Carotid body denervation in dogs: eupnea and the ventilatory response to hyperoxic hypercapnia.

We assessed the time course of changes in eupneic arterial PCO(2) (Pa(CO(2))) and the ventilatory response to hyperoxic rebreathing after removal of the carotid bodies (CBX) in awake female dogs. Elimination of the ventilatory response to bolus intravenous injections of NaCN was used to confirm CBX status on each day of data collection. Relative to eupneic control (Pa(CO(2)) = 40 +/- 3 Torr), all seven dogs hypoventilated after CBX, reaching a maximum Pa(CO(2)) of 53 +/- 6 Torr by day 3 post-CBX. There was no significant recovery of eupneic Pa(CO(2)) over the ensuing 18 days. Relative to control, the hyperoxic CO(2) ventilatory (change in inspired minute ventilation/change in end-tidal PCO(2)) and tidal volume (change in tidal volume/ change in end-tidal PCO(2)) response slopes were decreased 40 +/- 15 and 35 +/- 20% by day 2 post-CBX. There was no recovery in the ventilatory or tidal volume response slopes to hyperoxic hypercapnia over the ensuing 19 days. We conclude that 1) the carotid bodies contribute approximately 40% of the eupneic drive to breathe and the ventilatory response to hyperoxic hypercapnia and 2) there is no recovery in the eupneic drive to breathe or the ventilatory response to hyperoxic hypercapnia after removal of the carotid chemoreceptors, indicating a lack of central or aortic chemoreceptor plasticity in the adult dog after CBX.     

End-tidal CO2 response to low levels of inspired CO2 in awake beagle dogs

The steady-state end-tidal CO2 tension (PCO2) was examined during control and 1% CO2 inhalation periods in awake beagle dogs with an intact airway breathing through a low dead-space respiratory mask. A total of eight experiments were performed in four dogs, comprising 31 control observations and 23 CO2 inhalation observations. The 1% inhaled CO2 produced a significant increase in the steady-state end-tidal PCO2 comparable to the expected 1 Torr predicted from conventional CO2 control of ventilation. We conclude that 1% inhaled CO2 results in a hypercapnia. Any protocol that is to resolve the question of whether mechanisms are acting during low levels of inhaled CO2 such that ventilation increases without any change in arterial PCO2 must have sufficient resolving power to discriminate changes in gas tension in magnitude predicted from conventional (i.e., arterial PCO2) control of ventilation.     

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.     

The apneic threshold during non-REM sleep in dogs: sensitivity of carotid body vs. central chemoreceptors.

The relative importance of peripheral vs. central chemoreceptors in causing apnea/unstable breathing during sleep is unresolved. This has never been tested in an unanesthetized preparation with intact carotid bodies. We studied three unanesthetized dogs during normal sleep in a preparation in which intact carotid body chemoreceptors could be reversibly isolated from the systemic circulation and perfused. Apneic thresholds and the CO(2) reserve (end-tidal Pco(2) eupneic - end-tidal Pco(2) apneic threshold) were determined using a pressure support ventilation technique. Dogs were studied when both central and peripheral chemoreceptors sensed transient hypocapnia induced by the pressure support ventilation and again with carotid body isolation such that only the central chemoreceptors sensed the hypocapnia. We observed that the CO(2) reserve was congruent with4.5 Torr when the carotid chemoreceptors sensed the transient hypocapnia but more than doubled (>9 Torr) when only the central chemoreceptors sensed hypocapnia. Furthermore, the expiratory time prolongations observed when only central chemoreceptors were exposed to hypocapnia differed from those obtained when both the central and peripheral chemoreceptors sensed the hypocapnia in that they 1) were substantially shorter for a given reduction in end-tidal Pco(2), 2) showed no stimulus: response relationship with increasing hypocapnia, and 3) often occurred at a time (>45 s) beyond the latency expected for the central chemoreceptors. These findings agree with those previously obtained using an identical pressure support ventilation protocol in carotid body-denervated sleeping dogs (Nakayama H, Smith CA, Rodman JR, Skatrud JB, Dempsey JA. J Appl Physiol 94: 155-164, 2003). We conclude that hypocapnia sensed at the carotid body chemoreceptor is required for the initiation of apnea following a transient ventilatory overshoot in non-rapid eye movement sleep.     

