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.     

Differential effects of CO2 and H+ as central stimuli of respiration in the cat

Effects of H+ and CO2 as independent stimuli of central respiratory chemoreceptors were studied in anesthetized cats in which pH and PCO2 on the ventral surface of the medulla (pHe and PeCO2) could be monitored in response to intravenous acid infusion or CO2 inhalation or to a combination of CO2 inhalation and base infusion that allowed PeCO2 to vary at constant pHe. Respiratory responses to these changes were monitored by measuring tidal volume (VT), respiratory frequency (f), and total ventilation. Respiratory acidosis stimulated ventilation by increasing both VT and f. Mild metabolic acidosis (decrease in pHe less than 0.05) exerted similar effects, but more severe metabolic acidosis failed to produce further stimulation. Increasing or decreasing PeCO2 at constant pHe caused pronounced increases or decreases in respiration mediated both by VT and f. For the same change in PeCO2 the respiratory effects were, however, less pronounced when pHe was kept constant than when pHe was allowed to change with PeCO2. The results suggest that both CO2 and H+ exert independent effects on respiration via central chemoreceptors.     

Role of brain lactic acidosis in hypoxic depression of respiration

The role of lactic acidosis of progressive brain hypoxia (PBH) as both a central chemoreceptor stimulant and a general respiratory depressant was assessed by preventing lactate formation both locally and globally with dichloroacetate (DCA). Phrenic nerve activity (PN) and ventral medullary pH (Vm pH) responses to PBH (1% CO-40% O2-balance N2) were determined in anesthetized, paralyzed, peripherally chemodenervated, vagotomized cats while fraction of end-tidal CO2 (FETCO2) and mean arterial blood pressure (MABP) were maintained constant. Topical DCA near the central chemoreceptors prevented the progressive Vm acidosis of PBH and was associated with a slightly greater depression of PN for any given level of brain hypoxia [75 +/- 12% base-line mock cerebrospinal fluid compared with 63 +/- 11% base-line topical DCA at O2 content of arterial blood (CaO2) of 7.5 ml O2/dl]. Systemic DCA also prevented the progressive acidosis of PBH and significantly altered the profile of depression with PBH. Before DCA, PBH produced a progressive reduction in PN after reducing CaO2 by 20%. After DCA, PN was not significantly depressed until CaO2 was reduced to very low levels, whereupon there was a sharp decline in PN. Before DCA, reducing CaO2 to 6 ml O2/dl reduced PN by 41 +/- 16%, whereas after DCA there was no significant reduction in PN (4 +/- 5%). We conclude that 1) lactic acidosis near the central chemosensitive regions does produce a small stimulation of respiration during PBH but that 2) the overwhelming response to central lactic acidosis of PBH is respiratory depression.     

Mechanisms of respiratory response to isoproterenol in glomectomized cats

Effects of intravenous isoproterenol (2-3 micrograms) on arterial pressure, end-tidal CO2 partial pressure (PCO2), medullary extracellular fluid (ECF) pH, and phrenic activity were studied in 13 anesthetized paralyzed cats whose vagi and carotid sinus nerves were cut. The cats were servo-ventilated to keep PCO2 relatively constant. Injections of Ringer solution were without effect. Isoproterenol caused arterial pressure to fall, a transient small (1 Torr) increase of PCO2, increased venous CO2 return to the lungs, a medullary ECF acidosis, and a stimulation of respiration that continued to be elevated after arterial pressure, PCO2, and medullary ECF pH had returned to control. We show that the ECF acidosis is minimally due to the hypotension and to the small transient rise of PCO2. We also show that the respiratory response cannot be explained solely by the ECF acidosis. We conclude that, in addition to its known stimulation of peripheral chemoreceptors, isoproterenol causes medullary ECF to become acidic probably due to metabolic effects on neural tissue and has a separate direct stimulating effect on neurons in the brain.     

The essential role of carotid body chemoreceptors in sleep apnea

Sleep apnea is attributable, in part, to an unstable ventilatory control system and specifically to a narrowed "CO2 reserve" (i.e., the difference in P(a)CO2 between eupnea and the apneic threshold). Findings from sleeping animal preparations with denervated carotid chemoreceptors or vascularly isolated, perfused carotid chemoreceptors demonstrate the critical importance of peripheral chemoreceptors to the ventilatory responses to dynamic changes in P(a)CO2. Specifically, (i) carotid body denervation prevented the apnea and periodic breathing that normally follow transient ventilatory overshoots; (ii) the CO2 reserve for peripheral chemoreceptors was about one half that for brain chemoreceptors; and (iii) hypocapnia isolated to the carotid chemoreceptors caused hypoventilation that persisted over time despite a concomitant, progressive brain respiratory acidosis. Observations in both humans and animals are cited to demonstrate the marked plasticity of the CO2 reserve and, therefore, the propensity for apneas and periodic breathing, in response to changing background ventilatory stimuli.     

