Control of exercise hyperpnea during hypercapnia in humans

Previous studies have yielded conflicting results on the ventilatory response to CO2 during muscular exercise. To obviate possible experimental errors contributing to such variability, we have examined the CO2-exercise interaction in terms of the ventilatory response to exercise under conditions of controlled hypercapnia. Eight healthy male volunteers underwent a sequence of 5-min incremental treadmill exercise runs from rest up to a maximum CO2 output (VCO2) of approximately 1.5 l . min-1 in four successive steps. The arterial PCO2 (PaCO2) at rest was stabilized at the control level or up to 14 Torr above control by adding 0-6% CO2 to the inspired air. Arterial isocapnia (SD = 1.2 Torr) throughout each exercise run was maintained by continual adjustment of the inspired PCO2. At all PaCO2 levels the response in total ventilation (VE) was linearly related to exercise VCO2. Hypercapnia resulted in corresponding increases in both the slope (S) and zero intercept (V0) of the VE-VCO2 curve; these being directly proportional to the rise in PaCO2 (means +/- SE: delta S/ delta PaCO2, 2.73 +/- 0.28 Torr-1; delta V0/ delta PaCO2, 1.67 +/- 0.18 l . min-1 . Torr-1). Thus the ventilatory response to concomitant hypercapnia and exercise was characterized by a synergistic (additive plus multiplicative) effect, suggesting a positive interaction between these stimuli. The increased exercise sensitivity in hypercapnia is qualitatively consistent with the hypothesis that VE is controlled to minimize the conflicting challenges due to chemical drive and the mechanical work of breathing (Poon, C. S. In: Modelling and Control of Breathing, New York: Elsevier, 1983, p. 189-196).     

Exercise-induced hypercapnia in the horse

The effects of exercise intensity and duration on blood gases in thoroughbred horses were studied to characterize the apparent exercise-induced failure in pulmonary gas exchange that occurs in these animals. In response to 2 min of exercise, arterial CO2 tension (PaCO2) decreased in mild and moderate exercise, returned to normocapnic levels in moderate to heavy exercise, and rose 5-10 Torr above resting values during very heavy exercise when CO2 production (VCO2) exceeded 20 times the resting value, and mixed venous CO2 tension approximated 140 Torr. Exercise-induced hypoxemia occurred at the onset of heavy exercise and was associated with the absence of a hyperventilatory response and an alveolar-arterial PO2 difference that increased four to six times above rest with very heavy exercise. PaCO2 was related to VCO2 but not fb, as changes in breathing frequency (fb) of 8-20 breaths/min at comparable VCO2 did not affect PaCO2. Prolonging very heavy exercise from 2 to 4 min caused a severe metabolic acidosis (arterial pH less than 7.15) and hypoxemia was maintained; however, CO2 was no longer retained, as PaCO2 gradually fell to below resting levels, due to an increased tidal volume at constant fb. We conclude that a truly compensatory hyperventilation to very heavy exercise in the horse is not achieved because of the excessive volumes and flow rates required by their extraordinarily high VCO2 and VO2. On the other hand, the frank CO2 retention during short-term high-intensity exercise occurs even though the horse is not apparently mechanically obligated to tolerate it.     

Effects of altered CSF [H+] on ventilatory responses to exercise in the awake goat

