No effect of brain blood flow on ventilatory depression during sustained hypoxia

Minute ventilation (VE) during sustained hypoxia is not constant but begins to decline within 10-25 min in adult humans. The decrease in brain tissue PCO2 may be related to this decline in VE, because hypoxia causes an increase in brain blood flow, thus resulting in enhanced clearance of CO2 from the brain tissue. To examine the validity of this hypothesis, we measured VE and arterial and internal jugular venous blood gases simultaneously and repeatedly in 15 healthy male volunteers during progressive and subsequent sustained isocapnic hypoxia (arterial PO2 = 45 Torr) for 20 min. It was assumed that jugular venous PCO2 was an index of brain tissue PCO2. Mean VE declined significantly from the initial (16.5 l/min) to the final phase (14.1 l/min) of sustained hypoxia (P less than 0.05). Compared with the control (50.9 Torr), jugular venous PCO2 significantly decreased to 47.4 Torr at the initial phase of hypoxia but did not differ among the phases of hypoxia (47.2 Torr for the intermediate phase and 47.7 Torr for the final phase). We classified the subjects into two groups by hypoxic ventilatory response during progressive hypoxia at the mean value. The decrease in VE during sustained hypoxia was significant in the low responders (n = 9) [13.2 (initial phase) to 9.3 l/min (final phase of hypoxia), P less than 0.01], but not in the high responders (n = 6) (20.9-21.3 l/min, NS). This finding could not be explained by the change of arterial or jugular venous gases, which did not significantly change during sustained hypoxia in either group.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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.     

Effects of CO2 breathing on ventilatory response to sustained hypoxia in normal adults

The relationship between CO2 and ventilatory response to sustained hypoxia was examined in nine normal young adults. At three different levels of end-tidal partial pressure of CO2 (PETCO2, approximately 35, 41.8, and 44.3 Torr), isocapnic hypoxia was induced for 25 min and after 7 min of breathing 21% O2, isocapnic hypoxia was reinduced for 5 min. Regardless of PETCO2 levels, the ventilatory response to sustained hypoxia was biphasic, characterized by an initial increase (acute hypoxic response, AHR), followed by a decline (hypoxic depression). The biphasic response pattern was due to alteration in tidal volume, which at all CO2 levels decreased significantly (P less than 0.05), without a significant change in breathing frequency. The magnitude of the hypoxic depression, independent of CO2, correlated significantly (r = 0.78, P less than 0.001) with the AHR, but not with the ventilatory response to CO2. The decline of minute ventilation was not significantly affected by PETCO2 [averaged 2.3 +/- 0.6, 3.8 +/- 1.3, and 4.5 +/- 2.2 (SE) 1/min for PETCO2 35, 41.8, and 44.3 Torr, respectively]. This decay was significant for PETCO2 35 and 41.8 Torr but not for 44.3 Torr. The second exposure to hypoxia failed to elicit the same AHR as the first exposure; at all CO2 levels the AHR was significantly greater (P less than 0.05) during the first hypoxic exposure than during the second. We conclude that hypoxia exhibits a long-lasting inhibitory effect on ventilation that is independent of CO2, at least in the range of PETCO2 studied, but is related to hypoxic ventilatory sensitivity.     

Effects of adenosine on ventilatory responses to hypoxia and hypercapnia in humans

