Pulmonary control systems in exercise: update

We examined recent ideas and findings concerned with the regulation of ventilation and gas transport in moderate and heavy exercise. The primary mediation of exercise hyperpnea remains unknown and highly controversial, but two unique approaches to the problem have advanced our understanding of this neurohumoral regulatory scheme. On the one hand, experimental separation of the pulmonary and systemic circulations was used to reveal a vagally mediated ventilatory response that is clearly attributable to CO2 flow to the lung. This mechanism seems to be most effective as a homeostatic regulator of ventilatory control near resting levels of metabolic rate. On the other hand, a descending neurogenic drive to hyperpnea from the locomotor regions of the central nervous system was also demonstrated experimentally. The importance of regulatory feedback by conventional chemoreceptors in determining the precision of the hyperpneic response was emphasized in explaining the wide spectrum of arterial acid-base regulation during exercise in humans and non-human species. Two commonly accepted homeostatic regulators believed to be operative during heavy exercise were questioned, i.e., the compensatory hyperventilatory response and the maintenance of arterial oxygenation. For example, the hyperventilatory response was shown not to require metabolic acidosis; hyperventilation was not always observed at high work rates despite an abundance of chemical stimuli; and arterial hypoxemia occurred at very high metabolic rates in a significant number of highly fit athletes. These data implied that the capabilities of some aspects of even the healthy pulmonary system may be approached-or even exceeded-during heavy exercise.     

Intravenous acid infusion without lowering arterial pH stimulates breathing

The aim of this study was to determine whether increases in ventilation would occur during intravenous acid infusion even if systemic arterial pH was held constant. In six awake ponies, HCl (500 ml, approximately 0.312 M) was infused into the right atrium at a total dose of 1.0 meq/kg over 18 min while an equivalent dose of NaOH was infused into the left heart to restore systemic arterial pH to normal. Total ventilation increased at the onset of the infusion and remained elevated although systemic arterial pH was normal to slightly alkaline. The increase in ventilation during the initial 2 min of the infusion coincided with an increase in pulmonary arterial PCO2 and decrease in pulmonary arterial pH. As the infusion progressed, however, pulmonary arterial pH and PCO2 returned to near control values due to the recirculation of systemic arterial blood with an acid-base status that had been altered consequent to the hyperventilation. Pulmonary arterial blood pressure was increased significantly during the entire infusion. Infusion of equivalent doses of hypertonic saline led to only minor alterations in the variables that were measured. These experiments demonstrate that this dose of intravenous HCl can increase ventilation independent of reductions in systemic arterial pH. Because increases in ventilation and pulmonary arterial H+ were not well correlated throughout the entire infusion, and pulmonary arterial blood pressure was increased, it is not clear if the mechanism for this ventilatory response is due to stimulation of pulmonary chemoreceptors, pulmonary vascular mechanoreceptors, or some other mechanism unrelated to increases in systemic arterial H+ concentration.     

Ventilatory control in hypercapnia and exercise: optimization hypothesis

A model of the respiratory control system incorporating both chemical and respiratory neuromechanical feedbacks is proposed to describe the steady-state ventilatory responses to CO2 inhalation and exercise. It is postulated that ventilatory output (VE) is set by the respiratory center to minimize a net operating cost representing the conflicting challenges of arterial chemical imbalance and respiratory-mechanical discomfort (intolerance of effort), given, respectively, by a quadratic function of arterial PCO2 and a logarithmic function of VE. In addition, the system is assumed to be mechanically limited at maximum VE (Vmax). The predicted responses in VE during moderate hypercapnia, exercise, and ventilatory loading closely mimic those normally observed, even though no separate signal unique to exercise is assumed. As a quantitative validation, the model yielded good fits to ventilatory response data obtained in eight healthy subjects during eucapnic and hypercapnic exercise; the predicted Vmax averaged approximately 77% of the maximum voluntary ventilation in all subjects. The results demonstrate the plausibility of the proposed optimization mechanism and suggest an important role for respiratory-mechanical factors in the control of VE.     