Identification of a subsurface area in the ventral medulla sensitive to local changes in PCO2.

The exact location of the central respiratory chemoreceptors sensitive to changes in PCO2 has not yet been determined. To avoid the confounding effects of the cerebral circulation, we used the in vitro brain stem-spinal cord of neonatal rats (1-5 days old) to identify areas within 500 microns of the ventral surface of the medulla where changes in PCO2 evoked a sudden increase in the rate of respiratory neural activity. The preparation was superfused with mock cerebrospinal fluid (CSF) while maintained at constant temperature (26 +/- 1 degrees C) and pH (7.34). Respiratory frequency increased linearly with decreases in superfusate pH (r2 = 0.92, P less than 0.001), indicating that the respiratory circuitry for the detection of CO2 and stimulation of breathing was intact in this preparation. The search for central chemoreceptors was performed with a specially designed micropipette that allowed microejection of 2-10 nl of mock CSF equilibrated with different CO2-O2 gas mixtures. The pipette was advanced in 50- to 100-microns steps by use of a microdrive to a maximum depth of 500 microns from the surface of the ventral medulla. Depending on the location of the micropipette, ejection of CO2-acidified mock CSF at depths of 100-350 microns below the ventral surface of the medulla stimulated neural respiratory output. Using this response as an indication of the location of central respiratory chemoreceptors, we found that chemoreceptive elements were located in a column in the ventromedial medulla extending from the hypoglossal rootlets caudally to an area 0.75 mm caudal to VI nerve in the rostral medulla.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mathematische Analyse des Respirationssystems

The respiratory system is described as a control system. The controller consists of the peripheral and central chemoreceptors, the respiratory centre in the medulla oblongata and the controlling signal “alveolar ventilation”. The controlled system comprise three compartments (lung, brain, tissue) connected by the circulating blood. The controlled values of the system are explicit the arterial O₂-pressure and the CO₂-pressure of the brain-compartment. Hypoxia, hyperoxia and hypercapnia are the disturbing signals, which are caused by changing concentrations in the inspired gas. In this research both dynamic and steady-state behavior are studied. The steady-state and transient data of the model generally approach the findings of the experiments. The analysis of the efficiency of the regulation states the quality of the control system. In the on-and off-transients the CO₂-fractions of the alveolar gas, and in the off-transient the alveolar ventilation deviate from the experimental results in hypercapnic disturbances. Reasons for these differences and others existing between simulation and experiment are discussed.

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Effects on breathing in awake and sleeping goats of focal acidosis in the medullary raphe.

Our aim was to determine the effects of focal acidification in the raphe obscurus (RO) and raphe pallidus (RP) on ventilation and other physiological variables in both the awake and sleep states in adult goats. Through chronically implanted microtubules, 1) a focal acidosis was created by microdialysis of mock cerebrospinal fluid (mCSF), equilibrated with various levels of CO2, and 2) medullary extracellular fluid (ECF) pH was measured by using a custom-made pH electrode. Focal acidosis in the RO or RP, by dialyzing either 25 or 80% CO2 (mCSF pH approximately 6.8 or 6.3), increased (P < 0.05) inspiratory flow by 8 and 12%, respectively, while the animals were awake during the day, but not at night while they were awake or in non-rapid eye movement sleep. While the animals were awake during the day, there were also increases in heart rate and blood pressure (P < 0.05) but no significant change in metabolic rate or arterial Pco2. Dialysis with mCSF equilibrated with 25 or 80% CO2 reduced ECF pH by the same amount (25%) or three times more (80%) than when inspired CO2 was increased to 7%. During CO2 inhalation, the reduction in ECF pH was only 50% of the reduction in arterial pH. Finally, dialysis in vivo only decreased ECF pH by 19.1% of the change during dialysis in an in vitro system. We conclude that 1) the physiological responses to focal acidosis in the RO and RP are consistent with the existence of chemoreceptors in these nuclei, and 2) local pH buffering mechanisms act to minimize changes in brain pH during systemic induced acidosis and microdialysis focal acidosis and that these mechanisms could be as or more important to pH regulation than the small changes in inspiratory flow during a focal acidosis.     

