Chemoreceptor Response Research Articles

Cobalt stimulates carotid body chemoreceptors

Because cobalt administration is known to elicit erythropoietin response, it is a reasonable hypothesis that cobalt would also stimulate the O2-sensing process in the peripheral chemoreceptors. We tested this hypothesis by measuring the effects of cobalt chloride on carotid chemosensory fibers in pentobarbital-anesthetized cats that were paralyzed and artificially ventilated. Responses of carotid chemoreceptor afferents to graded doses of cobalt given by intra-arterial injections (0.08-2.10 mumols) were measured at constant blood gases. Responses of the same chemoreceptor afferents to hypoxia, before and after a saturation dose of cobalt, were measured. In two experiments carotid body tissue PO2 was also simultaneously measured. The chemosensory fibers showed prolonged excitation after a brief period of inhibition subsequent to cobalt administration. The stimulatory effect showed a dose-dependent saturation response. Cobalt augmented rather than blocked carotid chemoreceptor response to hypoxia. The effect of cobalt was not mediated by tissue PO2. These results are consistent with the hypothesis that cobalt stimulates the O2-sensing mechanism, although a direct effect of cobalt on the excitability of the chemosensory terminal remains a possibility.

Temperature effects on pulmonary receptor responses to airway pressure and CO2 in Alligator mississippiensis

The effects of body temperature (Tb) on pulmonary stretch receptor (PSR) and CO2-sensitive intrapulmonary chemoreceptor (IPC) response characteristics may have important effects on ventilatory control in reptiles. In this study, three questions were addressed: (1) what are the effects of Tb on PSR and IPC responses to airway pressure (Paw) and lung CO2 (PCO2); (2) what are the effects of acute (<12 h) vs chronic (>1 week) changes in Tb on both receptor groups; and (3) can predicted changes in the fractional dissociation of imidazole (αim), calculated via independent changes in Tb and PCO2, explain the CO2-sensitivity of either IPC or PSR? Single fiber PSR and IPC resonses to Paw, PCO2 and Tb were determined in 11 anesthetized Alligator mississippiensis (pentobarbital; 30 mg/kg), acclimated at 20°C(N = 5) or at 30°C (N = 6). PSR activity increased as Paw increased at both Tb, but PSR activity and sensitivity to Paw were lower at 20°C. The average Q10 was 2.1. Increasing inhaled CO2 from 1 to 7% decreased PSR activity by 27 ± 6% at 20°C and 18 ± 5% at 30°C. IPC activity decreased as PCO2 increased at both Tb, but IPC activity and sensitivity were reduced at 20°C. The average Q10 was 3.2. Increasing Paw from 2 to 10 cm H2O had inconsistent effects on IPC activity. There were no differences between the effects of acute or chronic changes in Tb on either PSR or IPC responses. Predicted changes in αim could not explain the CO2-sensitivity of either IPC or PSR. We conclude that PSR and IPC adapt rapidly to Tb changes. The larger Q10 of IPC suggests that the relative role of IPC vs PSR in ventilatory control may be greater at elevated body temperatures.

Effect of Thiopentone, Etomidate and Propofol on Carotid Body Chemoreceptor Activity in the Rabbit and the Cat

The response of the carotid body chemoreceptors to intracarotid administration of thiopentone, etomidate and propofol was tested in the rabbit and cat. Thiopentone 3-6 mg min-1 and etomidate 300-600 micrograms min-1 were mildly excitatory, shifting the oxygen and carbon dioxide response curves upwards. Propofol 1.5-3.0 mg min-1 was a potent chemodepressant and abolished discharge at PaO2 values greater than 8 kPa. Prolonged infusion of propofol at higher rates (6 mg min-1) abolished the response to hypoxia completely. The significance of these results is discussed in relation to the known ventilatory effects of the three anaesthetics.

