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.     

Branchial chemoreceptors mediate ventilatory responses to hypercapnic acidosis in channel catfish

The effects of hyperoxic hypercapnia on cardiovascular and ventilatory variables and blood gas and acid/base parameters were examined in conscious and anesthetized spontaneously breathing (ASB) channel catfish, Ictalurus punctatus. These separate experiments were designed to determine: (1) if channel catfish show a ventilatory response to hypercapnic acidosis when blood O(2) content is maintained in conscious animals; and (2) whether branchial receptors innervated by cranial nerves IX and X mediate this response. The combination of high O(2) and CO(2) tensions allowed the cardioventilatory effects of hypercapnic acidosis to be assessed independently of Root or Bohr mediated changes in blood O(2) content. In the absence of significant changes in dorsal or ventral aorta O(2) content, hyperoxic hypercapnia significantly stimulated ventilation, relative to hyperoxic exposure. Hypercapnic acidosis, however, had no significant effects on blood pressure or heart rate. Branchial denervation in ASB fish abolished the ventilatory response to hypercapnic acidosis. The results indicate that hypercapnic acidosis independently stimulates ventilation in channel catfish. This response is mediated by CO(2)/pH-sensitive branchial receptors innervated by cranial nerves IX and X.     

Evidence of a role for catecholamines in the control of breathing in fish

Summary Our current knowledge of the control of ventilation in fish is incomplete at all levels. The respiratory rhythm originates in a medullary central pattern generator (CPG), which has yet to be clearly identified and characterized. Its activity is directly modulated by inputs from elsewhere in the CNS and from peripheral mechanoreceptors. The central location of respiratory motoneurones, innervating the various respiratory muscles, has been described in detail for some fish, particularly elasmobranchs. We are still unclear, however, about the link between the CPG and the sequential firing of the motoneurones, which result in coordinated contractions of the respiratory muscles, and about the mechanisms that result in recruitment of feeding muscles into forced ventilation. In teleosts, ventilation is matched to oxygen requirements by stimulation of gill chemoreceptors, which seem to respond to oxygen content or supply. There is little evidence of a role for these receptors in elasmobranchs.Chemoreceptor stimulation evokes a number of reflex changes in the respiratory and cardiovascular systems of fish that are rapid in onset and seem adaptive (e.g. increased ventilation and a bradycardia in response to hypoxia). Conditions that result in hypoxaemia and the consequent ventilatory changes also cause an elevation in circulating catecholamine levels. We have explored the possibility of a causal relationship between these levels and the ventilatory response. Strong evidence for this relationship arises from experiments on hypoxia and acid infusion, which trigger a ventilatory increase and a rise in circulating catecholamines. Both ventilatory responses are blocked by an injection of propranolol, indicating that adrenoreceptors are involved in the response.The ventilatory response to hypoxia, in teleosts at least, occurs very rapidly, perhaps before any marked increase in circulating catecholamines and almost certainly before any blood-borne catecholamines could reach the respiratory neurones. This argues for an immediate neuronal reflex based on chemoreceptors in the gill region responding to hypoxia. Clearly, circulating catecholamines also affect ventilation through some action in the medulla and could act in concert with a direct neuronal chemoreceptive drive during hypoxia. The studies on acid infusion during hyperoxia, where there is an acidosis but no increase in ventilation or blood catecholamines, would argue against any hydrogen ion receptor, either peripheral or central, being involved in the reflex ventilatory response to acidotic conditions in fish.The release of catecholamines into the circulation, therefore, seems to be an absolute requirement for the ventilatory response to acidosis in fish. Present evidence supports a role for -adrenergic receptors on respiratory neurones, stimulated by changes in the levels of circulating catecholamines, in the control of ventilatory responses to marked changes in oxygen availability in fish, such as those occurring in the post-exercise acidotic state.     