Effects on breathing of focal acidosis at multiple medullary raphe sites in awake goats.

To gain insight into why there are chemoreceptors at widespread sites in the brain, mircrotubules were chronically implanted at two or three sites in the medullary raphe nuclei of adult goats (n = 7). After >2 wk, microdialysis (MD) probes were inserted into the microtubules to create focal acidosis (FA) in the awake state using mock cerebral spinal fluid (mCSF) equilibrated with 6.4% (pH = 7.3), 50% (pH = 6.5), or 80% CO(2) (pH = 6.3), where MD with 50 and 80% CO(2) reduces tissue pH by 0.1 and 0.18 pH unit, respectively. There were no changes in all measured variables with MD with 6.4% at single or multiple raphe sites (P > 0.05). During FA at single raphe sites, only 80% CO(2) elicited physiological changes as inspiratory flow was 16.9% above (P < 0.05) control. However, FA with 50 and 80% CO(2) at multiple sites increased (P < 0.05) inspiratory flow by 18.4 and 30.1%, respectively, where 80% CO(2) also increased (P < 0.05) tidal volume, heart rate, CO(2) production, and O(2) consumption. FA with 80% CO(2) at multiple raphe sites also led to hyperventilation (-2 mmHg), indicating that FA had effects on breathing independent of an increased metabolic rate. We believe these findings suggest that the large ventilatory response to a global respiratory brain acidosis reflects the cumulative effect of stimulation at widespread chemoreceptor sites rather than a large stimulation at a single site. Additionally, focal acidification of raphe chemoreceptors appears to activate an established thermogenic response needed to offset the increased heat loss associated with the CO(2) hyperpnea.     

Intracellular pH in hibernation and respiratory acidosis in the European hamster

Intracellular pH was determined (DMO method) in European hamsters, in the spontaneously-occurring respiratory acidosis of hibernation, in hypercapnia due to breathing 12% CO2 in air in euthermy in spring, and in euthermicnormocapnic controls. From euthermy to hibernation, the temperature coefficient of pH was lowest in blood plasma and brain, intermediate in striated muscles (thigh muscles and diaphragm), and highest in heart and liver (Fig. 1). Correspondingly, the estimated dissociation ratio of the protein imidazole buffer groups, alpha Im, decreased markedly in plasma and brain, denoting an acid titration, but varied little in liver and heart. Striated muscles were intermediate (Fig. 2). Like in other mammals, intracellular responses to short-term euthermic respiratory acidosis were characterized by a partial metabolic compensation in the brain and a small metabolic acidification in striated muscles. In hibernation, a powerful metabolic compensation took place in liver and heart, nearly restoring alpha Im, but none occurred in brain (Figs. 3 to 5). The existence of an intracellular acidosis in brain and striated muscles during hibernation is in keeping with an inhibitory role of acidosis, whereas the homeostasis of intracellular alpha Im in liver and heart would subserve the eurythermal functioning of metabolic regulations in these organs, like in most organs of ectotherms.     

Central chemoreceptors

When all peripheral chemoreceptors are denervated, animals continue to show increased ventilation when made to breathe CO2, indicating that receptors within the brain ("central chemoreceptors") are excited by acidity or changes in CO2. No cells have been identified within the brain that are indisputedly chemoreceptors for CO2 or H+, but there is abundant evidence that respiration can be affected by chemical, electrical, and thermal stimuli applied locally to the ventral surface of the medulla. Furthermore, the actions of traditional central chemical respiratory stimuli can be blunted or abolished after inhibition of neural function within this ventrolateral medullary shell (VMS). The VMS is an integrative region for cardiovascular and respiratory function and may be involved in nociception. The distinction between the former two is not always clear, but recent studies using microinjection techniques seem promising for identifying the respiratory substrates. The many recent advances elucidating anatomic connections between the VMS and other brain regions are important but do not directly address the question of the site of central respiratory chemosensitivity. Knowledge of such connections, however, should provide more definitive opportunities for addressing this question.     

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.     

CO(2) microdialysis in retrotrapezoid nucleus of the rat increases breathing in wakefulness but not in sleep.

