ATP is a key mediator of central and peripheral chemosensory transduction

Recent evidence suggests that ATP is a mediator of central (within the ventral surface of the medulla) and peripheral (within the carotid body) chemosensory transduction. This short review discusses the data obtained in experiments in vivo and in vitro supporting this hypothesis. P2 receptors for ATP are expressed within the ventrolateral medulla as well as by the peripheral chemosensory afferent neurones. Blockade of P2 receptors in the ventrolateral medulla attenuates the CO2-induced increase in respiration while blockade of purinergic signalling impairs carotid body function and diminishes the ventilatory response to hypoxia. Furthermore, ATP is released from the ventral surface of the medulla during hypercapnia and from the carotid body during hypoxia. Finally, exogenous ATP applied on the ventral surface of the medulla evokes rapid increase in phrenic nerve activity, while ATP applied to the carotid body evokes marked excitation of the carotid sinus nerve afferents. We suggest that in the ventrolateral medulla ATP is produced following CO2/H(+)-induced activation of central chemosensory elements (neuronal and/or glial) and acts within the respiratory network to produce physiologically relevant changes in ventilation. In the carotid body, ATP contributes in a significant manner to the transmission of the sensitivity of the carotid body to changes in arterial PO2 and may be considered as a key transmitter released by chemoreceptor cells to activate endings of the sinus nerve afferent fibres.     

Respiratory responses to hypercapnia and hypoxia in mice with genetic ablation of Kir5.1 (Kcnj16)

Inward rectifier (Kir) potassium channels contribute to the control of electrical activity in excitable tissues and their activity is modulated by many biochemical factors, including protons. Heteromeric Kir4.1-Kir5.1 channels are highly pH sensitive within the physiological range of pH changes and are strongly expressed by the peripheral chemosensors as well as in the brainstem pH-sensitive areas which mediate respiratory responses to changes in blood and brain levels of P(CO(2))/[H(+)]. In the present study, Kir5.1 knockout mice (Kir5.1(-/-)) were used to determine the role of these channels in the chemosensory control of breathing. We found that Kir5.1(-/-) mice presented with persistent metabolic acidosis and a clear respiratory phenotype. Despite metabolic acidosis, ventilation at rest and in hyperoxic hypercapnia were similar in wild-type and Kir5.1(-/-) mice. Ventilatory responses to hypoxia and normoxic hypercapnia were significantly reduced in Kir5.1(-/-) mice; however, carotid body chemoafferent responses to hypoxia and CO(2) were not affected. In the in situ brainstem-spinal cord preparations with denervated peripheral chemoreceptors, resting phrenic nerve activity and phrenic nerve responses to respiratory acidosis or isohydric hypercapnia were also similar in Kir5.1(-/-) and wild-type mice. In in situ preparations of Kir5.1(-/-) mice with intact peripheral chemoreceptors, application of CN(-) resulted in a significantly reduced phrenic nerve response, suggesting that the relay of peripheral chemosensory information to the CNS is compromised. We suggest that this compensatory modulation of the peripheral chemosensory inputs develops in Kir5.1(-/-) mice in order to counteract the effect of continuing metabolic acidosis on the activity of the peripheral chemoreceptors. These results therefore suggest that despite their intrinsic pH sensitivity, Kir4.1-Kir5.1 channels are dispensable for functional central and peripheral respiratory chemosensitivity.     

An integrated model of the human ventilatory control system: the response to hypercapnia.

This work presents a mathematical model of the human respiratory control system, based on physiological knowledge. It includes three compartments for gas storage and exchange (lungs, brain tissue and other body tissues), and various kinds of feedback mechanisms. These comprehend peripheral chemoreceptors in the carotid body, central chemoreceptors in the medulla and a central ventilatory depression. The latter acts by reducing the response of the central neural system to the afferent peripheral chemoreceptor activity during prolonged hypoxia of the brain tissue. Furthermore, the model considers local blood flow adjustments in response to O2 and CO2 arterial pressure changes. In this study, the model has been validated by simulating the response to square changes in alveolar PCO2, performed at different constant levels of alveolar PO2. A good agreement with data reported in the literature has been checked. Subsequently, a sensitivity analysis on the role of the main feedback mechanisms on ventilation response to CO2 has been performed. The results suggest that the ventilatory response to CO2 challenges during hyperoxia can be almost completely ascribed to the central chemoreflex, while, during normoxia, the peripheral chemoreceptors provide a modest contribution too. By contrast, the response to hypercapnic stimuli during hypoxia involves a complex superimposition among different factors with disparate dynamics. Hence, results suggest that the ventilatory response to hypercapnia during hypoxia is more complex than that provided by simple empirical models, and that discrimination between the central and peripheral components based on time constants may be misleading.     