Hypoxic and hypercapnic ventilatory responses in awake children with congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) has been thought to be a disorder of central chemoreceptor responsiveness. Previous studies in CCHS have shown decreased or absent ventilatory responsiveness to both hypercarbia and hypoxia. However, hypoxic responsiveness during wakefulness has not been systematically studied. We studied hypoxic and hypercapnic ventilatory responses during wakefulness in five children with CCHS (6 to 11 yr of age). To measure the hypercapnic response, the children rebreathed a hyperoxic hypercapnic mixture until PaCO2 reached 56 to 69 mm Hg. For the hypoxic response, the children rebreathed a hypoxic gas mixture, at mixed venous PCO2, until SaO2 had fallen to less than 78%. We found that the ventilatory responses to hypercapnia and hypoxia were very variable (linear correlation coefficients ranging from -0.44 to +0.63 for hypercapnic responses and from -0.15 to +0.77 for hypoxic responses), with no significant change from baseline in response to either stimulus. There was no evidence of progressive ventilatory stimulation despite increasing stimulus. Additionally, these children had no subjective sensation of dyspnea or discomfort. This establishes that hypoxic and hypercapnic ventilatory control is absent during wakefulness. Chemoreceptor control (peripheral and central) is, therefore, defective in all states in children with CCHS. We speculate that the defect in CCHS lies in central integration of the central and peripheral chemoreceptor signals.

Stimulus interaction between CO2 and almitrine in the cat carotid chemoreceptors

The hypothesis that augmentation of the carotid chemoreceptor response to hypoxia by almitrine is due in part to an increased response to CO2 was tested by using single or few fiber preparation of carotid body chemosensory fibers in 12 cats anesthetized with alpha-chloralose. To differentiate between the plausible mechanisms of effects, we also tested the responsiveness of the afferents to cyanide and nicotine before and after almitrine. After a saturation dose of almitrine (1 mg.kg-1 followed by 0.5 mg.kg-1.h-1) the chemosensory responses to CO2 strikingly increased even during hyperoxia: the afferents showing an increased transient peak activity at the onset of hypercapnia, an augmented steady-state response to CO2 stimulus, and a decreased arterial PCO2 stimulus threshold. Thus, the effect of almitrine on carotid chemoreceptor response to hypoxia could be explained, at least in part, by its multiplicative stimulus interaction with CO2. After almitrine, the chemoreceptor response to cyanide, which is dependent on arterial PO2, was not particularly augmented relative to those of nicotine. Accordingly, the O2-sensing mechanism does not appear to be the primary site of almitrine effect. The results also indicate that the site of CO2 chemoreception resides downstream from those of hypoxia.

Ganglioglomerular nerves influence responsiveness of cat carotid body chemoreceptors to almitrine

A bolus injection of almitrine bismesylate (0.5 mg · kg −1 i.v.) in anaesthetised artificially ventilated cats caused a significantly greater increase in carotid chemosensory discharge in animals with sectioned ipsilateral ganglioglomerular sympathetic nerves in comparison with a group in which these nerves were intact. Plasma levels of almitrine were similar in both groups. Responses to hypoxia and hypercapnia post-almitrine were also bigger if the ganglioglomerular nerves were cut. Domperidone (10–50 μg · kg −1 i.a), a dopamine D 2 receptor antagonist, greatly increased the responsiveness of chemoreceptors to almitrine in ganglioglomerular nerve-intact preparations. Almitrine-induced chemosensory activity was unaffected by illuminating the carotid bifurcation with light from a fibre optic lamp, regardless of whether or not the ganglioglomerular nerves were cut. It is concluded that almitrine may directly or indirectly activate an efferent pathway in the ganglioglomerular nerves to cause depression of chemoreceptor activity, possibly by releasing dopamine to act at D 2 dopamine receptors in the carotid body.