We investigated the effects of selective large changes in the acid-base environment of medullary chemoreceptors on the control of exercise hyperpnea in unanesthetized goats. Four intact and two carotid body-denervated goats underwent cisternal perfusion with mock cerebrospinal fluid (CSF) of markedly varying [HCO-3] (CSF [H+] = 21-95 neq/l; pH 7.68-7.02) until a new steady state of alveolar hypo- or hyperventilation was reached [arterial PCO2 (PaCO2) = 31-54 Torr]. Perfusion continued as the goats completed two levels of steady-state treadmill walking [2 to 4-fold increase in CO2 production (VCO2)]. With normal acid-base status in CSF, goats usually hyperventilated slightly from rest through exercise (-3 Torr PaCO2, rest to VCO2 = 1.1 l/min). Changing CSF perfusate [H+] changed the level of resting PaCO2 (+6 and -4 Torr), but with few exceptions, the regulation of PaCO2 during exercise (delta PaCO2/delta VCO2) remained similar regardless of the new ventilatory steady state imposed by changing CSF [H+]. Thus the gain (slope) of the ventilatory response to exercise (ratio of change in alveolar ventilation to change in VCO2) must have increased approximately 15% with decreased resting PaCO2 (acidic CSF) and decreased approximately 9% with increased resting PaCO2 (alkaline CSF). A similar effect of CSF [H+] on resting PaCO2 and on delta PaCO2/VCO2 during exercise also occurred in two carotid body-denervated goats. Our results show that alteration of the gain of the ventilatory response to exercise occurs on acute alterations in resting PaCO2 set point (via changing CSF [H+]) and that the primary stimuli to exercise hyperpnea can operate independently of central or peripheral chemoreception.     

Influence of proton availability on intracapillary CO2-HCO3(-)-H+ reactions in isolated rat lungs.

Transcapillary CO2 exchange entails a transient perfusate CO2-HCO3(-)-H+ disequilibrium, leading to net loading or unloading of blood HCO3-. Perfusate reequilibration may or may not reach completion during the time of capillary transit, depending on the rate of intracapillary CO2-HCO3(-)-H+ reactions. Failure to reestablish equilibrium within the "open" capillary system leads to continued reequilibration in the "closed" postcapillary vasculature with resultant shifts in postcapillary perfusate PCO2, pH, and [HCO3-]. In the present study, we determined the effects of perfusate nonbicarbonate buffer capacity (beta) on intracapillary CO2-HCO3(-)-H+ reactions in isolated saline-perfused rat lungs. Effects of beta on the rate of transcapillary CO2 excretion (VCO2) and the magnitude of the postcapillary perfusate pH disequilibrium were measured as a function of luminal vascular carbonic anhydrase (CA) activity. The data indicate that beta markedly influenced the kinetics and dynamics of intravascular CO2-HCO3(-)-H+ reactions. beta affected VCO2 and the relative enhancement of VCO2 by luminal vascular CA. The data emphasize the inadequacies of using traditional "equilibrium" models of the CO2-HCO3(-)-H+ system to investigate capillary CO2 transport and exchange, even in organs (e.g., lungs) that contain significant luminal vascular CA activity.     

Validation of a maskless CO2-response test for sleep and infant studies

The Hazinski method is an indirect, noninvasive, and maskless CO2-response test useful in infants or during sleep. It measures the classic CO2-response slope (i.e., delta VI/delta PCO2) divided by resting ventilation Sr = (VI'--VI')/(VI'.delta PCO2) between low (')- and high (')-inspired CO2 as the fractional increase of alveolar ventilation per Torr rise of PCO2. In steady states when CO2 excretion (VCO2') = VCO2', Hazinski CO2-response slope (Sr) may be computed from the alveolar exchange equation as Sr = (PACO2'--PICO2')/(PACO2'--PICO2') where PICO2 is inspired PCO2. To avoid use of a mask or mouthpiece, the subject breathes from a hood in which CO2 is mixed with inspired air and a transcutaneous CO2 electrode is used to estimate alveolar PCO2 (PACO2). To test the validity of this method, we compared the slopes measured simultaneously by the Hazinski and standard steady-state methods using a pneumotachograph, mask, and end-tidal, arterial, and four transcutaneous PCO2 samples in 15-min steady-state challenges at PICO2 23.5 +/- 4.5 and 37 +/- 4.1 Torr. Sr was computed using PACO2 and arterial PCO2 (PaCO2) as well as with the four skin PCO2 (PSCO2) values. After correction for apparatus dead space, the standard method was normalized to resting VI = 1, and its CO2 slope was designated directly measured normalized CO2 slope (Sx), permitting error to be calculated as Sr/Sx.(ABSTRACT TRUNCATED AT 250 WORDS)     