Adenosine infusion (100 micrograms X kg-1 X min-1) in humans stimulates ventilation but also causes abdominal and chest discomfort. To exclude the effects of symptoms and to differentiate between a central and peripheral site of action, we measured the effect of adenosine infused at a level (70-80 micrograms X kg-1 X min-1) below the threshold for symptoms. Resting ventilation (VE) and progressive ventilatory responses to isocapnic hypoxia and hyperoxic hypercapnia were measured in six normal men. Compared with a control saline infusion given single blind on the same day, adenosine stimulated VE [mean increase: 1.3 +/- 0.8 (SD) l/min; P less than 0.02], lowered resting end-tidal PCO2 (PETCO2) (mean fall: -3.9 +/- 0.9 Torr), and increased heart rate (mean increase: 16.1 +/- 8.1 beats/min) without changing systemic blood pressure. Adenosine increased the hypoxic ventilatory response (control: -0.68 +/- 0.4 l X min-1 X %SaO2-1, where %SaO2 is percent of arterial O2 saturation; adenosine: -2.40 +/- 1.2 l X min-1 X %SaO2-1; P less than 0.01) measured at a mean PETCO2 of 38.3 +/- 0.6 Torr but did not alter the hypercapnic response. This differential effect suggests that adenosine may stimulate ventilation by a peripheral rather than a central action and therefore may be involved in the mechanism of peripheral chemoreception.     

Respiratory control in humans after 8 h of lowered arterial PO2, hemodilution, or carboxyhemoglobinemia.

In humans exposed to 8 h of isocapnic hypoxia, there is a progressive increase in ventilation that is associated with an increase in the ventilatory sensitivity to acute hypoxia. To determine the relative roles of lowered arterial PO2 and oxygen content in generating these changes, the acute hypoxic ventilatory response was determined in 11 subjects after four 8-h exposures: 1) protocol IH (isocapnic hypoxia), in which end-tidal PO2 was held at 55 Torr and end-tidal PCO2 was maintained at the preexposure value; 2) protocol PB (phlebotomy), in which 500 ml of venous blood were withdrawn; 3) protocol CO, in which carboxyhemoglobin was maintained at 10% by controlled carbon monoxide inhalation; and 4) protocol C as a control. Both hypoxic sensitivity and ventilation in the absence of hypoxia increased significantly after protocol IH (P < 0.001 and P < 0.005, respectively, ANOVA) but not after the other three protocols. This indicates that it is the reduction in arterial PO2 that is primarily important in generating the increase in the acute hypoxic ventilatory response in prolonged hypoxia. The associated reduction in arterial oxygen content is unlikely to play an important role.     

Ventilatory acclimatization to hypoxia is not dependent on arterial hypoxemia

Goats were prepared so that one carotid body (CB) could be perfused with blood in which the gas tensions could be controlled independently from the blood perfusing the systemic arterial system, including the brain. Since one CB is functionally adequate, the nonperfused CB was excised. To determine whether systemic arterial hypoxemia is necessary for ventilatory acclimatization to hypoxia (VAH), the CB was perfused with hypoxic normocapnic blood for 6 h [means +/- SE: partial pressure of carotid body O2 (PcbO2), 40.6 +/- 0.3 Torr; partial pressure of carotid body CO2 (PcbCO2), 38.8 +/- 0.2 Torr] while the awake goat breathed room air to maintain systemic arterial normoxia. In control periods before and after CB hypoxia the CB was perfused with hyperoxic normocapnic blood. Changes in arterial PCO2 (PaCO2) were used as an index of changes in ventilation. Acute hypoxia (0.5 h of hypoxic perfusion) resulted in hyperventilation sufficient to reduce average PaCO2 by 6.7 Torr from control (P less than 0.05). Over the subsequent 5.5 h of hypoxic perfusion, average PaCO2 decreased further, reaching 4.8 Torr below that observed acutely (P less than 0.05). Acute CB hyperoxic perfusion (20 min) following 6 h of hypoxia resulted in only partial restoration of PaCO2 toward control values; PaCO2 remained 7.9 Torr below control (P less than 0.05). The progressive hyperventilation that occurred during and after 6 h of CB hypoxia with concomitant systemic normoxia is similar to that occurring with total body hypoxia. We conclude that systemic (and probably brain) hypoxia is not a necessary requisite for VAH.     