Carotid chemoreceptors in ventilatory responses to changes in venous CO2 load

We examined the role of the carotid chemoreceptors in the ventilatory response to changes in venous CO2 load in 12 awake sheep using a venovenous extracorporeal perfusion circuit and two carbon dioxide membrane lungs (CDML). Three of the sheep had undergone surgical denervation of the carotid bodies (CBD). In the nine intact sheep, as CO2 was removed from or added to the peripheral venous blood through the CDML under normoxic conditions, there was a linear relationship between the rate of pulmonary CO2 excretion (VCO2) and the resulting rate of ventilation over a VCO2 range of 0--800% of control, so that arterial PCO2 remained close to isocapnic. In contrast, in the three CBD sheep, the ventilatory response to changes in VCO2 was significantly decreased under normoxic conditions, resulting in marked hypercapnia. The results indicate that the carotid chemoreceptors exert a major influence on the ventilatory response to changes in venous CO2 load.     

Peripheral chemoreceptors in health and disease.

Peripheral chemoreceptors (carotid and aortic bodies) detect changes in arterial blood oxygen and initiate reflexes that are important for maintaining homeostasis during hypoxemia. This mini-review summarizes the importance of peripheral chemoreceptor reflexes in various physiological and pathophysiological conditions. Carotid bodies are important for eliciting hypoxic ventilatory stimulation in humans and in experimental animals. In the absence of carotid bodies, compensatory upregulation of aortic bodies as well as other chemoreceptors contributes to the hypoxic ventilatory response. Peripheral chemoreceptors are critical for ventilatory acclimatization at high altitude. They also contribute in part to the exercise-induced hyperventilation, especially with submaximal and heavy exercise. During pregnancy, hypoxic ventilatory sensitivity increases, perhaps due to the actions of estrogen and progesterone on chemoreceptors. Augmented peripheral chemoreceptors have been implicated in early stages of recurrent apneas, congestive heart failure, and certain forms of hypertension. It is likely that chemoreceptors tend to maintain oxygen homeostasis and act as a defense mechanism to prevent the progression of the morbidity associated with these diseases. Experimental models of recurrent apneas, congestive heart failure, and hypertension offer excellent opportunities to unravel the cellular mechanisms associated with altered chemoreceptor function.     

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.     

Chemoreceptor reflexes and cardiovascular control

Evidence is presented which indicates that in the absence of other known inputs to the nervous system and during controlled pulmonary ventilation, stimulation of the carotid body chemoreceptors causes bradycardia and selective peripheral vasoconstriction. These responses may be attenuated, however, by concomitant changes in respiration and arterial blood pressure, and by activity of higher parts of the brain stem. Stimulation of the aortic bodies in mammals in which they are functionally active, causes bradycardia or tachycardia and selective peripheral vasoconstriction. The reflex vascular effects from the peripheral arterial chemoreceptors are mediated by alpha-adrenergic sympathetic fibres. A potential mechanism exists therefore whereby the peripheral arterial chemoreceptors could contribute to the neurogenic component of hypertension.     

Role of acid-base balance in the chemoreflex control of breathing.

This paper uses a steady-state modeling approach to describe the effects of changes in acid-base balance on the chemoreflex control of breathing. First, a mathematical model is presented, which describes the control of breathing by the respiratory chemoreflexes; equations express the dependence of pulmonary ventilation on Pco(2) and Po(2) at the central and peripheral chemoreceptors. These equations, with Pco(2) values as inputs to the chemoreceptors, are transformed to equations with hydrogen ion concentrations [H(+)] in brain interstitial fluid and arterial blood as inputs, using the Stewart approach to acid-base balance. Examples illustrate the use of the model to explain the regulation of breathing during acid-base disturbances. They include diet-induced changes in sodium and chloride, altitude acclimatization, and respiratory disturbances of acid-base balance due to chronic hyperventilation and carbon dioxide retention. The examples demonstrate that the relationship between Pco(2) and [H(+)] should not be neglected when modeling the chemoreflex control of breathing. Because pulmonary ventilation controls Pco(2) rather than the actual stimulus to the chemoreceptors, [H(+)], changes in their relationship will alter the ventilatory recruitment threshold Pco(2), and thereby the steady-state resting ventilation and Pco(2).     

Nonperipheral chemoreceptor stimulation of ventilation by cyanide.