Relationship of CSF pH, O2, and CO2 responses in metabolic acidosis and alkalosis in humans

The effect of induced metabolic acidosis (48 h of NH4Cl ingestion, BE - 10.6 +/- 1.1) and alkalosis (43 h of NaHCO3- ingestion BE 8.8 +/- 1.6) on arterial and lumber CSF pH, Pco2, and HCO3- and ventilatory responses to CO2 and to hypoxia was assessed in five healthy men. In acidosis lumbar CSF pH rose 0.033 +/- 0.02 (P less than 0.05). In alkalosis CSF pH was unchanged. Ventilatory response lines to CO2 at high O2 were displaced to the left in acidosis (9.0 +/- 1.4 Torr) and to the right in alkalosis (4.5 +/- 1.5 Torr) with no change in slope. The ventilatory response to hypoxia (delta V40) was increased in acidosis (P less than 0.05) and it was decreased in four subjects in alkalosis (P, not significant). We conclude that the altered ventilatory drives of steady-state metabolic imbalance are mediated by peripheral chemoreceptors, and in acidosis the medullary respiratory chemoreceptor drive is decreased.     

CO2/H(+) sensing: peripheral and central chemoreception

H(+) is maintained constant in the internal environment at a given body temperature independent of external environment according to Bernard's principle of "milieu interieur". But CO2 relates to ventilation and H(+) to kidney. Hence, the title of the chapter. In order to do this, sensors for H(+) in the internal environment are needed. The sensor-receptor is CO2/H(+) sensing. The sensor-receptor is coupled to integrate and to maintain the body's chemical environment at equilibrium. This chapter dwells on this theme of constancy of H(+) of the blood and of the other internal environments. [H(+)] is regulated jointly by respiratory and renal systems. The respiratory response to [H(+)] originates from the activities of two groups of chemoreceptors in two separate body fluid compartments: (A) carotid and aortic bodies which sense arterial P(O2) and H(+); and (B) the medullary H(+) receptors on the ventrolateral medulla of the central nervous system (CNS). The arterial chemoreceptors function to maintain arterial P(O2) and H(+) constant, and medullary H(+) receptors to maintain H(+) of the brain fluid constant. Any acute change of H(+) in these compartments is taken care of almost instantly by pulmonary ventilation, and slowly by the kidney. This general theme is considered in Section 1. The general principles involving cellular CO2 reactions mediated by carbonic anhydrase (CA), transport of CO2 and H(+) are described in Section 2. Since the rest of the chapter is dependent on these key mechanisms, they are given in detail, including the role of Jacobs-Stewart Cycle and its interaction with carbonic anhydrase. Also, this section deals briefly with the mechanisms of membrane depolarization of the chemoreceptor cells because this is one mechanism on which the responses depend. The metabolic impact of endogenous CO2 appears in the section with a historical twist, in the context of acclimatization to high altitude (Section 3). Because low P(O2) at high altitude stimulates the peripheral chemoreceptors (PC) increasing ventilation, the endogenous CO2 is blown off, making the internal milieu alkaline. With acclimatization however ventilation increases. This alkalinity is compensated in the course of time by the kidney and the acidity tends to be restored, but the acidification is not great enough to increase ventilation further. The question is what drives ventilation during acclimatization when the central pH is alkaline? The peripheral chemoreceptor came to the rescue. Its sensitivity to P(O2) is increased which continues to drive ventilation further during acclimatization at high altitude even when pH is alkaline. This link of CO2 through the O2 chemoreceptor is described in Section 4 which led to hypoxia-inducible factor (HIF-1). HIF-1 is stabilized during hypoxia, including the carotid body (CB) and brain cells, the seat of CO2 chemoreception. The cells are always hypoxic even at sea level. But how CO2 can affect the HIF-1 in the brain is considered in this section. CO2 sensing in the central chemoreceptors (CC) is given in Section 5. CO(2)/H(+) is sensed by the various structures in the central nervous system but its respiratory and cardiovascular responses are restricted only to some areas. How the membranes are depolarized by CO2 or how it works through Na(+)/Ca(2+) exchange are discussed in this section. It is obvious, however, that CO2 is not maintained constant, decreasing with altitude as alveolar P(O2) decreases and ventilation increases. Rather, it is the [H(+)] that the organism strives to maintain at the expense of CO2. But then again, [H(+)] where? Perhaps it is in the intracellular environment. Gap junctions in the carotid body and in the brain are ubiquitous. What functions they perform have been considered in Section 6. CO2 changes take place in lung alveoli where inspired air mixes with the CO2 from the returning venous blood. It is the interface between the inspired and expired air in the lungs where CO2 change is most dramatic. As a result, various investigators have looked for CO2 receptors in the lung, but none have been found in the mammals. Instead, CO2/H(+) receptors were found in birds and amphibians. However, they are inhibited by increasing CO2/H(+), instead of stimulated. But the afferent impulses transmitted to the brain produced stimulation in the efferents. This reversal of afferent-efferent inputs is a curious situation in nature, and this is considered in Section 7. The NO and CO effects on CO2 sensing are interesting and have been briefly mentioned in Section 8. A model for CO2/H(+) sensing by cells, neurons and bare nerve endings are also considered. These NO effects, models for CO2/H(+) and O2-sensitive cells in the CNS have been considered in the perspectives. Finally, in conclusion, the general theme of constancy of internal environment for CO2/H(+) is reiterated, and for that CO2/H(+) sensors-receptors systems are essential. Since CO2/H(+) sensing as such has not been reviewed before, the recent findings in addition to defining basic CO2/H(+) reactions in the cells have been briefly summarized.     