Central chemoreceptors are widespread within the brain stem. We suggest that their function at some sites may vary with the state of arousal. In this study, we tested the hypothesis that the function of chemoreceptors in the retrotrapezoid nucleus (RTN) varies with sleep and wakefulness. In unanesthetized rats, we produced focal acidification of the RTN by means of a microdialysis probe (tip containing the semipermeable membrane = 1-mm length, 240-microm diameter, and 45-nl volume). With the use of a dialysate equilibrated with 25% CO(2), the tissue pH change (measured in anesthetized animals) was 1) limited to within 550 microm of the probe and, 2) at the probe tip, was equivalent to that observed with end-tidal PCO(2) of 63 Torr. This focal acidification of the RTN increased ventilation significantly by 24% above baseline, on average, in 13 trials in seven rats only during wakefulness. The effect was entirely due to an increase in tidal volume. During sleep defined by behavioral criteria, ventilation was unaffected, on average, in 10 trials in seven rats. During sleep, the chemoreceptors in the RTN appear to be inactive, or, if active, the respiratory control system either is not responding or is responding with very low gain. Because ventilation is increased during sleep with all central chemoreceptor sites stimulated via systemic CO(2) application, other central chemoreceptor locations must have enhanced effectiveness.     

Failure of pulmonary acidosis to increase respiratory drive.

Experiments were performed to determine whether increases in acidity isolated to the pulmonary circulation would stimulate hypothesized pulmonary chemoreceptors and increase respiratory drive in the anesthetized paralyzed mechanically ventilated cat (n = 9). Respiratory drive was assessed by measuring the frequency and amplitude of the integrated phrenic neurogram. To create an isolated pulmonary acidosis, blood returning to the lung was acidified by infusion of 0.3 M lactic acid (1.91 ml/min) into the inferior vena cava, while systemic arterial pH was restored to near normal levels by simultaneous infusion of base (0.3 M NaOH) into the left atrium. Six minutes after the start of this dual infusion of acid and base, right ventricular (pulmonary) pH decreased from 7.286 to 7.179 and PCO2 increased 7 Torr. Systemic arterial pH and PCO2 were unchanged from measurements immediately before the infusion. This level of pulmonary acidosis failed to increase respiratory drive as assessed by phrenic activity. To test the sensitivity of the preparation to known systemic arterial chemical stimuli, a combined pulmonary and systemic acidosis was elicited by infusion of 0.3 M lactic acid into the inferior vena cava and 0.3 M NaCl into the left atrium. This infusion significantly lowered both systemic arterial and pulmonary arterial pH (7.343 to 7.155 for systemic arterial pH and 7.286 to 7.067 for pulmonary pH) and increased phrenic efferent activity 45%. We conclude that phrenic efferent activity is unaffected by moderate reductions in the pH of the pulmonary circulation in the absence of a significant systemic arterial acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

CSF bicarbonate regulation in respiratory acidosis and alkalosis.

CSF bicarbonate regulation was studied in respiratory acidosis and alkalosis of 4h duration in antsthetized dogs. PCO2, pH, HCO3, ammonia, and lactate in CSF and arterial and safittal sinus bloof were measured when equal volumes of saline or acetazolamide (8 mg) were injected into lateral cerebral ventricles. The brain CO2 dissociation curve was determined at the end of all experiments. CSF and arterial bicarbonate increased 11.8 and 5.9 meg/l, respectively, in acidosis. Acetazolamide limited the rise in CSF bicarbonate to 4.2 meg/l, and prevented the CSF bicarbonate increase associated with hyperammonemia. During alkalosis CSF bicarbonate fell 6.5 meg/l and CSF lactate increased almost 2 meg/l while arterial bicarbonate fell 5.7 meg/l and lactate remained unchanged. Thus plasma bicarbonate changes account for some of the CSF unchanged. Thus plasma bicarbonate changes account for some of the CSF bicarbonate alterations in respiratory acid-base-disturbances. In acidosis additional CSF bicarbonate is formed by the choroid plexus and glial cells on the inner and outer surfaces of the brain--a reaction catalyzed by the locally present carbonic anhydrase. In alkalosis the greater fall in CSF bicarbonate than blood is due to selective brain and CSF lactic acidosis.     