Increased propensity for apnea via dopamine-induced carotid body inhibition in sleeping dogs.

We determined the effects of specific carotid body chemoreceptor inhibition on the propensity for apnea during sleep. We reduced the responsiveness of the carotid body chemoreceptors using intravenous dopamine infusions during non-rapid eye movement sleep in six dogs. Then we quantified the difference in end-tidal Pco(2) (Pet(CO(2))) between eupnea and the apneic threshold, the "CO(2) reserve," by gradually reducing Pet(CO(2)) transiently with pressure support ventilation at progressively increased tidal volume until apnea occurred. Dopamine infusions decreased steady-state eupneic ventilation by 15 +/- 6%, causing a mean CO(2) retention of 3.9 +/- 1.9 mmHg and a brief period of ventilatory instability. The apneic threshold Pet(CO(2)) rose 5.1 +/- 1.9 Torr; thus the CO(2) reserve was narrowed from -3.9 +/- 0.62 Torr in control to -2.7 +/- 0.78 Torr with dopamine. This decrease in the CO(2) reserve with dopamine resulted solely from the 20.5 +/- 11.3% increase in plant gain; the slope of the ventilatory response to CO(2) below eupnea was unchanged from normal. We conclude that specific carotid chemoreceptor inhibition with dopamine increases the propensity for apnea during sleep by narrowing the CO(2) reserve below eupnea. This narrowing is due solely to an increase in plant gain as the slope of the ventilatory response to CO(2) below eupnea was unchanged from normal control. These findings have implications for the role of chemoreceptor inhibition/stimulation in the genesis of apnea and breathing periodicity during sleep.     

Respiratory effects in humans of a 5-day elevation of end-tidal PCO2 by 8 Torr.

The aims of this study were to determine 1) whether ventilatory adaptation occurred over a 5-day exposure to a constant elevation in end-tidal PCO2 and 2) whether such an exposure altered the sensitivity of the chemoreflexes to acute hypoxia and hypercapnia. Ten healthy human subjects were studied over a period of 13 days. Their ventilation, chemoreflex sensitivities, and acid-base status were measured daily before, during, and after 5 days of elevated end-tidal PCO2 at 8 Torr above normal. There was no major adaptation of ventilation during the 5 days of hypercapnic exposure. There was an increase in ventilatory chemosensitivity to acute hypoxia (from 1.35 +/- 0.08 to 1.70 +/- 0.07 l/min/%; P < 0.01) but no change in ventilatory chemosensitivity to acute hypercapnia. There was a degree of compensatory metabolic alkalosis. The results do not support the hypothesis that the ventilatory adaptation to chronic hypercapnia would be much greater with constant elevation of alveolar PCO2 than with constant elevation of inspired PCO2, as has been used in previous studies and in which the feedback loop between ventilation and alveolar PCO2 is left intact.     

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.     

Transient ventilatory response to CO2 as a function of sleep state in full-term infants

The influence of sleep state on the transient (i.e., initial 60 s) and steady-state ventilatory responses to 2% CO2 inhalation was studied in 19 healthy full-term infants. A nasal mask pneumotachometer was used to measure ventilation and end-tidal CO2 partial pressure (PCO2) and enabled abrupt changes in the inspired gas concentration to be made. The magnitude of the change in minute ventilation for both the transient and steady-state responses to CO2 was not statistically different between active (AS) and quiet (QS) sleep. Nonetheless the greater variability in minute ventilation during AS compared with QS continued throughout the period of CO2 inhalation and was associated with a more variable change in ventilation in the individual infants during AS. There was a greater increase in end-tidal PCO2 over the first 60 s during AS (3.3 +/- 0.3 vs. 2.6 +/- 0.2 Torr, in AS and QS, respectively, P less than 0.03). This may indicate a smaller initial increase in alveolar ventilation, relative to CO2 delivery to the lungs, in response to CO2 inhalation during AS. Asynchronous chest wall movements were more common during AS than QS (P less than 0.005) and did not change with CO2. The inconsistent transient ventilatory response to CO2 during AS compared with QS may be important in the behavior of infants to spontaneous episodes of hypercapnia occurring during AS.     