Hyperoxic exposure affects the ventilatory response to hypoxia in awake rats

We tested whether hyperbaric O2 (HBO) has an adverse effect on the hypoxic ventilatory drive. Four groups of rats were exposed for 550 min to O2 at 1.67, 1.90, and 2.15 ATA and to air at 1.90 ATA, respectively. Ventilatory parameters (frequency, tidal volume, and minute ventilation) were measured using whole-body plethysmography, before the hyperbaric exposure, immediately after the exposure, and up to 20 days after the exposure. Resting ventilation was not affected after exposure at 1.90 ATA to air or at 1.67 ATA to O2. HBO at 1.90 and 2.15 ATA caused a reduction of frequency and an elevation of tidal volume at different inspired gases: air, 5% CO2 balance O2, 80% O2, and 4.5% O2. However, minute ventilation on the day after the hyperoxic exposure was not different from the control at either air, 5% CO2, or 80% O2 but was markedly attenuated on the first three breaths at 4.5% O2. The hypoxic ventilation decreased to 48 +/- 13 (SD) and 32 + 11% after 1.90 and 2.15 ATA, respectively. The ventilatory parameters recovered in the days after HBO. We conclude that HBO reversibly depresses the hypoxic ventilatory drive, most probably by a direct effect on the carotid O2 chemoreceptors.     

Digital Computer Simulation of Respiratory Response to Cerebrospinal Fluid PCO2 in the Cat

The respiratory control system is treated as linear with a transmission delay between ventilation and sensing points (chemoreceptors). To the accepted variables involving body gas stores, ventilatory effects, transmission effects, and steady state pH, P(CO2), P(O2) chemoreceptor response, certain detailed analysis of the central receptors have been added. By construction of a model for medullary CO(2) receptor utilizing expected values of CNS (central nervous system) circulation, CO(2) production, and tissue-buffering effects, results of experimental observation of the effects of alteration of CSF were simulated. The inclusion of CSF effects also allowed simulation of the response to alteration in inspired CO(2), hyperventilation, and the periodic breathing with prolongation of circulation time.     

Rate of rise of intrapulmonary CO2 drives breathing frequency in garter snakes.