Total CA activity in isolated perfused guinea pig lung by 18O-exchange method

The rate of exchange of 18O between alveolar CO2 and lung water was measured in isolated perfused guinea pig lungs to quantify carbonic anhydrase (CA) activity. The average lung CA activity, with a reaction velocity constant of 5.32 +/- 2.2 s-1, is sufficient to accelerate CO2 reactions in lung water by two orders of magnitude over the uncatalyzed rate at 22 degrees C and a PCO2 of 40 Torr. Three sulfonamide inhibitors of CA with different human erythrocyte membrane permeabilities were used to determine the availability of the enzyme to the perfusate. Ethoxzolamide, the most permeable at 0.1 microM (100 times its inhibition constant, of Ki) inhibited 85% of enzyme activity after exposure of the lung for 3 min and 94% of enzyme activity after 30 min, whereas 1.25 microM (320 times its Ki) acetazolamide (1/165 as permeable) only inhibited CA 28% at 3 min and 75% at 30 min. Benzolamide (less than 1/1,000 as permeable) at 4 microM (1,000 times its Ki) inhibited only approximately 17% of control CA activity by 5 min and 48% by 30 min after the start of perfusion. These data indicate the CA available to pulmonary capillary plasma is approximately 10% of the total lung CA activity, in agreement with published measurements on the homogenized lung.     

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.     

Effect of inspiratory resistive loading on control of ventilation during progressive exercise

Eight healthy volunteers performed gradational tests to exhaustion on a mechanically braked cycle ergometer, with and without the addition of an inspiratory resistive load. Mean slopes for linear ventilatory responses during loaded and unloaded exercise [change in minute ventilation per change in CO2 output (delta VE/delta VCO2)] measured below the anaerobic threshold were 24.1 +/- 1.3 (SE) = l/l of CO2 and 26.2 +/- 1.0 l/l of CO2, respectively (P greater than 0.10). During loaded exercise, decrements in VE, tidal volume, respiratory frequency, arterial O2 saturation, and increases in end-tidal CO2 tension were observed only when work loads exceeded 65% of the unloaded maximum. There was a significant correlation between the resting ventilatory response to hypercapnia delta VE/delta PCO2 and the ventilatory response to VCO2 during exercise (delta VE/delta VCO2; r = 0.88; P less than 0.05). The maximal inspiratory pressure generated during loading correlated with CO2 sensitivity at rest (r = 0.91; P less than 0.05) and with exercise ventilation (delta VE/delta VCO2; r = 0.83; P less than 0.05). Although resistive loading did not alter O2 uptake (VO2) or heart rate (HR) as a function of work load, maximal VO2, HR, and exercise tolerance were decreased to 90% of control values. We conclude that a modest inspiratory resistive load reduces maximum exercise capacity and that CO2 responsiveness may play a role in the control of breathing during exercise when airway resistance is artificially increased.     

Ventilatory control during exercise with increased respiratory dead space in goats

Our objectives were to determine 1) the effects of increased respiratory dead space (VD) on the ventilatory response to exercise and 2) whether changes in the ventilatory response are due to changes in chemoreceptor feedback (rest to exercise) vs. changes in the feedforward exercise stimulus. Steady-state ventilation (VI) and arterial blood gas responses to mild or moderate hyperoxic exercise in goats were compared with and without increased VD. Responses were compared using a simple mathematical model with the following assumptions: 1) steady state, 2) linear CO2 chemoreceptor feedback, 3) linear feedforward exercise stimulus proportional to CO2 production (VCO2) and characterized by an exercise gain (Gex), and 4) additive exercise stimulus and CO2 feedback producing the system gain (Gsys = delta VI/delta VCO2). Model predictions at constant Gex [assuming VD-to-tidal volume (VT) ratio independent of VCO2] are that increased VD/VT will 1) increase arterial PCO2 (PaCO2) and VI at rest and 2) increase Gsys via changes in chemoreceptor feedback due to a small increase in the PaCO2 vs. VCO2 slope. Experimental results indicate that increased VD increased VD/VT, PaCO2, and VI at rest and increased Gsys during exercise. However, measurable changes in the PaCO2 vs. VCO2 slope occurred only at high VD/VT or running speeds. Gex was estimated at each VD for each goat by using the model in conjunction with experimental measurements. With 0.2 liter VD, Gex increased 40% (P less than 0.01); with 0.6 liter VD, Gex increased 110% between 0 and 2.4 km/h and 5% grade (P less than 0.01) but not between 2.4 and 4.8 km/h. Thus, Gex is increased by VD through a limited range. In goats, increases in Gsys with increased VD result from increases in both Gex and CO2 chemoreceptor feedback. These results are consistent with other experimental treatments that increase the exercise ventilatory response, maintaining constant relative PaCO2 regulation, and suggest that a common mechanism linked to resting ventilatory drive modulates Gex.     