Blood-gas equilibration of CO2 and O2 in lungs of awake dogs during prolonged rebreathing

To reinvestigate the blood-gas CO2 equilibrium in lungs, rebreathing experiments were performed in five unanesthetized dogs prepared with a chronic tracheostomy and an exteriorized carotid loop. The rebreathing bag was initially filled with a gas mixture containing 6-8% CO2, 12, 21, or 39% O2, and 1% He in N2. During 4-6 min of rebreathing PO2 in the bag was kept constant by a controlled supply of O2 while PCO2 rose steadily from approximately 40 to 75 Torr. Spot samples of arterial blood were taken from the carotid loop; their PCO2 and PO2 were measured by electrodes and compared with the simultaneous values of end-tidal gas read from a mass spectrometer record. The mean end-tidal-to-arterial PO2 differences averaging 16, 4, and 0 Torr with bag PO2 about 260, 130, and 75 Torr, respectively, were in accordance with a venous admixture of about 1%. No substantial PCO2 differences between arterial blood and end-tidal gas (PaCO2 - PE'CO2) were found. The mean PaCO2 - PE'CO2 of 266 measurements in 70 rebreathing periods was -0.4 +/- 1.4 (SD) Torr. There was no correlation between PaCO2 - PE'CO2 and the level of arterial PCO2 or PO2. The mean PaCO2 - PE'CO2 became +0.1 Torr when the blood transit time from lungs to carotid artery (estimated at 6 s) and the rate of rise of bag PCO2 (4.5 Torr/min) were taken into account. These experimental results do not confirm the presence of significant PCO2 differences between arterial blood and alveolar gas in rebreathing equilibrium.     

Evidence for a central action of CO2 ventilatory stimulus in Pekin ducks (author's transl)]

Ventilatory responses to changes in PCO2 of the blood perfusing the central nervous system were studied breath by breath by pneumotachography in Pekin ducks under transient and steady condition. 1. Transients. In conscious birds, all the arteries to the cephalic region were tied or clamped, except the right internal carotid. The blood supply via the single remaining arterial pathway was transiently replaced, for about 15 sec, by injecting 2 ml of blood previously made either normocapnic (control PCO2 = 32 Torr) or hypercapnic (test; PCO2 = 76 Torr) from a syringe thermostated at 41 degrees C, under normal oxygenation (PO2 around 110 Torr) and mean endovascular pressure (107 mm Hg). During control injections, no significant ventilatory changes were observed. In contrast, test injections provoked an early and significant 20% increase in the minute volume of ventilation. 2. Steady conditions. Using cross-perfusion between pairs of anesthetized ducks, the head of a recipient animal (R) was vascularly isolated from the trunk and perfused by a donor (D), the nervous connections with the trunk remaining intact. When giving some CO2 to breathe to D (FICO2 = 0.05) while R breathed ambient air, arterial PCO2 increased in D and in the head of R, and hyperventilation occurred in both ducks. As a consequence of this hyperventilation, PCO2 decreased in the arterial blood and the end-tidal gas of R.     

Carotid body denervation eliminates apnea in response to transient hypocapnia.