Dynamics of the ventilatory response to central hypoxia in cats

The dynamics of the effect of central hypoxia on ventilation were investigated by the technique of artificial perfusion of the brain stem in alpha-chloralose-urethan-anesthetized cats. A two-channel roller pump and a four-way valve allowed switching the gas exchanger into and out of the extracorporeal circuit which controlled the brain stem perfusion. When isocapnic hypoxia (arterial PO2 range 18-59 Torr) was limited to the brain stem, a decline in ventilation was consistently found. In 12 cats 47 steps into and 48 steps out of central hypoxia were made. The ventilatory response was fitted using least squares with a model that consisted of a latency followed by a single-exponential function. The latencies for the steps into and out of hypoxia were not significantly different (P = 0.14) and were 32.3 +/- 4.0 and 25.1 +/- 3.6 (SE) s, respectively. The time constant for the steps into hypoxia (149.7 +/- 8.5 s) was significantly longer (P = 0.0002) than for the steps out of hypoxia (105.5 +/- 10.1 s). The time constants for the increase and decrease in ventilation after step changes in the central arterial PCO2 found in a previous study (J. Appl. Physiol. 66: 2168-2172, 1989) were not significantly different (P greater than 0.2) from the corresponding time constants in this study (for 7 cats common to both studies). Theories of the mechanisms behind hypoxic ventilatory decline need to account for the long latency, the similarity between the time constants for the ventilatory response to O2 and CO2, and the differences between the time constants for increasing and decreasing ventilation.     

Increased carotid body hypoxic sensitivity during acclimatization to hypobaric hypoxia

Mechanisms of ventilatory acclimatization to chronic hypoxia remain unclear. To determine whether the sensitivity of peripheral chemoreceptors to hypoxia increases during acclimatization, we measured ventilatory and carotid sinus nerve responses to isocapnic hypoxia in seven cats exposed to simulated altitude of 15,000 ft (barometric pressure = 440 Torr) for 48 h. A control group (n = 7) was selected for hypoxic ventilatory responses matched to the preacclimatized measurements of the experimental group. Exposure to 48 h of hypobaric hypoxia produced acclimatization manifested as decrease in end-tidal PCO2 (PETCO2) in normoxia (34.5 +/- 0.9 Torr before, 28.9 +/- 1.2 after the exposure) as well as in hypoxia (28.1 +/- 1.9 Torr before, 21.8 +/- 1.9 after). Acclimatization produced an increase in hypoxic ventilatory response, measured as the shape parameter A (24.9 +/- 2.6 before, 35.2 +/- 5.6 after; P less than 0.05), whereas values in controls remained unchanged (25.7 +/- 3.2 and 23.1 +/- 2.7; NS). Hypoxic exposure was associated with an increase in the carotid body response to hypoxia, similarly measured as the shape parameter A (24.2 +/- 4.7 in control, 44.5 +/- 8.2 in acclimatized cats). We also found an increased dependency of ventilation on carotid body function (PETCO2 increased after unilateral section of carotid sinus nerve in acclimatized but not in control animals). These results suggest that acclimatization is associated with increased hypoxic ventilatory response accompanied by enhanced peripheral chemoreceptor responsiveness, which may contribute to the attendant rise in ventilation.     

Depression of ventilation hypoxia in man.

In five normal male subjects, ventilation, PaO2, and PaCO2 were measured during the rapid progressive isocapnic production of hypoxia (5 min) and during the equally rapid isocapnic reversal of hypoxia. At similar PaO2, PaCO2, and pH, ventilation was less at a time when alveolar PO2 was increasing than when alveolar PO2 was decreasing. We interpret these results as showing that human ventilation is depressed by mild-to-moderate hypoxia (40-60 Torr), that such depression is probably central, and that it is ordinarily masked by peripheral chemoreceptor stimulation. We are not able to distinguish whether the ventilatory depression is caused by decreased central chemoreceptor PCO2 due to an increase in cerebral flow, direct hypoxic depressing of the central respiratory mechanism, or both.     

Triangularis sterni and phrenic nerve responses to progressive brain hypoxia.