Breath holding during intense exercise: arterial blood gases, pH, and lactate

Seven healthy endurance-trained [maximal O2 uptake (VO2max) = 57.1 +/- 4.1 ml.kg-1.min-1)] female volunteers (mean age 24.4 +/- 3.6 yr) served as subjects in an experiment measuring arterial blood gases, acid-base status, and lactate changes while breath holding (BH) during intense intermittent exercise. By the use of a counterbalance design, each subject repeated five intervals of a 15-s on:30-s off treadmill run at 125% VO2max while BH and while breathing freely (NBH). Arterial blood for pH, PO2, PCO2, O2 saturation (SO2) HCO3, and lactate was sampled from a radial arterial catheter at the end of each work and rest interval and throughout recovery, and the results were analyzed using repeated-measures analysis of variance. Significant reductions in pHa (delta mean = 0.07, P less than 0.01), arterial PO2 (delta mean = 24.2 Torr, P less than 0.01), and O2 saturation (delta mean = 4.6%, P less than 0.01) and elevations in arterial PCO2 (delta mean = 8.2 Torr, P less than 0.01) and arterial HCO3 (delta mean = 1.3 meq/l, P = 0.05) were found at the end of each exercise interval in the BH condition. All of the observed changes in arterial blood gases and acid-base status induced by BH were reversed during the rest intervals. During recovery, significantly (P less than 0.025) greater levels of arterial lactate were found in the BH condition.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma [H+] regulation and whole blood [CO2] in exercising ponies

The major objective was to determine in ponies whether factors in addition to changes in blood PCO2 contribute to changes in plasma [H+] during submaximal exercise. Measurements were made to establish in vivo plasma [H+] at rest and during submaximal exercise, and CO2 titration of blood was completed for both in vitro and acute in vivo conditions. In 19 ponies arterial plasma [H+] was decreased from rest 4.5 neq/l (P less than 0.05) during the 7th min of treadmill running at 6 mph, 5% grade (P less than 0.5). A 5.6-Torr exercise hypocapnia accounted for approximately 2.9 neq/l of this reduced [H+]. The non-PCO2 component of this alkalosis was approximately neq/l, and it was due presumably to a 1.7-meq/l increase from rest in the plasma strong ion difference (SID). Despite the arterial hypocapnia, mixed venous PCO2 was 2.7 Torr above rest during steady-state exercise. Nevertheless, mixed venous plasma [H+] was 1.2 neq/l above rest during exercise, which was presumably due to the increase in SID. Also studied was the effect of submaximal exercise on whole blood CO2 content (CCO2). In vitro, at a given PCO2 there was minimal difference in CCO2 between rest and exercise blood, but plasma [HCO3-] was greater for exercise blood than for rest blood. In vivo, during steady-state exercise, arterial plasma blood. In vivo, during steady-state exercise, arterial plasma [HCO3-] was unchanged or slightly elevated from rest, but CaCO2 was 4 vol% below rest.(ABSTRACT TRUNCATED AT 250 WORDS)     

Model implications of gas exchange dynamics on blood gases in incremental exercise