We determined the effects on breathing of transient ventilatory overshoots and concomitant hypocapnia, as produced by pressure support mechanical ventilation (PSV), in intact and carotid body chemoreceptor denervated (CBX) sleeping dogs. In the intact dog, PSV-induced transient increases in tidal volume and hypocapnia caused apnea within 10-11 s, followed by repetitive two-breath clusters separated by apneas, i.e., periodic breathing (PB). After CBX, significant expiratory time prolongation did not occur until after 30 s of PSV-induced hypocapnia, and PB never occurred. Average apneas of 8.4 +/- 1-s duration after a ventilatory overshoot required a decrease below eupnea of end-tidal Pco(2) 5.1 +/- 0.4 Torr below eupnea in the intact animal and 10.1 +/- 2 Torr in the CBX dog, where the former reflected peripheral and the latter central dynamic CO(2) chemoresponsiveness, as tested in the absence of peripheral chemoreceptor input. Hyperoxia when the dogs were intact shortened PSV-induced apneas and reduced PB but did not mimic the effects of CBX. We conclude that, during non-rapid eye movement sleep, carotid chemoreceptors are required to produce apneas that normally occur after a transient ventilatory overshoot and for PB.     

Evidence for hypoxic depression of CO2-ventilation response in carotid body-resected humans

Steady-state CO2-ventilation response curves with hyperoxia (end-tidal PO2 greater than 200 Torr) and mild hypoxia (end-tidal PO2 approximately equal to 60 Torr) were compared in five carotid body-resected (BR) patients and five control patients. The data were analyzed by fitting a linear equation, V = S(PETCO2-B), where V is minute ventilation S is the response curve slope. PETCO2 is end-tidal PCO2, and B is the response curve threshold. S slightly increased from hyperoxia to hypoxia in both BR and control groups. On the other hand, B moderately increased with hypoxia in BR patients, whereas it slightly decreased in controls. These changes were all not significant. However, in accordance with the change in B, the response curve to hypoxia at V of 10 1/min was significantly shifted in opposite directions in the two groups, i.e., rightward and leftward shift in BR and control groups, respectively. Thus the average magnitude of V calculated at PETCO2 of 40 Torr in hypoxia was significantly lower in BR patients than in controls (P less than 0.01). We conclude that this hypoxic depression of the CO2-ventilation response found in BR patients may have resulted, at least in part, from modulation of the brain stem neural mechanisms that were elicited by loss of afferent discharges from the carotid body.     

Ventilatory control during exercise with peripheral chemoreceptor stimulation: hypoxia vs. domperidone

Hypoxia potentiates the ventilatory response to exercise, eliciting a greater decrease in arterial PCO2 (PaCO2) from rest to exercise than in normoxia. The mechanism of this hypoxia-exercise interaction requires intact carotid chemoreceptors. To determine whether carotid chemoreceptor stimulation alone is sufficient to elicit the mechanism without whole body hypoxia, ventilatory responses to treadmill exercise were compared in goats during hyperoxic control conditions, moderate hypoxia (PaO2 = 38-44 Torr), and peripheral chemoreceptor stimulation with the peripheral dopamine D2-receptor antagonist, domperidone (Dom; 0.5 mg/kg iv). Measurements with Dom were made in both hyperoxia (Dom) and hypoxia (Dom/hypoxia). Finally, ventilatory responses to inspired CO2 at rest were compared in each experimental condition because enhanced CO2 chemoreception might be expected to blunt the PaCO2 decrease during exercise. At rest, PaCO2 decreased from control with Dom (-5.0 +/- 0.9 Torr), hypoxia (-4.1 +/- 0.5 Torr), and Dom/hypoxia (-11.1 +/- 1.2 Torr). The PaCO2 decrease from rest to exercise was not significantly different between control (-1.7 +/- 0.6 Torr) and Dom (-1.4 +/- 0.8 Torr) but was significantly greater in hypoxia (-4.3 +/- 0.7 Torr) and Dom/hypoxia (-3.5 +/- 0.9 Torr). The slope of the ventilation vs. CO2 production relationship in exercise increased with Dom (16%), hypoxia (18%), and Dom/hypoxia (68%). Ventilatory responses to inspired CO2 at rest increased from control to Dom (236%) and Dom/hypoxia (295%) and increased in four of five goats in hypoxia (mean 317%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Arterial-alveolar CO2 equilibration in exercising dogs during prolonged rebreathing

