2 lower than normoxic level with simultaneous decreases of f and tidal volume. An increase in CO2 stimulus or the prevention of arterial hypotension during hypoxia by infusing a vasoconstrictor agent (phenylephrine) inhibited the occurrence of ventilatory depression in both the CSN intact and denervated animals. In all cases studied, the reduction in f resulted mainly from the prolongation of expiratory time (TE). The results suggest that in the anesthetized rat the effect of respiratory stimulation from carotid chemoreceptor afferents becomes inadequate to offset the prolongation of TE due to the central hypoxia at lower PETO2, and that the neural process for regulating TE is the major site of deterioration during central hypoxic inhibition. Roles of CO2 stimulus and systemic circulatory conditions in the generation of HVD were also discussed.     

Bilateral carotid body resection in man enhances hypoxic tachycardia

In three groups of subjects we studied heart rate (HR) and ventilatory responses to progressive eucapnic hypoxia, steady-state hypercapnia with and without hypoxia, and hyperoxic and hypoxic breathholding (BH). Groups were six subjects about 25 years after bilateral carotid body resection (BR), eight subjects of an equally long period after unilateral resection (UR), and three control subjects similar to the study groups in age and pulmonary function (C). During progressive hypoxia, HR increased more in BR than in UR and C subjects. Ventilatory response was lowest in BR subjects (as expected). Steady-state hypoxic hypercapnia (end-tidal PO2, 60 Torr) depressed HR significantly more in C than in BR and UR subjects. Again, ventilatory response was lower in BR than in C subjects. HR progressively increased during BH initiated in hyperoxia (end-tidal PO2, 200 Torr) and hypoxia (end-tidal PO2, 70 Torr). In the BR group, the HR increment during hypoxia was significantly larger than that during hyperoxia. No such difference was apparent in UR and C groups. Thus, hypoxia with or without hypercapnia tends to accelerate HR in BR subjects whereas either less tachycardia or slowing is seen in UR and C subjects.     

Chronic intermittent hypoxia enhances cat chemosensory and ventilatory responses to hypoxia

The carotid body (CB) chemoreceptors may play an important role in the enhanced hypoxic ventilatory response induced by chronic intermittent hypoxia (CIH). We studied the effects of cyclic hypoxic episodes of short duration on cat cardiorespiratory reflexes, heart rate variability, and CB chemosensory activity. Cats were exposed to cyclic hypoxic episodes  ( P _O2∼ 75 Torr)  repeated during 8 h for 2–4 days. Cats were anaesthetized with sodium pentobarbitone (40 mg kg⁻¹ i.p. , followed by 8–12 mg i.v. ), and ventilatory and cardiovascular responses to NaCN (0.1–100 μg kg⁻¹ i.v. ) and several isocapnic levels of oxygen  ( P _O2∼ 20–740 Torr)  were studied. After studying the reflex responses, we recorded the CB chemosensory responses induced by the same stimuli. Results showed that CIH for 4 days selectively enhanced cat CB ventilatory ( V _T and V _I) responses to hypoxia, while responses to NaCN remained largely unchanged. Similarly, basal CB discharges and responses to acute hypoxia  ( P _O2 < 100 Torr)  were larger in CIH than in control cats, without modification of the responses to NaCN. Exposure to CIH did not increase basal arterial pressure, heart rate, or their changes induced by acute hypoxia or hyperoxia. However, the spectral analysis of heart rate variability of CIH cats showed a marked increase of the low-/high-frequency ratio and an increase of the power spectral distribution of low frequencies of heart rate variability. Thus, the enhanced CB reactivity to hypoxia may contribute to the augmented ventilatory response to hypoxia, as well as to modified heart rate variability due to early changes in autonomic activity.     

Increased hypoxic ventilatory response during 8 weeks at 3800 m altitude

Acclimatization to chronic hypoxia (CH) increases ventilation (V(I)) and the isocapnic hypoxic ventilatory response (HVR) over 2-14 days but hypoxic desensitization blunts the HVR after years of CH. We tested for hypoxic desensitization during the first 2 months of CH by studying five normal subjects at sea level (SL) and for 8 weeks at 3800 m (CH, PI(O(2)) approximately 90 Torr). We measured the isocapnic HVR (Delta V(I)/Delta Sa(O(2)) and tested for hypoxic ventilatory decline (HVD) by stepping Sa(O(2)) to 80% after 14 min at 90%. The HVR increased significantly after 2 days and remained significantly elevated for 8 weeks of CH. HVD was similar at SL and during 8 weeks of CH. Hence, hypoxic desensitization of the HVR does not occur after only 8 weeks of hypoxia and the increased HVR during this time does not involve changes in HVD.     