Garter snakes increase ventilation in response to elevated venous PCO2 without a concomitant rise in arterial PCO2 (Furilla et al. Respir. Physiol. 83: 47-60, 1991). Elevating venous PCO2 will increase the PCO2 gradient between pulmonary arterial blood and intrapulmonary gas during inspiration, leading to a greater rate of rise of intrapulmonary CO2 after inspiration. Because the lung contains CO2-sensitive receptors, I assessed the effect of the rate of rise of intrapulmonary CO2 on ventilation in unidirectionally ventilated snakes. CO2 concentration was altered using a digital gas mixer connected to a personal computer. Breathing frequency was highly correlated with the rate of rise intrapulmonary CO2 but only slightly affected by peak intrapulmonary CO2. On the other hand, tidal volume was more closely related to peak intrapulmonary CO2 than to the rate of rise of CO2. Bilateral pulmonary or cervical vagotomy nearly eliminated the ventilatory response associated with altered CO2 rise times but had little influence on the tidal volume response to the rate of rise of CO2. The mechanism whereby breathing frequency is controlled by the rate of rise of intrapulmonary CO2 is likely to originate with intrapulmonary chemoreceptors and may be important in the control of breathing during exercise.     

Respiration during recovery from exercise: effects of trapping and release of femoral blood flow

To investigate the contribution of vascular and metabolic stimuli to the sustained hyperpnea after exercise, the respiratory effects of obstructing and then releasing the femoral blood flow were recorded in 15 normal volunteers during recovery from steady-state cycle exercise (80 W). Obstruction was achieved using cuffs around the upper thighs, inflated for the first 2 min of recovery to a pressure of 200 mmHg. Cuff inflation significantly reduced ventilation during recovery compared with control (P less than 0.001); the subsequent release of pressure was accompanied by an increase in ventilation (averaging 3.2 l/min), which began on the first breath after release. This preceded a rise in end-tidal CO2 (maximum 8.3 Torr increase), which first became significant on the fourth breath after release and led to a further rise in ventilation. The first-breath increase in ventilation after cuff release persisted, although slightly attenuated (averaging 2.5 l/min), in additional experiments with inspired O2 fraction of 1.0. The pattern of ventilatory response was also similar when the experiments were performed with 5% CO2 in air as the inspirate. The immediate rise in ventilation on cuff release, together with the persistent response on 100% O2, suggests that the vascular changes resulting from cuff release exert an influence on ventilation independent of the effects of released metabolites on the known chemoreceptors. The persistence of the response on 5% CO2 indicates that CO2-sensitive lung afferents do not have a major role in these responses.     

Optimization of the method of progressive hypercapnia by determination of the sensitivity threshold

Ventilatory response to CO2 rebreathing is a method which allows to evaluate the reactivity of chemoreceptors. However this method doesn't study the sensibility threshold, i.e. the Pe.t.CO2 value for which the ventilatory response appears clearly. This sensibility threshold was measured in 10 healthy subjects by rebreathing a gas mixture: 7% CO2 and 50% O2 to avoid hypoxy. It was defined as the value of Pe.t.CO2 for which the ventilation was above the tidal ventilation + 2 standard deviations. The sensibility threshold (51 +/- 4.35 mm Hg) was independent of the reactivity slope represented by the slope of the linear relation between minute ventilation (VE) and Pe.t.CO2 (1.34 +/- 0.60 l/min/mm Hg/m2) and consequently appears as an interesting parameter in order to evaluate the ventilatory response to CO2 by rebreathing.     

Response time and sensitivity of the ventilatory response to CO2 in unanesthetized intact dogs: central vs. peripheral chemoreceptors.

We assessed the speed of the ventilatory response to square-wave changes in alveolar P(CO2) and the relative gains of the steady-state ventilatory response to CO2 of the central chemoreceptors vs. the carotid body chemoreceptors in intact, unanesthetized dogs. We used extracorporeal perfusion of the reversibly isolated carotid sinus to maintain normal tonic activity of the carotid body chemoreceptor while preventing it from sensing systemic changes in CO2, thereby allowing us to determine the response of the central chemoreceptors alone. We found the following. 1) The ventilatory response of the central chemoreceptors alone is 11.2 (SD = 3.6) s slower than when carotid bodies are allowed to sense CO2 changes. 2) On average, the central chemoreceptors contribute approximately 63% of the gain to steady-state increases in CO2. There was wide dog-to-dog variability in the relative contributions of central vs. carotid body chemoreceptors; the central exceeded the carotid body gain in four of six dogs, but in two dogs carotid body gain exceeded central CO2 gain. If humans respond similarly to dogs, we propose that the slower response of the central chemoreceptors vs. the carotid chemoreceptors prevents the central chemoreceptors from contributing significantly to ventilatory responses to rapid, transient changes in arterial P(CO2) such as those after periods of hypoventilation or hyperventilation ("ventilatory undershoots or overshoots") observed during sleep-disordered breathing. However, the greater average responsiveness of the central chemoreceptors to brain hypercapnia in the steady-state suggests that these receptors may contribute significantly to ventilatory overshoots once unstable/periodic breathing is fully established.     