Modulation of experimentally-induced cough by stimulation of nasal mucosa in cats and guinea pigs

We measured ventilation (VI) and arterial blood gases in Pekin ducks during acclimatization to 3800 m altitude for 1-90 days. Four experimental series were conducted over 4 years using both natural altitude and a hypobaric chamber. PaCO2 decreased to 3.5 Torr, relative to the value measured during acute hypoxia after 1 day and remained at this level for up to 90 days. However, PaO2 did not increase. Arterial pH showed an unexpected metabolic alkalosis during the first hours at altitude but after 3 days, a metabolic acidosis partially compensated the respiratory alkalosis and pHa was constant thereafter. When normoxia was restored after hypoxia, PaCO2 was 5.5 Torr less than the original normoxic control value, but PaO2 was not increased. VI showed variable changes during acclimatization but if metabolic rate was constant in our study, as reported by others, then effective parabronchial V(VP) increased during acclimatization. Increased VP tends to restore PaO2 toward normoxic levels and decreases adverse effects of gas exchange limitation, which apparently increased during acclimatization in ducks.     

Ventilatory pattern and chemosensitivity in M1 and M3 muscarinic receptor knockout mice

Acetylcholine (ACh) acting through muscarinic receptors is thought to be involved in the control of breathing, notably in central and peripheral chemosensory afferents and in regulations related to sleep-wake states. By using whole-body plethysmography, we compared baseline breathing at rest and ventilatory responses to acute exposure (5 min) to moderate hypoxia (10% O(2)) and hypercapnia (3 and 5% CO(2)) in mice lacking either the M(1) or the M(3) muscarinic receptor, and in wild-type matched controls. M(1) knockout mice showed normal minute ventilation (V(E)) but elevated tidal volume (V(T)) at rest, and normal chemosensory ventilatory responses to hypoxia and hypercapnia. M(3) knockout mice had elevated V(E) and V(T) at rest, a reduced V(T) response slope to hypercapnia, and blunted V(E) and frequency responses to hypoxia. The results suggest that M(1) and M(3) muscarinic receptors play significant roles in the regulation of tidal volume at rest and that the afferent pathway originating from peripheral chemoreceptors involves M(3) receptors.     

Ventilatory roll off during sustained hypercapnia is gender specific in pekin ducks

The objective of the present study was to examine the relative roles of peripheral versus central mechanisms in producing ventilatory adjustments in pekin ducks during prolonged (5 h) hypercapnia (5% inspired CO2), and to determine whether these adjustments differed between male and female ducks. After 20 min of CO2 exposure, intact ducks increased total ventilation (VE) 2.5-3-fold above control values, due to large increases (approximately 200%) in tidal volume (VT) and slightly smaller increases (approximately 140%) in breathing frequency (fR). This response was accompanied by respiratory acidosis (pHa fell from approximately 7.46 to approximately 7.41) and hypercapnia (PaCO2 increased from approximately 35 to approximately 40 Torr). In males, VE fell progressively thereafter due exclusively to a fall in fR, in parallel with a rapid partial recovery of pH (to 7.44) while PaCO2 continued to climb (to approximately 42 Torr). In females, VE remained elevated during hypercapnia, and no pH recovery occurred. This suggests that a respiratory decline resulting from acid-base compensation (probably due to HCO3- mobilization) occurred in males but not in females. Bicarbonate mobilization, and thus pH compensation, may have been reduced in females due to the CaCO3 requirements of eggshell formation. In males, the acute ventilatory response was reduced slightly by denervation of the carotid bodies or intrapulmonary chemoreceptors, but there was no effect of denervation of either receptor group on the responses to prolonged CO2. We conclude that pH compensation triggered by constant or increasing PaCO2, acting at central chemoreceptors, likely mediates the respiratory adjustments seen in male pekin ducks during hypercapnia. Furthermore, we suggest that this ventilatory response be considered a gender-specific hypercapnic ventilatory roll off, in the context of the various time domains of the hypercapnic ventilatory response.     