To assess the ventilatory responses elicited by changes of tissue hypoxia, sodium cyanide (0.12 mg/kg-min for 10 min) was infused into the upper abdominal aorta of anesthetized dogs. These infusions produced decreases in oxygen consumption, increases in arterial lactate concentration, and increases in arterial lactate/pyruvate ratio. Coincident with these metabolic changes of hypoxia, minute ventilation (VE) increased 228 +/- SE 36% and arterial PCO2 decreased 21 +/- SE 2 mmHg; therefore, pH increased both in arterial blood in and cisternal cerebrospinal fluid. Following infusion of cyanide into the abdominal aorta, small quantities of cyanide (48 +/- SE 14 mumol/liter) appeared in carotid arterial blood. To evaluate the possibility that the observed increases in VE were due to stimulation of peripheral arterial chemoreceptors by the recirculating cyanide, the carotid and aortic chemoreceptors were denervated in four dogs. Nonetheless, after intra-aortic infusion of sodium cyanide (1.2 mg/kg), ventilation in these chemodenervated animals again increased considerably (154 +/- SE 36%). In order to explore the possibility that cyanide infusion can stimulate ventilation by an extracranial mechanism, heads of vagotomized dogs (including the carotid bodies) were perfused entirely by donor dogs. The intra-aortic infusion of sodium cyanide (0.9 mg/kg) into these head-perfused animals still caused large increases in VE (163 +/- SE 19%). It is concluded that intra-aortic cyanide infusions stimulate VE by an extracranial mechanism other than the carotid and aortic chemoreceptors.     

Effects of dopamine on chemoreflexes in breathing

The effects of intravenous infusion of dopamine (20 microgram.min) on the steady-state ventilatory and carotid chemoreceptor responses to successive levels of isocapnic hypoxia and hyperoxic hypercapnia were investigated in cats anesthetized with alpha-chloralose. Dopamine infusion was followed by a maximal decrease in ventilation in about 20 s. Thereafter, the effect diminished and stabilized. Termination of dopamine infusion was promptly followed by an increase in ventilation. These ventilatory responses were smaller than the corresponding carotid chemoreceptor responses. The steady-state effect of dopamine infusion was to diminish ventilation at all levels of arterial O2 tension, the decrease being greater during hypoxia than that during hyperoxia. Bilateral section of the carotid sinus nerves significantly diminished but did not abolish the inhibitory effect of dopamine on ventilation during hyperoxia. Thus the ventilatory depression due to dopamine infusion is not entirely due to its effect on the carotid chemoreceptors. Dopamine decreased ventilatory responses to successive levels of hypercapnia by the same magnitude without changing the slope of the response curves. The steady-state relationship between chemoreceptor activity and ventilation shows that the ventilatory equivalent for carotid chemoreceptor activity is increased during dopamine infusion because of its greater inhibitory effect on carotid chemoreceptor activity than on ventilation with the decrease of arterial O2 tension.     

Role of chemical afferents in the maintenance of rhythmic respiratory movements

In seven anesthetized cats central chemosensitivity was eliminated (cold block) and peripheral chemoreceptors were either stimulated or eliminated (sectioned) to test whether nonchemical vagal afferents can maintain rhythmic ventilation and to determine the relative contribution of the carotid and aortic chemoreceptors to ventilatory drive without central chemosensitivity. Elimination of all chemical afferents invariably induced apnea, whereas ventilation was reduced from 533 to 159 ml X min-1 during cold block of central chemosensitivity and to 478 ml X min-1 after sectioning both sinus nerves. Cold block with only the aortic chemoreceptors and vagal afferents intact produced apnea in four of six cases tested. Stimulation of peripheral chemoreceptors during cold block remained effective and interrupted apnea in three of the four cats with only aortic chemoreceptors intact. We conclude that the nonchemical vagal respiratory afferents alone are unable to maintain rhythmic ventilation. Respiratory rhythm generation is, under the conditions of our experiments, critically dependent on sufficient afferent input from chemical afferents. Of these, central chemosensitivity plays the major role, followed by carotid body and, least importantly, by aortic afferents.     