Regulation of breathing at birth

The factors which regulate the transition to lung gas exchange in the newborn are not well understood. The transition begins within seconds of birth with the newborn's first breath and is largely complete by 30 min of age at which time breathing is continuous, and arterial blood gas tensions and pH approach stable newborn values. Experiments indicate that sensory stimulation caused by cutaneous cooling or sciatic nerve stimulation can result in the initiation of breathing within seconds. Thus, massive sensory stimulation of the newborn caused by labour and delivery probably plays an important role in promoting the rapid onset of lung ventilation. Any delay in the onset of lung gas exchange causes a rise in arterial PCO2 and fall in pH which would stimulate breathing probably via stimulation of the central chemoreceptors. Since an impairment of CO2 elimination is usually observed after birth, a rise in arterial PCO2 likely stimulates breathing in the newborn. However, this impairment is transient and is usually corrected within 30 min to 2 h of age. Recent experiments suggest that placental perfusion inhibits the fetal central respiratory system and that this effect may be mediated by a placentally-produced respiratory inhibitor. Thus, withdrawal of a respiratory inhibitor from the circulation may play an important role in maintaining breathing in the newborn after sensory stimulation wanes and arterial PCO2 returns to normal fetal levels.     

Intra- and extracellular pH of the brain in vivo studied by 31P-NMR during hyper- and hypocapnia.

Studies were performed to determine the pH relationships among the extracellular, intracellular, and arterial blood compartments in the brain in vivo. Resolution of the extracellular monophosphate resonance peak from the intracellular peak in 31P nuclear magnetic resonance (NMR) spectra of sheep brain with the calvarium intact enabled pH measurement in these respective compartments. Sheep were then subjected to both hyper- and hypoventilation, which resulted in a wide range of arterial PCO2 and pH values. Linear regression analysis of pH in these compartments yielded slopes of 0.56 +/- 0.05 for extracellular pH (pHe) vs. arterial pH, 0.43 +/- 0.078 for intracellular pH (pHi) vs. pHe, and 0.23 +/- 0.056 for pHi vs. arterial pH. These data indicate that CO2 buffering capacity is different and decreases from the intracellular to extracellular to arterial blood compartments. Separation of the extracellular space from the vascular space may be a function of the blood-brain barrier, which contributes to the buffering capability of the extracellular compartment. A marked decrease in the pH gradient between the extracellular and intracellular space occurs during hypercarbia and may influence mechanisms of central respiratory control.     

ECF pH dynamics within the ventrolateral medulla: a microelectrode study

Using pH-sensitive microelectrodes, we evaluated pH dynamics of extracellular fluid (ECF) within the ventrolateral medulla (VLM) beneath the central chemoceptive areas in anesthetized, spontaneously breathing cats. Static ECF pH was acid in the superficial layers (less than 1 mm), compared with the overlying cerebrospinal fluid pH that became alkaline gradually during the experiments. In the deeper VLM areas (1-3 mm), no systematic gradients of ECF pH were observed. We found various, isolated regions where intravertebral artery injections of CO2-saturated saline evoked acidic shift of ECF pH in the time course analogous to ventilatory augmentation. Those responsive regions were found to be scattered not only in the superficial layers but also in the deeper VLM areas, although many nonresponsive regions were also intermingled among them. Occlusions of the principal vessels supplying the tested VLM regions diminished but failed to abolish the ECF pH responses to the CO2 loadings, suggesting a collateral blood flow by fine pial vessels. The present study suggests a possibility that the pH-dependent central chemoreceptors, if any, would be scattered in the deeper VLM areas as well as the superficial layers.     

Location of central respiratory chemoreceptors in the developing tadpole

The location of central respiratory chemoreceptors in amphibian larvae may change as the central chemoreceptive function shifts from driving gill to driving lung ventilation during metamorphosis. We examined this possibility in the in vitro brain stem of the pre- and postmetamorphic Rana catesbeiana tadpole by microinjecting hypercapnic artificial cerebrospinal fluid (aCSF) while recording fictive lung ventilation. The rostral and caudal brain stem were separately explored systematically using injections of 11 nl of aCSF equilibrated with 100% CO2 that transiently acidified a 500-microm region, producing a maximum reduction in pH of 0.23 +/- 0.06 at the site of injection. In postmetamorphic tadpoles, chemoreceptive sites were concentrated in the rostral compared with the caudal brain stem. No such segregation was observed in the premetamorphic tadpole. We conclude that, as in lung rhythmogenic function, respiratory chemosensitivity emerges rostrally in the amphibian brain stem during development.     

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.