Differential respiratory effects of HCO3- and CO2 applied on ventral medullary surface of rats

To estimate whether H+ is the unique stimulus of the medullary chemosensor, ventilatory effects of HCO3- and/or CO2 applied on the ventral medullary surface using an improved superfusion technique and of CO2 inhalation were compared in halothane-anesthetized spontaneously breathing rats. Superfusion with low [HCO3-]-acid mock cerebrospinal fluid (CSF) (normal Pco2) induced a significant increase in ventilation, with an accompanying reduction in endtidal Pco2 (PETco2). High [HCO3-]-alkaline CSF depressed ventilation. Changes in Pco2 of superfusing CSF, on the other hand, had no significant effect despite the similar changes in pH. Simultaneous decrease in [HCO3-] and Pco2 of mock CSF with normal pH also maintained stimulated respiration. CO2 inhalation during superfusion with various [HCO3-] solutions caused further increase in ventilation as PETco2 increased. The results suggest that the surface area of the rat ventral medulla contains HCO3- (or H+)-sensitive respiratory neural substrates which are, however, little affected by CO2 in the subarachnoid fluid. A CO2 (or CO2-induced H+)-sensitive chemosensor responsible for the increase in ventilation during CO2 inhalation may exist elsewhere functionally apart from the HCO3- (or H+)-sensitive sensor in the examined surface area.     

An evaluation of cobalt chloride as an O2-sensitive chemoreceptor stimulant in channel catfish

The effects of cobalt chloride on heart rate, blood pressure, ventilatory frequency and opercular pressure amplitude in channel catfish, Ictalurus punctatus were measured to evaluate the potential of cobalt as a histochemical probe to study mechanisms of oxygen chemoreception, as well as assess the general effects of cobalt on the cardioventilatory physiology of fishes. Cobalt, like cyanide, has been previously used to stimulate oxygen chemoreceptors and hypoxic reflexes in mammals but there is little information on the cardioventilatory effects of cobalt on fish. Catfish were exposed to increasing concentrations (1-20 mg/kg) of cobalt in the water (external) or injections into the dorsal aorta (internal) and the cardioventilatory effects recorded. Mean arterial pressure showed a significant, dose-dependent increase in response to cobalt injections. Heart rate increased slowly, but significantly after cobalt injections but the magnitude of change was not dose-dependent. There was a small increase in ventilatory rate but no effect on amplitude. External cobalt had similar effects but the responses were weaker. Although cobalt stimulated some cardioventilatory reflexes the pattern and magnitude of the responses were noticeably different from those of cyanide and hypoxia. The results suggest that the cardioventilatory reflexes stimulated by cobalt were not mediated by O(2)-sensitive chemoreceptors and that cobalt is not an effective O(2) receptor stimulant in fishes.     

Potentiation of exercise ventilatory response by airway CO2 and dead space loading.

We examined the effects of different modes of airway CO2 load on the ventilation-CO2 output (VE-VCO2) relationship during mild to moderate exercise. Four young and three older male subjects underwent incremental steady-state treadmill exercise while breathing a mixture of CO2 in O2 (CO2 loading) or 100% O2 with and without a large external dead space [DS loading and control (C), respectively]. During DS loading, the elevated arterial PCO2 (PaCO2) remained constant from rest to mild exercise and began to increase only at higher work rates. To achieve similar chemical drive, the same PaCO2 levels were established during CO2 loading by external PCO2 forcing. In the young group, CO2 loading resulted in a steepening of the VE-VCO2 relationship compared with C, whereas in the older group the reverse pattern was found. DS loading resulted in a consistent increase in the VE-VCO2 slope compared with C and CO2 loading [39.1 +/- 5.6 (mean +/- SD) vs. 24.9 +/- 5.0 and 26.7 +/- 4.4, respectively] in all subjects. The difference in potentiation of VE-VCO2 by CO2 and DS loading was not due to differences in mean chemical drive or changes in breathing pattern. Thus changes in the profile of airway CO2 influx may have an independent influence on ventilatory CO2-exercise interaction. Peripheral chemoreceptors mediation, although important, is not obligatory for this behavior.     