In humans, arterial PCO2 (PaCO2) has been demonstrated to be regulated at or near resting levels in the steady state of moderate exercise (i.e., for work rates not associated with a sustained lactic acidosis). To determine how PaCO2 might be expected to behave under the nonsteady-state conditions of incremental exercise testing, the influence of the dynamic characteristics of the primary variables that determine PaCO2 was explored by means of computer modeling. We constructed a dynamic model that utilized previously reported experimental estimates for the kinetic response parameters of ventilation (VE) and CO2 output (VCO2). In response to incremental work rate forcings, the model yielded an increase in PaCO2, which reflected the disparity between the VE and VCO2 time constants; this hypercapnic condition was maintained despite VE and VCO2 both increasing linearly with respect to the input work rate profile. The degree of hypercapnia increased with the rate of the incremental forcing, reaching 9 Torr for a 50-W/min forcing. In conclusion, therefore, sustained increases in PaCO2 during nonsteady-state incremental exercise should be interpreted with caution, because this is the predicted response even in subjects with normal ventilatory control and lung function.     

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)     

Effect of plasma carbonic anhydrase on ventilation in exercising dogs

Recent studies suggest pH sampled by arterial chemoreceptors may not equal that sampled by external pH electrodes, because the uncatalyzed hydration of CO2 in plasma is a slow reaction (t 1/2 approximately 9 S). The importance of this reaction rate to ventilatory control (particularly during exercise) is not known. We studied the effect of catalyzing the CO2-pH reaction in three awake exercising dogs with chronic tracheostomies and carotid loops; the dogs were trained to run on a treadmill. Respiration frequency, tidal volume, total ventilation, and end-tidal partial pressure of CO2 (PCO2) were continuously monitored. Periodically, carotid artery blood was drawn and analyzed for partial pressure of O2 (PO2), PCO2, pH, and plasma carbonic anhydrase (CA) activity. Measurements were made during steady-state exercise (3 mph and 10% grade), during a control period, after injection of a 5 ml bolus of saline, and after injection of 5 mg/kg of bovine CA dissolved in 5 ml of saline. This dose of CA increased the reaction rate by more than 80-fold. Neither the control nor the CA injections significantly altered the ventilatory parameters. Saline and CA date differed by less than 5% in ventilation, 1 Torr in arterial PCO2, 0.01 in pH units, and 1.5 Torr in end-tidal PCO2. Thus the of CO2 hydration in plasma is not a significant factor in ventilatory control.     

Blood osmolality during in vivo changes of CO2 pressure

In 16 experiments male subjects, age 22.4 +/- 0.5 (SE) yr, inspired CO2 for 15 min (8% end-tidal CO2) or hyperventilated for 30 min (2.5% end-tidal CO2). Osmolality (Osm) and acid-base status of arterialized venous blood were determined at short intervals until 30 min after hypo- and hypercapnia, respectively. During hypocapnia [CO2 partial pressure (PCO2) -2.31 +/- 0.32 kPa (-17.4 Torr), pH + 0.19 units], Osm decreased by 3.9 +/- 0.3 mosmol/kg H2O; during hypercapnia [PCO2 + 2.10 +/- 0.28 kPa (+15.8 Torr), pH -0.12 units], Osm increased by 5.8 +/- 0.7 mosmol/kg H2O. Presentation of the data in Osm-PCO2 or Osm-pH diagrams yields hysteresis loops probably caused by exchange between blood and tissues. The dependence of Osm on PCO2 must result mainly from CO2 buffering and therefore from the formation of bicarbonate. In spite of the different buffer capacities in various body compartments, water exchange allows rapid restoration of osmotic equilibrium throughout the organism. Thus delta Osm/delta pH during a PCO2 jump largely depends on the mean buffer capacity of the whole body. The high estimated buffer value during hypercapnia (38 mmol/kg H2O) compared with hypocapnia (19 mmol/kg H2O) seems to result from very strong muscle buffering during moderate acidosis.     

Effect of acetazolamide on gas exchange and acid-base control after maximal exercise.