Arterial-alveolar equilibration of CO2 during exercise was studied by normoxic CO2 rebreathing in six dogs prepared with a chronic tracheostomy and exteriorized carotid loop and trained to run on a treadmill. In 153 simultaneous measurements of PCO2 in arterial blood (PaCO2) and end-tidal gas (PE'CO2) obtained in 46 rebreathing periods at three levels of mild-to-moderate steady-state exercise, the mean PCO2 difference (PaCO2-PE'CO2) was -1.0 +/- 1.0 (SD) Torr and was not related to O2 uptake or to the level of PaCO2 (30-68 Torr). The small negative PaCO2-PE'CO2 is attributed to the lung-to-carotid artery transit time delay which must be taken into account when both PaCO2 and PE'CO2 are continuously rising during rebreathing (average rate 0.22 Torr/s). Assuming that blood-gas equilibrium for CO2 was complete, a lung-to-carotid artery circulation time of 4.6 s accounts for the observed uncorrected PaCO2-PE'CO2 of -1.0 Torr. The results are interpreted to indicate that in rebreathing equilibrium PCO2 in arterial blood and alveolar gas are essentially identical. This conclusion is at variance with previous studies in exercising humans during rebreathing but is in full agreement with our recent findings in resting dogs.     

Control of ventilation during exercise in patients with central venous-to-systemic arterial shunts

The diversion of systemic venous blood into the arterial circulation in patients with intracardiac right-to-left shunts represents a pathophysiological condition in which there are alterations in some of the potential stimuli for the exercise hyperpnea. We therefore studied 18 adult patients with congenital (16) or noncongenital (2) right-to-left shunts and a group of normal control subjects during constant work rate and progressive work rate exercise to assess the effects of these alterations on the dynamics of exercise ventilation and gas exchange. Minute ventilation (VE) was significantly higher in the patients than in the controls, both at rest (10.7 +/- 2.4 vs. 7.5 +/- 1.2 l/min, respectively) and during constant-load exercise (24.9 +/- 4.8 vs. 12.7 +/- 2.61 l/min, respectively). When beginning constant work rate exercise from rest, the ventilatory response of the patients followed a pattern that was distinct from that of the normal subjects. At the onset of exercise, the patients' end-tidal PCO2 decreased, end-tidal PO2 increased, and gas exchange ratio increased, indicating that pulmonary blood was hyperventilated relative to the resting state. However, arterial blood gases, in six patients in which they were measured, revealed that despite the large VE response to exercise, arterial pH and PCO2 were not significantly different from resting values when sampled during the first 2 min of moderate-intensity exercise. Arterial PCO2 changed by an average of only 1.4 Torr after 4.5-6 min of exercise. Thus the exercise-induced alveolar and pulmonary capillary hypocapnia was of an appropriate degree to compensate for the shunting of CO2-rich venous blood into the systemic arterial circulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Carotid body excision significantly changes ventilatory control in awake rats

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

Selected contribution: chemoreflex responses to CO2 before and after an 8-h exposure to hypoxia in humans.

The ventilatory sensitivity to CO2, in hyperoxia, is increased after an 8-h exposure to hypoxia. The purpose of the present study was to determine whether this increase arises through an increase in peripheral or central chemosensitivity. Ten healthy volunteers each underwent 8-h exposures to 1) isocapnic hypoxia, with end-tidal PO2 (PET(O2)) = 55 Torr and end-tidal PCO2 (PET(CO2)) = eucapnia; 2) poikilocapnic hypoxia, with PET(O2) = 55 Torr and PET(CO2) = uncontrolled; and 3) air-breathing control. The ventilatory response to CO2 was measured before and after each exposure with the use of a multifrequency binary sequence with two levels of PET(CO2): 1.5 and 10 Torr above the normal resting value. PET(O2) was held at 250 Torr. The peripheral (Gp) and the central (Gc) sensitivities were calculated by fitting the ventilatory data to a two-compartment model. There were increases in combined Gp + Gc (26%, P < 0.05), Gp (33%, P < 0.01), and Gc (23%, P = not significant) after exposure to hypoxia. There were no significant differences between isocapnic and poikilocapnic hypoxia. We conclude that sustained hypoxia induces a significant increase in chemosensitivity to CO2 within the peripheral chemoreflex.     