Activity of the respiratory muscles that are not normally active during eupnea (genioglossal and abdominal) has been shown to be more vulnerable to hypoxic depression than inspiratory diaphragmatic activity. We hypothesized that respiratory muscles that are active at eupnea would be equally vulnerable to isocapnic progressive brain hypoxia (PBH). Phrenic (PHR) and triangularis sterni nerve (TSN) activity were recorded in anesthetized peripherally chemodenervated vagotomized ventilated cats. Hypercapnia [arterial PCO2 (PaCO2) = 57 +/- 3 (SE) Torr] produced parallel increases in peak PHR and TSN activity. PBH [0.5% CO-40% O2-59.5% N2, arterial O2 content (CaO2) reduced from 13.1 +/- 1.0 to 3.7 +/- 0.3 vol%] resulted in parallel decreases of peak PHR and TSN activity to neural apnea. PBH was continued until PHR gasping ensued (CaO2 = 2.9 +/- 0.2 vol%); TSN activity remained silent during gasping. After 6-12 min of recovery (95% O2-5% CO2; CaO2 = 7.8 +/- 0.8 vol%; PaCO2 = 55 +/- 2 Torr), peak PHR activity was increased to 110 +/- 18% (% of activity at 9% CO2) whereas peak TSN activity was augmented to 269 +/- 89%. The greater augmentation of TSN activity during the recovery period could not be explained solely by hypercapnia. In conclusion, we found that 1) TSN expiratory and PHR inspiratory activities are equally vulnerable to hypoxic depression and 2) recovery from severe hypoxia is characterized by a profound augmentation of TSN expiratory activity.     

Cerebral oxygen availability by NIR spectroscopy during transient hypoxia in humans

The effects of mild hypoxia on brain oxyhemoglobin, cytochrome a,a3 redox status, and cerebral blood volume were studied using near-infrared spectroscopy in eight healthy volunteers. Incremental hypoxia reaching 70% arterial O2 saturation was produced in normocapnia [end-tidal PCO2 (PETCO2) 36.9 +/- 2.6 to 34.9 +/- 3.4 Torr] or hypocapnia (PETCO2 32.8 +/- 0.6 to 23.7 +/- 0.6 Torr) by an 8-min rebreathing technique and regulation of inspired CO2. Normocapnic hypoxia was characterized by progressive reductions in arterial PO2 (PaO2, 89.1 +/- 3.5 to 34.1 +/- 0.1 Torr) with stable PETCO2, arterial PCO2 (PaCO2), and arterial pH and resulted in increases in heart rate (35%) systolic blood pressure (14%), and minute ventilation (5-fold). Hypocapnic hypoxia resulted in progressively decreasing PaO2 (100.2 +/- 3.6 to 28.9 +/- 0.1 Torr), with progressive reduction in PaCO2 (39.0 +/- 1.6 to 27.3 +/- 1.9 Torr), and an increase in arterial pH (7.41 +/- 0.02 to 7.53 +/- 0.03), heart rate (61%), and ventilation (3-fold). In the brain, hypoxia resulted in a steady decline of cerebral oxyhemoglobin content and a decrease in oxidized cytochrome a,a3. Significantly greater loss of oxidized cytochrome a,a3 occurred for a given decrease in oxyhemoglobin during hypocapnic hypoxia relative to normocapnic hypoxia. Total blood volume response during hypoxia also was significantly attenuated by hypocapnia, because the increase in volume was only half that of normocapnic subjects. We conclude that cytochrome a,a3 oxidation level in vivo decreases at mild levels of hypoxia. PaCO is an important determinant of brain oxygenation, because it modulates ventilatory, cardiovascular, and cerebral O2 delivery responses to hypoxia.     