To investigate the interactions between the systems that contribute to acid-base homeostasis after severe exercise, we studied the effects of carbonic anhydrase inhibition on exchange of strong ions and CO2 in six subjects after 30 s of maximal isokinetic cycling exercise. Each subject exercised on two randomly assigned occasions, a control (CON) condition and 30 min after intravenous injection of 1,000 mg acetazolamide (ACZ) to inhibit blood carbonic anhydrase activity. Leg muscle power output was similar in the two conditions; peak O2 uptake (VO2) after exercise was lower in ACZ (2,119 +/- 274 ml/min) than in CON (2,687 +/- 113, P less than 0.05); peak CO2 production (VCO2) was also lower (2,197 +/- 241 in ACZ vs. 3,237 +/- 87 in CON, P less than 0.05) and was accompanied by an increase in the recovery half-time from 1.7 min in CON to 2.3 min in ACZ. Whereas end-tidal PCO2 was lower in ACZ than in CON, arterial PCO2 (PaCO2) was higher, and a large negative end-tidal-to-arterial difference (less than or equal to 20 Torr) was present in ACZ on recovery. In ACZ, postexercise increases in arterial plasma [Na+] and [K+] were greater but [La-] was lower. Arteriovenous differences across the forearm showed a greater uptake of La- and Cl- in CON than in ACZ. Carbonic anhydrase inhibition with ACZ, in addition to impairing equilibration of the CO2 system to the acid-base challenge of exercise, was accompanied by changes in equilibration of strong inorganic ions. A lowered plasma [La-] was not accompanied by greater uptake of La- by inactive muscle.     

Arterial blood gases and acid-base status of dogs during graded dynamic exercise

The objective of this study was to determine whether arterial PCO2 (PaCO2) decreases or remains unchanged from resting levels during mild to moderate steady-state exercise in the dog. To accomplish this, O2 consumption (VO2) arterial blood gases and acid-base status, arterial lactate concentration ([LA-]a), and rectal temperature (Tr) were measured in 27 chronically instrumented dogs at rest, during different levels of submaximal exercise, and during maximal exercise on a motor-driven treadmill. During mild exercise [35% of maximal O2 consumption (VO2 max)], PaCO2 decreased 5.3 +/- 0.4 Torr and resulted in a respiratory alkalosis (delta pHa = +0.029 +/- 0.005). Arterial PO2 (PaO2) increased 5.9 +/- 1.5 Torr and Tr increased 0.5 +/- 0.1 degree C. As the exercise levels progressed from mild to moderate exercise (64% of VO2 max) the magnitude of the hypocapnia and the resultant respiratory alkalosis remained unchanged as PaCO2 remained 5.9 +/- 0.7 Torr below and delta pHa remained 0.029 +/- 0.008 above resting values. When the exercise work rate was increased to elicit VO2 max (96 +/- 2 ml X kg-1 X min-1) the amount of hypocapnia again remained unchanged from submaximal exercise levels and PaCO2 remained 6.0 +/- 0.6 Torr below resting values; however, this response occurred despite continued increases in Tr (delta Tr = 1.7 +/- 0.1 degree C), significant increases in [LA-]a (delta [LA-]a = 2.5 +/- 0.4), and a resultant metabolic acidosis (delta pHa = -0.031 +/- 0.011). The dog, like other nonhuman vertebrates, responded to mild and moderate steady-state exercise with a significant hyperventilation and respiratory alkalosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Background ventilatory stimulus as a determinant of load compensation

Compensation for inspiratory flow-resistive loading was compared during progressive hypercapnia and incremental exercise to determine the effect of changing the background ventilatory stimulus and to assess the influence of the interindividual variability of the unloaded CO2 response on evaluation of load compensation in normal subjects. During progressive hypercapnia, ventilatory response was incompletely defended with loading (mean unloaded delta VE/delta PCO2 = 3.02 +/- 2.29, loaded = 1.60 +/- 0.67 1.min-1.Torr-1 CO2, where VE is minute ventilation and PCO2 is CO2 partial pressure; P less than 0.01). Furthermore the degree of defense of ventilation with loading was inversely correlated with the magnitude of the unloaded CO2 response. During exercise, loading produced no depression in ventilatory response (mean delta VE/delta VCO2 unloaded = 20.5 +/- 1.9, loaded = 19.2 +/- 2.5 l.min-1.l-1.min-1 CO2 where VCO is CO2 production; P = NS), and no relationship was demonstrated between degree of defense of the exercise ventilatory response and the unloaded CO2 response. Differences in load compensation during CO2 rebreathing and exercise suggest the presence of independent ventilatory control mechanisms in these states. The type of background ventilatory stimulus should therefore be considered in load compensation assessment.     