Influence of progesterone on arterial blood and CSF acid-base balance in women

To study the mechanism of the action of progesterone on pulmonary ventilation during pregnancy, arterial and cerebrospinal fluid (CSF) acid-base parameters were measured in 59 pregnant and 36 nonpregnant women at the periods of follicular phase, luteal phase, early pregnancy, late pregnancy, and puerperium. Marked respiratory alkalosis in both arterial blood and CSF was observed in pregnancy and puerperium. The degree of hypocapnia observed in the luteal phase and during pregnancy was closely related to the progesterone level in arterial blood. In conclusion, it is unlikely that the observed hyperventilation results from stimulation at the central chemosensitive areas or peripheral chemoreceptors.     

Alpha 2 adrenergic control of ventilation in the rat]

In anaesthetized rats, ventilatory stimulation induced by phentolamine, an alpha sympatholytic agent, emphasizes the role of some adrenergic mechanisms in the control of the respiratory centres activity. Phentolamine (5 and 10 mg.kg-1, iv) stimulates ventilation after a 4 s latency, tidal volume and respiratory rate being both increased. A same response can also be provoked 10 min later, by a second identical iv administration, systemic blood pressure remaining then stable at its previous low level. Hyperventilation is also observed when phentolamine is injected in totally denervated rats, without any remaining baro- or chemosensitivity. Stimulation is thus due to a central activity in relation with the release of inhibitory influences. Phentolamine also causes hyperventilation after prazosin pretreatment indicating that the alpha 1 adrenergic blockade is not involved in the post-phentolamine stimulation. This is an alpha 2 adrenergic transmission dependent mechanism. Variation of the systemic blood pressure is not the main mechanism involved in the hyperventilation induced by phentolamine. Meanwhile, baroreceptor activity modulates the central response to the drug, as shown by the negative influence of the post-vasopressin arterial hypertension. Hyperoxia is also a modulating factor acting by two ways: an inhibition of the peripheral chemoreceptors activity is added to an arterial hypertension. On the other side, activation of these chemoreceptors by almitrine bismesilate increases the respiratory responses to phentolamine. As already shown by one of us (Lagneuax, 1986), phentolamine pretreated rats are more responsive to hypoxia and to almitrine. Moreover, these phentolamine pretreated rats are protected against cardiovascular collapses and against apnea, frequently observed during hypoxia without CO2 compensation.     

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.     

Hypoxic ventilatory response and arterial desaturation during heavy work

Arterial desaturation in athletes during intense exercise has been reported by several authors, yet the etiology of this phenomenon remains obscure. Inadequate pulmonary ventilation, due to a blunted respiratory drive, has been implicated as a factor. To investigate the relationship between the ventilatory response to hypoxia, exercise ventilation, and arterial desaturation, 12 healthy male subjects [age, 23.8 +/- 3.6 yr; height, 181.6 +/- 5.6 cm; weight, 73.7 +/- 6.2 kg; and maximal O2 uptake (VO2max), 63.0 +/- 2.2 ml.kg-1 min-1] performed a 5-min treadmill test at 100% of VO2max, during which arterial blood samples and ventilatory data were collected every 15 s. Alveolar PO2 (PAO2) was determined using the ideal gas equation. On a separate occasion the ventilatory response to isocapnic hypoxia was measured. Arterial PO2 decreased by an average of 29 Torr during the test, associated with arterial desaturation [arterial O2 saturation (SaO2) 92.0%]. PAO2 was maintained; however, alveolar-arterial gas pressure difference increased progressively to greater than 40 Torr. Minimal hypocapnia was observed, despite marked metabolic acidosis. There was no significant correlation observed between hypoxic drives and ventilation-to-O2 uptake ratio or SaO2 (r = 0.1 and 0.06, respectively, P = NS). These data support the conclusions that hypoxic drives are not related to maximal exercise ventilation or to the development of arterial desaturation during maximal exercise.     

Relationship between arterial oxygen desaturation and ventilation during maximal exercise.