Brain hypoxia preferentially stimulates genioglossal EMG responses to CO2

Although the dominant respiratory response to hypoxia is stimulation of breathing via the peripheral chemoreflex, brain hypoxia may inhibit respiration. We studied the effects of two levels of brain hypoxia without carotid body stimulation, produced by inhalation of CO, on ventilatory (VI) and genioglossal (EMGgg) and diaphragmatic (EMGdi) responses to CO2 rebreathing in awake, unanesthetized goats. Neither delta VI/delta PCO2 nor VI at a PCO2 of 60 Torr was significantly different between the three conditions studied (0%, 25%, and 50% carboxyhemoglobin, HbCO). There were also no significant changes in delta EMGdi/delta PCO2 or EMGdi at a PCO2 of 60 Torr during progressive brain hypoxia. In contrast, delta EMGgg/delta PCO2 and EMGgg at a PCO2 of 60 Torr were significantly increased at 50% HbCO compared with either normoxia or 25% HbCO (P less than 0.05). The PCO2 threshold at which inspiratory EMGgg appeared was also decreased at 50% HbCO (45.6 +/- 2.6 Torr) compared with normoxia (55.0 +/- 1.4 Torr, P less than 0.02) or 25% HbCO (53.4 +/- 1.6 Torr, P less than 0.02). We conclude that moderate brain hypoxia (50% HbCO) in awake, unanesthetized animals results in disproportionate augmentation of EMGgg relative to EMGdi during CO2 rebreathing. This finding is most likely due to hypoxic cortical depression with consequent withdrawal of tonic inhibition of hypoglossal inspiratory activity.     

Two temporal components within the human pulmonary vascular response to approximately 2 h of isocapnic hypoxia.

The time course of the pulmonary vascular response to hypoxia in humans has not been fully defined. In this investigation, study A was designed to assess the form of the increase in pulmonary vascular tone at the onset of hypoxia and to determine whether a steady plateau ensues over the following approximately 20 min. Twelve volunteers were exposed twice to 5 min of isocapnic euoxia (end-tidal Po(2) = 100 Torr), 25 min of isocapnic hypoxia (end-tidal Po(2) = 50 Torr), and finally 5 min of isocapnic euoxia. Study B was designed to look for the onset of a slower pulmonary vascular response, and, if possible, to determine a latency for this process. Seven volunteers were exposed to 5 min of isocapnic euoxia, 105 min of isocapnic hypoxia, and finally 10 min of isocapnic euoxia. For both studies, control protocols consisting of isocapnic euoxia were undertaken. Doppler echocardiography was used to measure cardiac output and the maximum tricuspid pressure gradient during systole, and estimates of pulmonary vascular resistance were calculated. For study A, the initial response was well described by a monoexponential process with a time constant of 2.4 +/- 0.7 min (mean +/- SE). After this, there was a plateau phase lasting at least 20 min. In study B, a second slower phase was identified, with vascular tone beginning to rise again after a latency of 43 +/- 5 min. These findings demonstrate the presence of two distinct phases of hypoxic pulmonary vasoconstriction, which may result from two distinct underlying processes.     

Sustained microgravity reduces the human ventilatory response to hypoxia but not to hypercapnia.

We measured the isocapnic hypoxic ventilatory response and the hypercapnic ventilatory response by using rebreathing techniques in five normal subjects (ages 37-47 yr) before, during, and after 16 days of exposure to microgravity (microG). Control measurements were performed with the subjects in the standing and supine postures. In both microG and in the supine position, the hypoxic ventilatory response, as measured from the slope of ventilation against arterial O(2) saturation, was greatly reduced, being only 46 +/- 10% (microG) and 52 +/- 11% (supine) of that measured standing (P < 0.01). During the hypercapnic ventilatory response test, the ventilation at a PCO(2) of 60 Torr was not significantly different in microG (101 +/- 5%) and the supine position (89 +/- 3%) from that measured standing. Inspiratory occlusion pressures agreed with these results. The findings can be explained by inhibition of the hypoxic but not hypercapnic drive, possibly as a result of an increase in blood pressure in carotid baroreceptors in microG and the supine position.     