Peripheral and central dopamine receptors in respiratory control

The role of peripheral and central dopaminergic mechanisms in respiratory control was studied in anesthetized cats. In one series, we simultaneously measured carotid chemoreceptor and ventilatory responses to hypoxia and hypercapnia before and after a saturation dose of intravenous domperidone, a peripheral dopamine (D 2) receptor antagonists. Both carotid chemoreptor and ventilatory responses were augmented by domperidone essentially in proportion, suggesting that they reflected the increase of peripheral chemoreceptor activity. Haloperidol which crosses into the brain from blood, given subsequent to domperidone, did not further affect carotid chemoreceptor responses but attenuated ventilatory responses to hypoxia without significantly altering those to hypercapnia. Thus, the additional ventilatory effect of haloperidol is mediated through central dopaminergic mechanisms involving peripheral chemoreflex pathway alone. In another series, the anesthetized cats were paralyzed and artificially ventilated to study carotid chemoreceptor responses to step increases in the end-tidal P CO 2 before and after domperidone. Domperidone significantly augmented the responses to CO 2. The results support the hypothesis that both peripheral and central dopaminergic mechanisms play a significant modulatory role in chemoreflex respiratory control.

Carotid chemoreceptor function and structure in the atherosclerotic rabbit: respiratory and cardiovascular responses to hyperoxia, hypoxia and hypercapnia.

We tested the following hypothesis: if carotid body blood flow, and hence the relationship of the frequency of discharge in chemoreceptor afferent fibres to arterial PO2, were affected by atherosclerotic change, then a modification of the control of the respiratory and cardiovascular systems might result. Carotid body reflexes were therefore studied in conscious atherosclerotic rabbits and a control group of normal animals breathing 100% O2, three hypoxic gas mixtures to which was added sufficient CO2 to maintain the arterial PCO2 constant, and 2% and 4% CO2 in 21% O2 and N2. When breathing room air, the atherosclerotic rabbits breathed at a higher respiratory frequency and lower tidal volume than the normal animals, although there was no difference in the respiratory minute volume. The respiratory and cardiovascular responses to hyperoxia, isocapnic hypoxia and hypercapnia were essentially the same in both groups of animals. Serial sections of the carotid bodies showed pathological changes including interstitial fibrosis in the caudal part with interstitial haemorrhages. The proximal part of the ascending pharyngeal artery, the vessel supplying the organ, and its origin from the external carotid, and the arterioles in the caudal part of the carotid body were nearly always occluded to a varying extent by atheromatous plaques. The capillaries appeared normal under light microscopy. The rostral-caudal lengths of the carotid bodies were similar in the two groups. We conclude that the peripheral arterial chemoreceptor responses in atherosclerotic rabbits are relatively normal even though the arteries to, and arterioles within, the carotid body are partly occluded.

Awake inspiratory airway occlusion in normal humans is followed by hyperpnea and hypocapnia

The ventilatory response following 15 seconds of inspiratory airway occlusion at functional residual capacity (FRC) was studied in nine normal supine awake subjects. Expired minute ventilation (V e), CO 2 output (v̊V CO2), tidal volume (V t), and end-tidal P CO2(P et CO2) were measured on a bbreath-by-breath basis. Alveolar P CO2 rose 5.6 mm Hg during the apnea ( P<0.001). Ventilation rose 10.8 L/min on the first breath following apnea and remained elevated above control measurements for five breaths ( P<0.05). The persistent hyperpnea was due to an increase in tidal volume and was associated with alveolar hypocapnia for 6 breaths or 30 sec ( P<0.05) and an increase in CO 2 output for 4 breaths ( P<0.05). Changes in end-tidal P CO2 correlated with excess CO 2 output relative to control measurements immediately prior to airway occlusion ( P<0.03). After 15 sec airway occlusion at FRC, there is alveolar hypercapnia with a 2.6-fold first breath rise in ventilation. Persistent alveolar hyperventilation lasting 30 sec following airway occlusion may be due to delays in central chemoreceptor response or an afterdischarge phenomenon. This overshoot hypocapnia following airway occlusion may have some relevance to the development of central apneas following obstructive apnea episodes.