Effect of hypoxia on ventilatory and arousal responses to CO2 during NREM sleep with and without flurazepam in young adults

We examined the ventilatory response to CO2 at two levels of oxygenation during wakefulness and sleep in healthy young adults before and after the ingestion of a single dose of 30 mg flurazepam. Progressive hypercapnia was produced at two levels of arterial O2 saturation (greater than 99 and 87%) by having subjects re-breathe from a tight-fitting face mask and a reservoir bag containing gas mixtures with two different O2 concentrations. Ventilation was measured with an inductive plethysmograph. O2 saturation was measured with an ear oximeter. Sleep was monitored using standard techniques by recording the electroencephalogram, eye movements, and chin electromyogram. During wakefulness, hypoxia increased the slope of the ventilatory response to CO2 and shifted the response slightly to the left. NREM sleep lowered the slope of the CO2 response under both hyperoxic and hypoxic conditions. The slope of the hyperoxic CO2 response curve was not affected by flurazepam during wakefulness or sleep. After administration of flurazepam to the subjects, the shift of the CO2 response curve to the left produced by hypoxia (additive effect) during NREM sleep was slightly less as compared to control, but hypoxia still increased the slope of the CO2 ventilatory response. During hypoxic hypercapnia, the PCO2 at arousal from sleep was significantly lower than during hyperoxic hypercapnia, but the level of ventilation at arousal during hypercapnia was similar in the control condition and after flurazepam. We conclude that (a) both natural and flurazepam-induced sleep depress ventilatory responses to hyperoxic and hypoxic hypercapnia and alter, in a complex fashion, the effects of hypoxia and hypercapnia on ventilation; and (b) hypoxia and hypercapnia interact as arousal stimuli in both natural and flurazepam-induced sleep.     

Ventilatory control in humans: constraints and limitations

Below the lactate threshold ((thetaL)), ventilation (V(E))responds in close proportion to CO(2) output to regulate arterial partial pressure of CO(2) (PaCO2). While ventilatory control models have traditionally included proportional feedback (central and carotid chemosensory) and feedforward (central and peripheral neurogenic) elements, the mechanisms involved remain unclear. Regardless, putative control schemes have to accommodate the close dynamic 'coupling' between and V(E) and V(CO2). Above (thetaL), PaCO2 is driven down to constrain the fall of arterial pH by a compensatory hyperventilation, probably of carotid body origin. When V(E) requirements are high (as in highly fit endurance athletes), V(E) can attain limiting proportions. Not only does this impair gas exchange at these work rates, but there may be an associated high metabolic cost for generation of respiratory muscle power, which may be sufficient to divert a fraction of the cardiac output away from the muscles of locomotion to the respiratory muscles, further compromising exercise tolerance.     

Vasopressin, ACTH, and corticosteroids during hypercapnia and graded hypoxia in dogs

We examined the interaction of graded hypoxia and hypercapnia on stimulation of vasopressin (AVP), ACTH, and corticosteroids in nonsurgically stressed, pentobarbital-anesthetized, gallamine-paralyzed ventilated dogs. Partial pressure of O2 in arterial blood (PaO2) levels of approximately 26-29, 38-41, 54-57, and 83-88 Torr were achieved by altering the fractional concentration of O2 in dry inspired gas with a normocapnic (PaCO2, 35 Torr) and hypercapnic (PaCO2, 59 Torr) background. Normocapnic hypoxia produced a PaO2-dependent increase in AVP, ACTH, and corticosteroids. The threshold PaO2 for AVP was lower (approximately 35 Torr) than for ACTH (approximately 45 Torr). AVP, ACTH, and corticosteroids at all PaO2 levels were higher during hypercapnia. In addition, an ACTH and corticosteroid dose-response correlation estimated the threshhold ACTH to be 20-30 pg/ml. The PaO2-dependent hormone increases and the augmentation of these relationships by hypercapnia are consistent with a peripheral chemoreceptor-mediated reflex. In addition, hypoxia and hypercapnia did not seem to alter the high sensitivity of the adrenal cortex for ACTH.     

Chemosensory ventilatory responses in the mutant mice with Presbyterian hemoglobinopathy

The working hypothesis of this study was that chronically increased tissue oxygenation would facilitate respiratory endurance to chemical stimuli. We investigated the ventilatory responses to hypoxia and hypercapnia before and after carotid chemodenervation in the anesthetized, spontaneously breathing Presbyterian, which carry a low affinity variant of hemoglobin, and in wild-type mice. We found a dampening of all chemosensory responses in Presbyterian hemoglobinopathy. Particularly, the Presbyterian mouse with intact carotid body innervation was more vulnerable to hypoxia than the wild-type mouse, showing an accelerated decline in breathing frequency which was not counterbalanced by tidal respiration. We further found that chemodenervation in the Presbyterian mouse, performed in normoxia, led to respiratory arrest. The study shows enhanced susceptibility of respiration to hypoxia and indispensability of neural input from the carotid body for upholding the central respiratory controller's function in Presbyterian hemoglobinopathy. The study also suggests a relationship between hemoglobin-oxygen dissociation and respiration, which points to a metabolic, tissue oxygenation-linked component of respiratory regulation.     