Hypercapnia and response of cerebral blood flow to hypoxia in newborn lambs

Individual effects of hypoxic hypoxia and hypercapnia on the cerebral circulation are well described, but data on their combined effects are conflicting. We measured the effect of hypoxic hypoxia on cerebral blood flow (CBF) and cerebral O2 consumption during normocapnia (arterial PCO2 = 33 +/- 2 Torr) and during hypercapnia (60 +/- 2 Torr) in seven pentobarbital-anesthetized lambs. Analysis of variance showed that neither the magnitude of the hypoxic CBF response nor cerebral O2 consumption was significantly related to the level of arterial PCO2. To determine whether hypoxic cerebral vasodilation during hypercapnia was restricted by reflex sympathetic stimulation we studied an additional six hypercapnic anesthetized lambs before and after bilateral removal of the superior cervical ganglion. Sympathectomy had no effect on base-line CBF during hypercapnia or on the CBF response to hypoxic hypoxia. We conclude that the effects of hypoxic hypoxia on CBF and cerebral O2 consumption are not significantly altered by moderate hypercapnia in the anesthetized lamb. Furthermore, we found no evidence that hypercapnia results in a reflex increase in sympathetic tone that interferes with the ability of cerebral vessels to dilate during hypoxic hypoxia.     

Diuretic effect of hypoxia, hypocapnia, and hyperpnea in humans: relation to hormones and O(2) chemosensitivity.

We studied the contributions of hypoxemia, hypocapnia, and hyperpnea to the acute hypoxic diuretic response (HDR) in humans and evaluated the role of peripheral O(2) chemosensitivity and renal hormones in HDR. Thirteen healthy male subjects (age 19-38 yr) were examined after sodium equilibration (intake: 120 mmol/day) during 90 min of normoxia (NO), poikilocapnic hypoxia (PH), and isocapnic hypoxia (IH) (days 1-3, random order, double blind), as well as normoxic voluntary hyperpnea (HP; day 4), matching ventilation during IH. O(2) saturation during PH and IH was kept equal to a mean level measured between 30 and 90 min of breathing 12% O(2) in a pretest. Urine flow during PH and IH (1.81 +/- 0.92 and 1.94 +/- 1.03 ml/min, respectively) but not during HP (1.64 +/- 0.96 ml/min) significantly exceeded that during NO (control, 1.38 +/- 0.71 ml/min). Urine flow increases vs. each test day's baseline were significant with PH, IH, and HP. Differences in glomerular filtration rate, fractional sodium clearance, urodilatin, systemic blood pressure, or leg venous compliance were excluded as factors of HDR. However, slight increases in plasma and urinary endothelin-1 and epinephrine with PH and IH could play a role. In conclusion, the early HDR in humans is mainly due to hypoxia and hypocapnia. It occurs without natriuresis and is unrelated to O(2) chemosensitivity (hypoxic ventilatory response).     

Evidence of impaired hypoxic vasodilation after intermediate-duration hypoxic exposure in humans

Systemic hemodynamics, including forearm blood flow and ventilatory parameters, were evaluated in 21 subjects before and after exposure to 8 h of poikilocapnic hypoxia. To evaluate the role of sympathetic nervous system activation in the changes, in 10 of these subjects, we measured muscle sympathetic nerve activity (MSNA) before and after exposure, and the remaining 11 subjects received intra-arterial phentolamine infusion in the brachial artery to define vascular tone in the absence of sympathetically mediated vasoconstriction. Short-term ventilatory acclimatization occurred as evidenced by a decrease in resting Pco(2) (from 42 +/- 1.4 to 37 +/- 0.96 mmHg) and by an increase in the slope of the ventilatory response to acute hypoxia [from 0.7 +/- 0.1 to 1.2 +/- 0.2 l.min(-1).%Sp(O(2)) (blood O(2) saturation from pulse oximetry)] after exposure. Subjects demonstrated a significant increase in resting heart rate (from 61 +/- 2 to 65 +/- 2 beats/min) and diastolic blood pressure (from 64.8 +/- 2.7 to 70.4 +/- 2.0 mmHg). MSNA did not change significantly after exposure, although there was a trend toward a decrease in burst frequency (from 19.8 +/- 4.1 to 14.3 +/- 1.2 bursts/min). Forearm vascular resistance showed a significant decrease after termination of exposure (from 37.7 +/- 3.6 to 27.6 +/- 2.7 mmHg.ml(-1).min.100 g tissue, P < 0.05). Initially, progressive isocapnic hypoxia elicited significant vasodilation, but after 8 h of poikilocapnic hypoxic exposure, the acute challenge failed to change forearm vascular resistance. Local alpha-blockade with phentolamine restored the vasodilatory response to acute hypoxia in the postexposure setting.     