The Cell Biology of Vertebrate Taste Receptors

New technologies in neurophysiology and ultrastructural research are bringing about rapid advances in our understanding of taste, particularly at the cellular level. The model of chemosensory processing in the taste bud presented here can now be explored in great detail. The synaptic organization of the taste bud indicates a potential for intriguing peripheral integrative mechanisms, including cross-talk between taste cells, summation of chemoreceptor responses by interneurons (basal cells) in the taste bud, and centrifugal control of taste buds via efferent input from the CNS. Figure 2 summarizes these findings. The existence of voltage-gated ionic channels on taste cells and their unequal distribution in apical and basolateral membrane suggests mechanisms for chemosensory transduction: A primary event in the transduction process for many taste stimuli is likely to be the closure of apical potassium channels, thus leading to a depolarizing receptor potential. The closure of these apical potassium channels is probably mediated via cyclic nucleotides or intracellular Ca2+.

Interactions between hypoxia, acetylcholine and dopamine in the carotid body of rabbit and cat.

1. Acetylcholine (ACh) and dopamine (DA) were either infused into the carotid artery or applied directly to the surface of the carotid body of twenty-six rabbits and fifteen cats. Afferent discharge of single chemoreceptor units was recorded at a range of Pa,O2 (arterial O2 pressure) values during drug administration. 2. There were no observable systemic effects of either drug when applied to the surface of the carotid body. 3. Acetylcholine tended to depress afferent discharge when applied to the surface of the rabbit carotid body or when infused into the carotid sinus. In the cat, intracarotid and surface application of ACh had mild and inconsistent effects. DA consistently depressed discharge in both species independent of the route of administration. Antagonists of ACh and DA failed to abolish the chemoreceptor response to hypoxia. 4. The changes in afferent discharge elicited by all drugs were small compared with the range of discharge rates attained with physiological stimuli. The effects of ACh and DA were more marked in hyperoxia than in hypoxia for both routes of administration, disappearing at Pa,O2 values close to 20 Torr (7.5 Torr = 1 kPa). 5. A role for DA in the maintenance of the hypoxic response was investigated in six rabbits. After 15 min of hypoxia (Pa,O2 = 21.8 +/- 1.1 Torr; mean +/- S.E.M.) the discharge of single chemoreceptor fibres adapted moderately (to 79.3 +/- 5.2% of maximum discharge). Following administration of domperidone or haloperidol (1.0-5.3 mg kg-1, I.V.) the same fibres responded with equal magnitude to the onset of the hypoxic stimulus but showed a significantly larger adaptation (to 48.5 +/- 4.4%). 6. It is concluded that endogenous ACh and DA are unlikely to mediate the transduction process of the carotid body, but DA may play a role in preventing adaptation to a prolonged hypoxic stimulus.

EFFECT OF THIOPENTONE, ETOMIDATE AND PROPOFOL ON CAROTID BODY CHEMORECEPTOR ACTIVITY IN THE RABBIT AND THE CAT

The response of the carotid body chemoreceptors to intracarotid administration of thiopentone, etomidate and propofol was tested in the rabbit and cat. Thiopentone 3-6 mg min-1 and etomidate 300-600 micrograms min-1 were mildly excitatory, shifting the oxygen and carbon dioxide response curves upwards. Propofol 1.5-3.0 mg min-1 was a potent chemodepressant and abolished discharge at PaO2 values greater than 8 kPa. Prolonged infusion of propofol at higher rates (6 mg min-1) abolished the response to hypoxia completely. The significance of these results is discussed in relation to the known ventilatory effects of the three anaesthetics.

EFFECT OF HALOTHANE, ENFLURANE AND ISOFLURANE ON CAROTID BODY CHEMORECEPTOR ACTIVITY IN THE RABBIT AND THE CAT

The response of the carotid body chemoreceptors to administration of halothane, enflurane and isoflurane was tested in the rabbit and cat. In the steady-state all three volatile anaesthetics, in doses up to 1%, were mildly chemodepressant. The oxygen response curves were shifted downwards, but hypoxic stimuli below 5.3 kPa overcame this chemodepression. Two-point carbon dioxide response curves were also shifted downwards, but with no change in slope. Possible mechanisms involved in the chemoreceptor response to transient and steady-state anaesthetic administration are discussed.