Carotid body chemosensory activity and ventilatory chemoreflexes in cats persist after combined cholinergic-purinergic block

Acetylcholine (ACh) and ATP have been proposed as excitatory co-transmitters operating at synapses between glomus cells and sensory nerve endings of the carotid body (CB). To test such hypothesis, we performed experiments on cats under pentobarbitone anesthesia and breathing spontaneously. Cholinergic and purinergic agonists and antagonists were given into one common carotid artery. Chemoreflex ventilatory changes initiated from the ipsilateral CB or chemosensory activity from the ipsilateral carotid nerve were recorded. Agonists ACh, nicotine, epibatidine, ATP, betagamma-methylene-ATP and gammaS-ATP induced transient chemoreflex enhancements of ventilation or increased chemosensory activity. When given in combination, mecamylamine and suramin suppressed both nicotine- and ATP-induced ventilatory chemoreflexes or chemosensory responses. However, neither chemoreflex hyperventilation induced by brief hypoxic exposures or steady-state hypoxic levels, nor chemosensory excitation elicited by these maneuvers were eliminated. Asphyxia-induced chemosensory excitation was not reduced by combined blockade of ACh and ATP receptors. Furthermore, ventilatory or chemosensory depression evoked by 100% O2 tests was unmodified, thus evidencing that basal chemosensory drive in normoxia was not suppressed by combined cholinergic-purinergic blockade. Therefore, although ACh and ATP may participate in chemoexcitation of the CB, their involvement fails to explain the origin of chemosensory discharges from synaptic transmission between glomus cells and chemosensory nerve endings of the CB.     

Low-dose acetazolamide reduces the hypoxic ventilatory response in the anesthetized cat

Low intravenous dose acetazolamide causes a decrease in steady-state CO(2) sensitivity of both the peripheral and central chemoreflex loops. The effect, however, on the steady-state hypoxic response is unknown. In the present study, we measured the effect of 4 mg x kg(-1) acetazolamide (i.v.) on the isocapnic steady-state hypoxic response in anesthetized cats. Before and after acetazolamide administration, the eucapnic steady-state hypoxic response in these animals was measured by varying inspiratory P(O2) levels to achieve steady-state Pa(O2) levels between hyperoxia Pa(O2) approximately 55 kPa, approximately 412 mmHg) and hypoxia (Pa(O2) approximately 7 kPa, approximately 53 mmHg). The hypoxic ventilatory response was described by the exponential function V(I) = G exp (-DP(o2) + A with an overall hypoxic sensitivity G, a shape parameter D and ventilation during hyperoxia A. Acetazolamide significantly reduced G from 3.057 +/- 1.616 to 1.573 +/- 0.8361 min(-1) (mean +/- S D). Parameter A increased from 0.903 +/- 0.257 to 1.193 +/- 0.321 min(-1), while D remained unchanged. The decrease in overall hypoxic sensitivity by acetazolamide is probably mediated by an inhibitory effect on the carotid bodies and may have clinical significance in the treatment of sleep apneas, particularly those cases that are associated with an increased ventilatory sensitivity to oxygen and/or carbon dioxide.     

Respiratory, cerebrovascular and cardiovascular responses to isocapnic hypoxia

We simultaneously measured respiratory, cerebrovascular and cardiovascular responses to 10-min of isoxic hypoxia at three constant CO(2) tensions in 15 subjects. We observed four response patterns, some novel, for ventilation, middle cerebral artery blood flow velocity, heart rate and mean arterial blood pressure. The occurrence of the response patterns was correlated between some measures. Isoxic hyperoxic and hypoxic ventilatory sensitivities to CO(2) derived from these responses were equivalent to those measured with modified (Duffin) rebreathing tests, but cerebrovascular sensitivities were not. We suggest the different ventilatory response patterns reflect the time course of carotid body afferent activity; in some individuals, carotid body function changes during hypoxia in more complex ways than previously thought. We concluded that isoxic hyperoxic and hypoxic ventilatory sensitivities to CO(2) can be measured using multiple hypoxic ventilatory response tests only if care is taken choosing the isocapnic CO(2) levels used, but a similar approach to measuring the cerebrovascular response to isocapnic hyperoxia and hypoxia is unfeasible.     