Ventilatory responses to chemoreceptor stimulation after hypoxic acclimatization in awake goats

Our objective was to test the hypothesis that exposure to prolonged hypoxia results in altered responsiveness to chemoreceptor stimulation. Acclimatization to hypoxia occurs rapidly in the awake goat relative to other species. We tested the sensitivity of the central and peripheral chemoreceptors to chemical stimuli before and after 4 h of either isocapnic or poikilocapnic hypoxia (arterial PO2 40 Torr). We confirmed that arterial PCO2 decreased progressively, reaching a stable value after 4 h of hypoxic exposure (poikilocapnic group). In the isocapnic group, inspired minute ventilation increased over the same time course. Thus, acclimatization occurred in both groups. In goats, isocapnic hypoxia did not result in hyperventilation on return to normoxia, whereas poikilocapnic hypoxia did cause hyperventilation, indicating a different mechanism for acclimatization and the persistent hyperventilation on return to normoxia. Goats exposed to isocapnic hypoxia exhibited an increased slope of the CO2 response curve. Goats exposed to poikilocapnic hypoxia had no increase in slope but did exhibit a parallel leftward shift of the CO2 response curve. Neither group exhibited a significant change in response to bolus NaCN injections or dopamine infusions after prolonged hypoxia. However, both groups demonstrated a similar significant increase in the ventilatory response to subsequent acute exposure to isocapnic hypoxia. The increase in hypoxic ventilatory sensitivity, which was not dependent on the modality of hypoxic exposure (isocapnic vs. poikilocapnic), reinforces the key role of the carotid chemoreceptors in ventilatory acclimatization to hypoxia.     

Attenuated carotid body hypoxic sensitivity after prolonged hypoxic exposure

Prolonged exposure to hypoxia is accompanied by decreased hypoxic ventilatory response (HVR), but the relative importance of peripheral and central mechanisms of this hypoxic desensitization remain unclear. To determine whether the hypoxic sensitivity of peripheral chemoreceptors decreases during chronic hypoxia, we measured ventilatory and carotid sinus nerve (CSN) responses to isocapnic hypoxia in five cats exposed to simulated altitude of 5,500 m (barometric pressure 375 Torr) for 3-4 wk. Exposure to 3-4 wk of hypobaric hypoxia produced a decrease in HVR, measured as the shape parameter A in cats both awake (from 53.9 +/- 10.1 to 14.8 +/- 1.8; P less than 0.05) and anesthetized (from 50.2 +/- 8.2 to 8.5 +/- 1.8; P less than 0.05). Sustained hypoxic exposure decreased end-tidal CO2 tension (PETCO2, 33.3 +/- 1.2 to 28.1 +/- 1.3 Torr) during room-air breathing in awake cats. To determine whether hypocapnia contributed to the observed depression in HVR, we also measured eucapnic HVR (PETCO2 33.3 +/- 0.9 Torr) and found that HVR after hypoxic exposure remained lower than preexposed value (A = 17.4 +/- 4.2 vs. 53.9 +/- 10.1 in awake cats; P less than 0.05). A control group (n = 5) was selected for hypoxic ventilatory response matched to the baseline measurements of the experimental group. The decreased HVR after hypoxic exposure was associated with a parallel decrease in the carotid body response to hypoxia (A = 20.6 +/- 4.8) compared with that of control cats (A = 46.9 +/- 6.3; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)