Step changes in end-tidal CO2: methods and implications.

A dynamic end-tidal forcing technique for producing step changes in end-tidal CO2 with end-tidal O2 held constant independent of the ventilation response or the mixed venous return is introduced for characterizing the human ventilation response to end-tidal CO2 step changes for both normoxic (PAO2 = 125 Torr) and hypoxic (PAO2 = 60 Torr) conditions. The ventilation response approaches a steady state within 5 min. In normoxia, the on-transient is faster than the off-transient, presumably reflecting the action of cerebral blood flow. The hypoxic step response is faster than the normoxic response presumably reflecting the increased contribution from the carotid body. The delay in the ventilation response after the change in end-tidal CO2 is less in hypoxia than in normoxia and reflects the action of a transport delay and that of a virtual delay. These delays are interpreted with respect to the high-frequency phase shift data for the same subject, generated using sinusoidal end-tidal forcing. The methods of others for experiments utilizing step changes in inspired CO2 are considered with respect to our methods.     

Effect of water alkalinity on gill CO2 exchange and internal PCO2 in aquatic animals

In addition to metabolic CO2 production and gill ventilatory flow rate, expired water PCO2 is very dependent on water acid-base balance in a complex way. This is particularly true in carbonated waters at low ambient PCO2 and high pH, where CO2 excreted in the gill water may be buffered by carbonate ions, leading to an increased CO2 capacitance coefficient. The higher the carbonate alkalinity (CA) and the lower the inspired PCO2 (i.e., the higher the inspired water pH), the stronger the carbonate buffering and the smaller the increase of PCO2 in the gill water during respiratory CO2 exchanges. As a consequence, as shown by a number of reported data, increasing the CA leads to blood hypocapnia and respiratory alkalosis at constant low, but not at high, inspired PCO2. In the low range of inspired PCO2, internal PCO2 becomes very sensitive to even small changes of water PCO2, which may explain at least in part the large variability of reported blood PCO2 values in gill breathers. Water CA also influences the amplitude of respiratory acid-base disturbances caused by changes of the gill ventilatory flow rate. Carbonate buffering of excreted CO2 and thus dependence of blood PCO2 on water alkalinity requires catalysis of CO2 hydration by carbonic anhydrase, that must be available from the water side of the gill epithelium.     

Changes in respiratory control in humans induced by 8 h of hyperoxia.

In humans, 8 h of isocapnic hypoxia causes a progressive rise in ventilation associated with increases in the acute ventilatory responses to hypoxia (AHVR) and hypercapnia (AHCVR). To determine whether 8 h of hyperoxia causes the converse of these effects, three 8-h protocols were compared in 14 subjects: 1) poikilocapnic hyperoxia, with end-tidal PO(2) (PET(O(2))) = 300 Torr and end-tidal PCO(2) (PET(CO(2))) uncontrolled; 2) isocapnic hyperoxia, with PET(O(2)) = 300 Torr and PET(CO(2)) maintained at the subject's normal air-breathing level; and 3) control. Ventilation was measured hourly. AHVR and AHCVR were determined before and 0.5 h after each exposure. During isocapnic hyperoxia, after an initial increase, ventilation progressively declined (P < 0.01, ANOVA). After exposure to hyperoxia, 1) AHVR declined (P < 0.05); 2) ventilation at fixed PET(CO(2)) decreased (P < 0.05); and 3) air-breathing PET(CO(2)) increased (P < 0.05); but 4) no significant changes in AHCVR or intercept were demonstrated. In conclusion, 8 h of hyperoxia have some effects opposite to those found with 8 h of hypoxia, indicating that there may be some "acclimatization to hypoxia" at normal sea-level values of PO(2).