DIDS decreases CSF HCO3- and increases breathing in response to CO2 in awake rabbits

An inhibitor of the HCO3-/Cl- exchange carrier protein, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) or vehicle was infused in mock cerebrospinal fluid (CSF) via the cisterna magna in conscious rabbits at 10 mumol/l for 40 min at 10 microliter/min. Neither treatment had any effect over 2-5 h on the non-CO2-stimulated CSF ion values or blood gases. With CO2 stimulation such that arterial PCO2 (PaCO2) was increased 25 Torr over 3 h, DIDS treatment significantly decreased the stoichiometrically opposite changes in CSF [HCO3-] and [Cl-] that normally accompany hypercapnia and reflect ionic mechanisms of CSF pH regulation. Expressed as delta CSF [HCO3-]/delta PaCO2, DIDS treatment decreased the CSF ionic response by 35%. In a separate paired study design DIDS administration via the same protocol had no effect on resting ventilation but significantly increased the ventilation and tidal volume responses to a 28-Torr increase in PaCO2. Expressed as change in minute ventilation divided by delta PaCO2, DIDS treatment produced a 39.6% increase. The results support the concept of a DIDS-inhibitable anion exchange carrier being involved in CSF pH regulation in hypercapnia and suggest a DIDS-related effect on the ventilatory response to CO2.     

Effects of acetazolamide on cerebral acid-base balance

Acetazolamide (AZ) inhibition of brain and blood carbonic anhydrase increases cerebral blood flow by acidifying cerebral extracellular fluid (ECF). This ECF acidosis was studied to determine whether it results from high PCO2, carbonic acidosis (accumulation of H2CO3), or lactic acidosis. Twenty rabbits were anesthetized with pentobarbital sodium, paralyzed, and mechanically ventilated with 100% O2. The cerebral cortex was exposed and fitted with thermostatted flat-surfaced pH and PCO2 electrodes. Control values (n = 14) for cortex ECF were pH 7.10 +/- 0.11 (SD), PCO2 42.2 +/- 4.1 Torr, PO2 107 +/- 17 Torr, HCO3- 13.8 +/- 3.0 mM. Control values (n = 14) for arterial blood were arterial pH (pHa) 7.46 +/- 0.03 (SD), arterial PCO2 (PaCO2) 32.0 +/- 4.1 Torr, arterial PO2 (PaO2) 425 +/- 6 Torr, HCO3- 21.0 +/- 2.0 mM. After intravenous infusion of AZ (25 mg/kg), end-tidal PCO2 and brain ECF pH immediately fell and cortex PCO2 rose. Ventilation was increased in nine rabbits to bring ECF PCO2 back to control. The changes in ECF PCO2 then were as follows: pHa + 0.04 +/- 0.09, PaCO2 -8.0 +/- 5.9 Torr, HCO3(-)-2.7 +/- 2.3 mM, PaO2 +49 +/- 62 Torr, and changes in cortex ECF were as follows: pH -0.08 +/- 0.04, PCO2 -0.2 +/- 1.6 Torr, HCO3(-)-1.7 +/- 1.3 mM, PO2 +9 +/- 4 Torr. Thus excess acidity remained in ECF after ECF PCO2 was returned to control values. The response of intracellular pH, high-energy phosphate compounds, and lactic acid to AZ administration was followed in vivo in five other rabbits with 31P and 1H nuclear magnetic resonance spectroscopy.(ABSTRACT TRUNCATED AT 250 WORDS)