Measuring the ventilatory response to hypoxia

After defining the current approach to measuring the hypoxic ventilatory response this paper explains why this method is not appropriate for comparisons between individuals or conditions, and does not adequately measure the parameters of the peripheral chemoreflex. A measurement regime is therefore proposed that incorporates three procedures. The first procedure measures the peripheral chemoreflex responsiveness to both hypoxia and CO₂ in terms of hypoxia's effects on the sensitivity and ventilatory recruitment threshold of the peripheral chemoreflex response to CO₂. The second and third procedures employ current methods for measuring the isocapnic and poikilocapnic ventilatory responses to hypoxia, respectively, over a period of 20 min. The isocapnic measure is used to determine the time course characteristics of hypoxic ventilatory decline and the poikilocapnic measure shows the ventilatory response to a hypoxic environment. A measurement regime incorporating these three procedures will permit a detailed assessment of the peripheral chemoreflex response to hypoxia that allows comparisons to be made between individuals and different physiological and environmental conditions.     

Respiratory plasticity after perinatal hyperoxia is not prevented by antioxidant supplementation

Perinatal hyperoxia attenuates the hypoxic ventilatory response in rats by altering development of the carotid body and its chemoafferent neurons. In this study, we tested the hypothesis that hyperoxia elicits this plasticity through the increased production of reactive oxygen species (ROS). Rats were born and raised in 60% O(2) for the first two postnatal weeks while treated with one of two antioxidants: vitamin E (via milk from mothers whose diet was enriched with 1000 IU vitamin E kg(-1)) or a superoxide dismutase mimetic, manganese(III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP; via daily intraperitoneal injection of 5-10 mg kg(-1)); rats were subsequently raised in room air until studied as adults. Peripheral chemoreflexes, assessed by carotid sinus nerve responses to cyanide, asphyxia, anoxia and isocapnic hypoxia (vitamin E experiments) or by hypoxic ventilatory responses (MnTMPyP experiments), were reduced after perinatal hyperoxia compared to those of normoxia-reared controls (all P<0.01); antioxidant treatment had no effect on these responses. Similarly, the carotid bodies of hyperoxia-reared rats were only one-third the volume of carotid bodies from normoxia-reared controls (P <0.001), regardless of antioxidant treatment. Protein carbonyl concentrations in the blood plasma, measured as an indicator of oxidative stress, were not increased in neonatal rats (2 and 8 days of age) exposed to 60% O(2) from birth. Collectively, these data do not support the hypothesis that perinatal hyperoxia impairs peripheral chemoreceptor development through ROS-mediated oxygen toxicity.     

Low-dose acetazolamide reduces the hypoxic ventilatory response in the anesthetized cat

Low intravenous dose acetazolamide causes a decrease in steady-state CO(2) sensitivity of both the peripheral and central chemoreflex loops. The effect, however, on the steady-state hypoxic response is unknown. In the present study, we measured the effect of 4 mg x kg(-1) acetazolamide (i.v.) on the isocapnic steady-state hypoxic response in anesthetized cats. Before and after acetazolamide administration, the eucapnic steady-state hypoxic response in these animals was measured by varying inspiratory P(O2) levels to achieve steady-state Pa(O2) levels between hyperoxia Pa(O2) approximately 55 kPa, approximately 412 mmHg) and hypoxia (Pa(O2) approximately 7 kPa, approximately 53 mmHg). The hypoxic ventilatory response was described by the exponential function V(I) = G exp (-DP(o2) + A with an overall hypoxic sensitivity G, a shape parameter D and ventilation during hyperoxia A. Acetazolamide significantly reduced G from 3.057 +/- 1.616 to 1.573 +/- 0.8361 min(-1) (mean +/- S D). Parameter A increased from 0.903 +/- 0.257 to 1.193 +/- 0.321 min(-1), while D remained unchanged. The decrease in overall hypoxic sensitivity by acetazolamide is probably mediated by an inhibitory effect on the carotid bodies and may have clinical significance in the treatment of sleep apneas, particularly those cases that are associated with an increased ventilatory sensitivity to oxygen and/or carbon dioxide.