Hemodynamic and ventilatory response to different levels of hypoxia and hypercapnia in carotid body-denervated rats

OBJECTIVE:

Chemoreceptors play an important role in the autonomic modulation of circulatory and ventilatory responses to changes in arterial O₂ and/or CO₂. However, studies evaluating hemodynamic responses to hypoxia and hypercapnia in rats have shown inconsistent results. Our aim was to evaluate hemodynamic and respiratory responses to different levels of hypoxia and hypercapnia in conscious intact or carotid body-denervated rats.

METHODS:

Male Wistar rats were submitted to bilateral ligature of carotid body arteries (or sham-operation) and received catheters into the left femoral artery and vein. After two days, each animal was placed into a plethysmographic chamber and, after baseline measurements of respiratory parameters and arterial pressure, each animal was subjected to three levels of hypoxia (15, 10 and 6% O₂) and hypercapnia (10% CO₂).

RESULTS:

The results indicated that 15% O₂ decreased the mean arterial pressure and increased the heart rate (HR) in both intact (n = 8) and carotid body-denervated (n = 7) rats. In contrast, 10% O₂ did not change the mean arterial pressure but still increased the HR in intact rats, and it decreased the mean arterial pressure and increased the heart rate in carotid body-denervated rats. Furthermore, 6% O₂ increased the mean arterial pressure and decreased the HR in intact rats, but it decreased the mean arterial pressure and did not change the HR in carotid body-denervated rats. The 3 levels of hypoxia increased pulmonary ventilation in both groups, with attenuated responses in carotid body-denervated rats. Hypercapnia with 10% CO₂ increased the mean arterial pressure and decreased HR similarly in both groups. Hypercapnia also increased pulmonary ventilation in both groups to the same extent.

CONCLUSION:

This study demonstrates that the hemodynamic and ventilatory responses varied according to the level of hypoxia. Nevertheless, the hemodynamic and ventilatory responses to hypercapnia did not depend on the activation of the peripheral carotid chemoreceptors.     

Carotid sinus nerve responses and ventilatory acclimatization to hypoxia in adult rats following 2 weeks of postnatal hyperoxia

Adult rats have decreased carotid body volume and reduced carotid sinus nerve, phrenic nerve, and ventilatory responses to acute hypoxic stimulation after exposure to postnatal hyperoxia (60% O2, PNH) during the first 4 weeks of life. Moreover, sustained hypoxic exposure (12%, 7 days) partially reverses functional impairment of the acute hypoxic phrenic nerve response in these rats. Similarly, 2 weeks of PNH results in the same phenomena as above except that ventilatory responses to acute hypoxia have not been measured in awake rats. Thus, we hypothesized that 2-week PNH-treated rats would also exhibit blunted chemoafferent responses to acute hypoxia, but would exhibit ventilatory acclimatization to sustained hypoxia. Rats were born into, and exposed to PNH for 2 weeks, followed by chronic room-air exposure. At 3-4 months of age, two studies were performed to assess: (1) carotid sinus nerve responses to asphyxia and sodium cyanide in anesthetized rats and (2) ventilatory and blood gas responses in awake rats before (d0), during (d1 and d7), and 1 day following (d8) sustained hypoxia. Carotid sinus nerve responses to i.v. NaCN and asphyxia (10 s) were significantly reduced in PNH-treated versus control rats; however, neither the acute hypoxic ventilatory response nor the time course or magnitude of ventilatory acclimatization differed between PNH and control rats despite similar levels of PaO2 . Although carotid body volume was reduced in PNH rats, carotid body volumes increased during sustained hypoxia in both PNH and control rats. We conclude that normal acute and chronic ventilatory responses are related to retained (though impaired) carotid body chemoafferent function combined with central neural mechanisms which may include brainstem hypoxia-sensitive neurons and/or brainstem integrative plasticity relating both central and peripheral inputs.     