Effects of hypercapnia and hypocapnia on ventilatory variability and the chaotic dynamics of ventilatory flow in humans

In humans, lung ventilation exhibits breath-to-breath variability and dynamics that are nonlinear, complex, sensitive to initial conditions, unpredictable in the long-term, and chaotic. Hypercapnia, as produced by the inhalation of a CO(2)-enriched gas mixture, stimulates ventilation. Hypocapnia, as produced by mechanical hyperventilation, depresses ventilation in animals and in humans during sleep, but it does not induce apnea in awake humans. This emphasizes the suprapontine influences on ventilatory control. How cortical and subcortical commands interfere thus depend on the prevailing CO(2) levels. However, CO(2) also influences the variability and complexity of ventilation. This study was designed to describe how this occurs and to test the hypothesis that CO(2) chemoreceptors are important determinants of ventilatory dynamics. Spontaneous ventilatory flow was recorded in eight healthy subjects. Breath-by-breath variability was studied through the coefficient of variation of several ventilatory variables. Chaos was assessed with the noise titration method (noise limit) and characterized with numerical indexes [largest Lyapunov exponent (LLE), sensitivity to initial conditions; Kolmogorov-Sinai entropy (KSE), unpredictability; and correlation dimension (CD), irregularity]. In all subjects, under all conditions, a positive noise limit confirmed chaos. Hypercapnia reduced breathing variability, increased LLE (P = 0.0338 vs. normocapnia; P = 0.0018 vs. hypocapnia), increased KSE, and slightly reduced CD. Hypocapnia increased variability, decreased LLE and KSE, and reduced CD. These results suggest that chemoreceptors exert a strong influence on ventilatory variability and complexity. However, complexity persists in the quasi-absence of automatic drive. Ventilatory variability and complexity could be determined by the interaction between the respiratory central pattern generator and suprapontine structures.     

In vivo study on medullary H(+)-sensitive neurons

Using the micro pressure ejection technique, we examined responses of medullary neurons with nonphasic discharges (164 units) to direct application of acidified mock cerebrospinal fluid (CSF, pH 6.85-7.05) in decerebrated spontaneously breathing cats. We found 16 H(+)-sensitive cells; they were excited promptly on application of approximately 500 pl of acidified mock CSF in the vicinity of the neuron under investigation, whereas they were unaffected by microejection of the control mock CSF (pH 7.25-7.60). Of the 16 H(+)-sensitive cells, 10 units were further found to be excited by transcapillary stimulation of the central chemoreceptors by using a method of intravertebral arterial injection of CO2-saturated saline. The discharges increased in a similar time course to that of ventilatory augmentation. Distributions of these 10 specific H(+)-sensitive cells were found in the vicinity of nucleus tractus solitarii as well as deep in the ventrolateral medulla. The present results suggest a possibility that pH-dependent central chemoreceptors, if any, would be located in two distinct medullary regions described in this study.     

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.     