The purpose of the present study was to investigate the contribution of ventilation to arterial O2 desaturation during maximal exercise. Nine untrained subjects and 22 trained long-distance runners [age 18-36 yr, maximal O2 uptake (VO2max) 48-74 ml.min-1 x kg-1] volunteered to participate in the study. The subjects performed an incremental exhaustive cycle ergometry test at 70 rpm of pedaling frequency, during which arterial O2 saturation (SaO2) and ventilatory data were collected every minute. SaO2 was estimated with a pulse oximeter. A significant positive correlation was found between SaO2 and end-tidal PO2 (PETO2; r = 0.72, r2 = 0.52, P < 0.001) during maximal exercise. These statistical results suggest that approximately 50% of the variability of SaO2 can be accounted for by differences in PETO2, which reflects alveolar PO2. Furthermore, PETO2 was highly correlated with the ventilatory equivalent for O2 (VE/VO2; r = 0.91, P < 0.001), which indicates that PETO2 could be the result of ventilation stimulated by maximal exercise. Finally, SaO2 was positively related to VE/VO2 during maximal exercise (r = 0.74, r2 = 0.55, P < 0.001). Therefore, one-half of the arterial O2 desaturation occurring during maximal exercise may be explained by less hyperventilation, specifically for our subjects, who demonstrated a wide range of trained states. Furthermore, we found an indirect positive correlation between SaO2 and ventilatory response to CO2 at rest (r = 0.45, P < 0.05), which was mediated by ventilation during maximal exercise. These data also suggest that ventilation is an important factor for arterial O2 desaturation during maximal exercise.     

Ventilatory responses to chemoreceptor stimulation after hypoxic acclimatization in awake goats

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

Chronic hypoxia enhances the phrenic nerve response to arterial chemoreceptor stimulation in anesthetized rats.

Chronic exposure to hypoxia results in a time-dependent increase in ventilation called ventilatory acclimatization to hypoxia. Increased O(2) sensitivity of arterial chemoreceptors contributes to ventilatory acclimatization to hypoxia, but other mechanisms have also been hypothesized. We designed this experiment to determine whether central nervous system processing of peripheral chemoreceptor input is affected by chronic hypoxic exposure. The carotid sinus nerve was stimulated supramaximally at different frequencies (0.5-20 Hz, 0.2-ms duration) during recording of phrenic nerve activity in two groups of anesthetized, ventilated, vagotomized rats. In the chronically hypoxic group (7 days at 80 Torr inspired PO(2)), phrenic burst frequency (f(R), bursts/min) was significantly higher than in the normoxic control group with carotid sinus nerve stimulation frequencies >5 Hz. In the chronically hypoxic group, peak amplitude of integrated phrenic nerve activity ( integral Phr, percent baseline) or change in integral Phr was significantly greater at stimulation frequencies between 5 and 17 Hz, and minute phrenic activity ( integral Phr x f(R)) was significantly greater at stimulation frequencies >5 Hz. These experiments show that chronic hypoxia facilitates the translation of arterial chemoreceptor afferent input to ventilatory efferent output through a mechanism in the central nervous system.     

Ibuprofen Blunts Ventilatory Acclimatization to Sustained Hypoxia in Humans

Ventilatory acclimatization to hypoxia is a time-dependent increase in ventilation and the hypoxic ventilatory response (HVR) that involves neural plasticity in both carotid body chemoreceptors and brainstem respiratory centers. The mechanisms of such plasticity are not completely understood but recent animal studies show it can be blocked by administering ibuprofen, a nonsteroidal anti-inflammatory drug, during chronic hypoxia. We tested the hypothesis that ibuprofen would also block the increase in HVR with chronic hypoxia in humans in 15 healthy men and women using a double-blind, placebo controlled, cross-over trial. The isocapnic HVR was measured with standard methods in subjects treated with ibuprofen (400mg every 8 hrs) or placebo for 48 hours at sea level and 48 hours at high altitude (3,800 m). Subjects returned to sea level for at least 30 days prior to repeating the protocol with the opposite treatment. Ibuprofen significantly decreased the HVR after acclimatization to high altitude compared to placebo but it did not affect ventilation or arterial O₂ saturation breathing ambient air at high altitude. Hence, compensatory responses prevent hypoventilation with decreased isocapnic ventilatory O₂-sensitivity from ibuprofen at this altitude. The effect of ibuprofen to decrease the HVR in humans provides the first experimental evidence that a signaling mechanism described for ventilatory acclimatization to hypoxia in animal models also occurs in people. This establishes a foundation for the future experiments to test the potential role of different mechanisms for neural plasticity and ventilatory acclimatization in humans with chronic hypoxemia from lung disease.     

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.