Polysomnographic Studies of Infants Who Subsequently Died of Sudden Infant Death Syndrome

The polygraphic findings from 11 future victims of sudden infant death syndrome (SIDS) are reported and compared with those of matched pairs of control infants. The recordings had been done to alleviate parental anxiety about sleep apnea. Four infants had siblings who were victims of SIDS. Two infants were studied 3.5 to 9.5 weeks before their deaths because of an unexplained apparent life-threatening event that had occurred during sleep. For each victim of SIDS, two control infants were selected from the 2,000 infants who had been tested in the same hospitals. They were matched for sex, gestational age, postnatal age, and weight at birth with the SIDS victims. Their polygraphic recordings had been performed within similar conditions. Each record was allocated a random code number and was analyzed without knowledge of the patient's identity by two independent scorers. Most sleep and cardiorespiratory variables studied did not differentiate SIDS victims from control infants. Only four variables significantly characterized the future SIDS victims: the maximal duration of central apneas, the number of sighs followed by a central apnea, the presence of obstructive apneas, and the presence of mixed apneas. Central apneas were longer during all sleep states in the SIDS victims compared with their matched controls, but none exceeded 14 seconds. Sighs immediately followed by an apnea were significantly less frequent in the future SIDS group. Obstructive and mixed sleep apneas were seen in eight of 11 SIDS victims and in only three of 22 control infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Intracisternal DIDS enhances ventilatory response to rebreathing CO2 in rats.

In 11 anesthetized rats, we tested the hypothesis that carrier-mediated anion transport in part determines the medullary chemoreceptor response to acute hypercapnia by infusing the transport inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) in mock cerebrospinal fluid (CSF) into the cisterna magna. In five additional rats with sham CSF infusion, we found no effect of mock CSF on the response to rebreathing CO2. Dye infused into the cistern stained the putative chemoreceptor areas on the ventral surface of the medulla. DIDS, at 10 to 1,000 nM, increased the respiratory response to CO2 in a dose-related manner but had no effect on arterial pressure or heart rate. At 1,000 nM, the hypercapnic minute ventilation response was almost doubled because of both volume and rate of breathing. We conclude that the net effect of anion transport is to mitigate the stimulus to the medullary chemoreceptors during acute hypercapnia.

CO2 control of the respiratory system: Plant dynamics and stability analysis

A stability analysis of respiratory chemical control is developed using a mathematical model of CO2 mass transport dynamics. Starting with a 3-compartment model of CO2 stores that distinguishes alveolar, muscle, and other tissue, model reduction techniques are applied to obtain a first-order representation of the respiratory plant. This model contains an effective tissue volume for CO2, whose derived value is much smaller than previously predicted. To investigate oscillatory instabilities, a controller which incorporates only peripheral chemoreceptor responses was added to the first-order plant model. An explicit stability index (SI) is obtained analytically from a linearized version of this model. SI varies directly with the controller gain and circulation delay time and inversely with the effective tissue volume and inspired CO2 concentration. Numerical simulations using the first-order nonlinear model show that SI is a good predictor of system stability. According to the linearized model, the system is stable for SI less than 1; from the nonlinear model, the system is stable for SI less than 1.1. For typical normal adults, the SI value is well within the stable region.