Upper airway CO2 receptors in tegu lizards: localization and ventilatory sensitivity

1. Tidal volume, end-tidal CO2, and ventilatory frequency in Tupinambis nigropunctatus were measured in response to CO2 (1-4%) delivered to either the mouth or nares. Additionally, the sensitivity of the ventilatory response to nasal CO2 was evaluated at CO2 concentrations less than 1%. The ventilatory parameters were also measured in response to CO2 (1-4%) delivered to the nares after the olfactory peduncle was transected. 2. It was found that (0.4-4%) nasal CO2 depressed ventilatory frequency by 9% to 83% respectively, while tidal volume was not significantly altered. CO2 (1-4%) delivered to the mouth produced no apparent changes in any of the ventilatory parameters. Following transection of the olfactory peduncle, nasal CO2 was ineffective in producing any change in ventilatory frequency or depth. 3. These findings indicate that CO2-sensitive receptors are located in either the nasal or vomeronasal membranes of tegu lizards and that the olfactory peduncle must be intact for these receptors to affect ventilatory changes in response to elevated CO2 concentrations. The receptors are capable of mediating a ventilatory response to CO2 concentrations lower than those found in either expired air or in confined spaces such as occupied burrows. 4. The discrepancies in the ventilatory responses of lizards and snakes to inspired CO2 reported in past experiments may be partially explained by the presence of nasal or vomeronasal CO2-sensitive receptors.     

Short-term modulation of the exercise ventilatory response in young men.

Arterial isocapnia is a hallmark of moderate exercise in humans and is maintained even when resting arterial Pco(2) (Pa(CO(2))) is raised or lowered from its normal level, e.g., with chronic acid-base changes or acute increases in respiratory dead space. When resting ventilation and/or Pa(CO(2)) are altered, maintenance of isocapnia requires active adjustments of the exercise ventilatory response [slope of the ventilation (Ve)-CO(2) production (Vco(2)) relationship, DeltaVe/DeltaVco(2)]. On the basis of animal studies, it has been proposed that a central neural mechanism links the exercise ventilatory response to the resting ventilatory drive without need for changes in chemoreceptor feedback from rest to exercise, a mechanism referred to as short-term modulation (STM). We tested the hypothesis that STM is elicited by increased resting ventilatory drive associated with added external dead space (DS) in humans. Twelve young men were studied in control conditions and with added DS (200, 400, and 600 ml; randomized) at rest and during mild-to-moderate cycle exercise. DeltaVe/DeltaVco(2) increased progressively as DS volume increased (P < 0.0001). While resting end-tidal Pco(2) (Pet(CO(2))) increased with DS, the change in Pet(CO(2)) from rest to exercise was not increased, indicating that increased chemoreceptor feedback from rest to exercise cannot account for the greater exercise ventilatory response. We conclude that STM of the exercise ventilatory response is induced in young men when resting ventilatory drive is increased with external DS, confirming the existence of STM in humans.     

Effect of aging on ventilatory response to exercise and CO2

Studies were performed to determine the effects of aging on the ventilatory responsiveness to two known respiratory stimulants, inhaled CO2 and exercise. Although explanation of the physiological mechanisms underlying development of exercise hyperpnea remains elusive, there is much circumstantial evidence that during exercise, however mediated, ventilation is coupled to CO2 production. Thus matched groups of young and elderly subjects were studied to determine the relationship between increasing ventilation and increasing CO2 production (VCO2) during steady-state exercise and the change in their minute ventilation in response to progressive hypercapnia during CO2 rebreathing. We found that the slope of the ventilatory response to hypercapnia was depressed in elderly subjects when compared with the younger control group (delta VE/delta PCO2 = 1.64 +/- 0.21 vs. 2.44 +/- 0.40 l X min-1 X mmHg-1, means +/- SE, respectively). In contrast, the slope of the relationship between ventilation and CO2 production during exercise in the elderly was greater than that of younger subjects (delta VE/delta VCO2 = 29.7 +/- 1.19 vs. 25.3 +/- 1.54, means +/- SE, respectively), as was minute ventilation at a single work load (50 W) (32.4 +/- 2.3 vs. 25.7 +/- 1.54 l/min, means +/- SE, respectively). This increased ventilation during exercise in the elderly was not produced by arterial O2 desaturation, and increased anaerobiasis did not play a role. Instead, the increased ventilation during exercise seems to compensate for increased inefficiency of gas exchange such that exercise remains essentially isocapnic. In conclusion, in the elderly the ventilatory response to hypercapnia is less than in young subjects, whereas the ventilatory response to exercise is greater.