Differential sensitivity to hypoxic inhibition of respiratory processes in the anesthetized rat

To estimate the sensitivity to hypoxic inhibition of various regulatory processes for respiration, changes in breathing pattern during hypoxic ventilatory depression (HVD) were analyzed in the halothane-anesthetized spontaneously breathing rat using a "progressive isocapnic hypoxia test." In the carotid sinus nerve (CSN) intact rats, ventilatory augmentation was followed by depression due to reduction in respiratory frequency (f) at end-tidal PO2 (PETO2) levels below 50-60 mmHg despite increased afferent activities from the carotid chemoreceptors. After CSN section, ventilation was progressively depressed at PETO2 lower than normoxic level with simultaneous decreases of f and tidal volume. An increase in CO2 stimulus or the prevention of arterial hypotension during hypoxia by infusing a vasoconstrictor agent (phenylephrine) inhibited the occurrence of ventilatory depression in both the CSN intact and denervated animals. In all cases studied, the reduction in f resulted mainly from the prolongation of expiratory time (TE). The results suggest that in the anesthetized rat the effect of respiratory stimulation from carotid chemoreceptor afferents becomes inadequate to offset the prolongation of TE due to the central hypoxia at lower PETO2, and that the neural process for regulating TE is the major site of deterioration during central hypoxic inhibition. Roles of CO2 stimulus and systemic circulatory conditions in the generation of HVD were also discussed.     

Ventilation- and carotid chemoreceptor discharge-response to hypoxia during induced hypothermia in halothane anesthetized rat

It has been hypothesized that respiratory "gain" to hypoxic stimulus is not depressed in hypothermic animals though ventilation and that metabolic O(2) demand (Vo(2)) decreases with reduction in body temperature. The present study addressed this hypothesis by quantitative analysis of ventilatory and carotid chemoreceptor responsiveness to hypoxia during induced hypothermia in halothane anesthetized and spontaneously breathing rats. Rectal temperature was lowered from 37 degrees C (normothermia) to 30 and 25 degrees C by cooling body surface at comparable anesthetic depth without inducing shivering. Ventilation (V(E)), V(O2), PaO(2) and carotid chemoreceptor afferent discharges were measured during hyperoxic and hypoxic gas breathing. PaO(2) values at the same Fi(O2) (range 0. 35-0.08) decreased progressively as rectal temperature decreased. Both the V(E)/V(O2)- and chemoreceptor discharge-response curves shifted toward a lower PaO(2) range with a slight increase in the response slopes during hypothermia. The results indicated that the sensitivity of carotid chemoreceptor and ventilatory responses to hypoxia did not decrease at reduced body temperature. It is concluded that carotid chemoreceptor mediated regulation of ventilation is tightly coupled to changes in PaO(2 )range in halothane anesthetized rats during induced hypothermia.     

Characterization of hypoxia-induced ventilatory depression in newborn piglets

We evaluated the hypothesis that a 'central oxygen detector' in the brainstem is necessary for depressions of ventilatory activity to be manifested in the newborn. Decerebrate piglets, ventilated with 100 % O(2), were studied following neuromuscular blockade. The vagi and carotid sinus nerves were sectioned bilaterally in order to remove the influence of the peripheral chemoreceptors. Activity of the phrenic nerve was recorded as the index of the central respiratory rhythm. This activity declined and, in some preparations, ceased upon ventilation with air or a hypoxic gas, at either normocapnia or hypercapnia. The degree of depression in hypercapnic hypoxia was greatest in the youngest piglets. Following a medial section of the brainstem, extending to the caudal pons, the depression was reduced. In some preparations, a similar reduction followed the placement of radiofrequency lesions in the caudal ventromedial pons. We conclude that a region of the caudal mesencephalon or pons is necessary for the manifestation of depressions of ventilatory activity in the newborn pig.     

Separation of carotid body chemoreceptor responses to O2 and CO2 by oligomycin and by antimycin A

The cat carotid chemoreceptor O2 and CO2 responses can be separated by oligomycin and by antimycin A. Both of these agents greatly diminish or abolish the chemoreceptor O2 response but not the nicotine or CO2 responses. After either oligomycin or antimycin, the responses to increases and decreases in arterial CO2 partial pressure (PaCO2) consisted of increases and decreases in activity characterized respectively by exaggerated overshoots and undershoots. These were eliminated by the carbonic anhydrase inhibitor, acetazolamide, suggesting that they resulted from changes in carotid body tissue pH. The steady-state PaCO2 response remaining after oligomycin was no longer dependent on arterial O2 partial pressure (PaO2). All effects of antimycin were readily reversible in about 20 min. The separation of the responses to O2 and CO2 indicates that there may be at least partially separate pathways of chemoreception for these two stimuli. The similarity of the oligomycin and antimycin results supports the metabolic hypothesis of chemoreception.