Carotid body chemoreceptor and ventilatory responses to sustained hypoxia and hypercapnia in the cat

To understand the role of carotid chemoreceptor activity in the ventilatory responses to sustained hypoxia (30 min) the following measurements were made in cats anesthetized with alpha-chloralose: (1) carotid chemoreceptor and ventilatory responses to isocapnic hypoxia and to hypercapnia during hypernoxia; (2) caratoid chemoreceptor responses to isocapnic hypoxia after dopamine receptor blockade; and (3) ventilatory responses to hypoxia after bilateral section of caratoid sinus nerves (CSN). Transition to hypoxia ( Pa o 2 ⋍ 52 Torr) from hyperoxia gradually increased carotid chemoreceptor activity by ten fold and ventilation by two fold without any detectable overshoot. Termination of isocapnic hypoxia with hyperoxia (Pa o 2 > 300 Torr) at 30 min promptly restored the carotid chemoreceptor activity to prehypoxic level. Ventilation also decreased promptly, but remained above the control value. Induction of Hypercapnia (from 31.8 Torr to 43.9 Torr) during hyperoxia was followed by a prompt increase in the chemoreceptor activity by four fold which subsequently diminished, and by a gradual four fold increase in ventilation. Termination of hypercapnia after 30 min was followed by a prompt return of chemoreceptor activity and by a slow return of ventilation to near control levels. Dopamine receptor blockade increased carotid chemoreceptor responsiveness to acute hypoxia but did not alter the response pattern during sustained hypoxia. After bilateral CSN section, ventilation decreased during maintained hypoxia. Thus, a stimulatory peripheral and inhibitory central effects of hypoxia could produce a biphasic ventilatory response to short-term hypoxia in the anesthetized cat with intact CSN but did not manifest it. The results suggest that the chemosensory input not only promptly stimulates ventilation but also prevents the subsequent depressant effect of hypoxia on the brain=stem respiratory mechanisms and hence presumably a biphasic ventilatory response in the anesthetisized cat.

Single breath of CO2 as a clinical test of the peripheral chemoreflex.

Peripheral chemoreceptor responsiveness is usually examined clinically by hypoxic testing, but the usefulness of this approach is limited by safety considerations, and the interpretation of results may be confounded by the direct central nervous system effects of hypoxia. Therefore we examined the single-breath (SB) CO2 test to determine its reproducibility and applicability as a clinical test of peripheral chemoreceptor function. The technique involved the inhalation of a SB of 13% CO2 in air. The ventilatory response was determined from the increase in ventilation (VE) during the first 20 s after the test breath and from the difference in end-tidal PCO2 between the test breath and preceding control breaths. The peak increase in VE occurred during the second or third breath after the test breath, corresponding to a delay of approximately 10 s. The mean of 10 SB tests administered at 2- to 3-min intervals was taken as the subject's response. Five healthy subjects were tested in this manner on each of 6 consecutive days with the response having an interday coefficient of variation of 25 +/- 6% (SD). The response in 26 healthy females (aged 22-61 yr) was 0.32 +/- 0.11 l.min-1.Torr-1, and in 26 healthy males (aged 24-69 yr) the response was 0.38 +/- 0.14 (P NS). No significant correlation was found between the age of the subjects and their ventilatory response. Thirty-six of the subjects also underwent hyperoxic CO2 rebreathing tests, the response to which is dependent on central chemoreceptor function. No correlation was found between rebreathing and SB tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Do oxygen tension variations contribute to the respiratory oscillations of chemoreceptor discharge in the cat?

1. A high-frequency high-flow ventilator has been developed which will produce abrupt changes in alveolar gas tensions. We have used it to study the individual contributions of PCO2 and PO2 in producing the oscillations which occur in the discharge of carotid chemoreceptors in the cat with respiration, by producing repeated end-tidal alternations (i) of PCO2 in constant hypoxia, (ii) of PO2 in constant normocapnia and (iii) of both PO2 and PCO2, i.e. of asphyxia. 2. The chemoreceptor response to alternations of PCO2 was always brisker than that to alternations of PO2 at 2, 4 or 8 s cycle durations. 3. An increase in the frequency of the alveolar alternation shortened the difference between the response times to PCO2 and PO2 but it increased the phase difference between the stimulus and the response waveforms. 4. With 4 s cycles, in normocapnic hypoxia, PCO2 was 2.9 times more effective (impulses s-1 Torr-1) than PO2 in producing oscillations in discharge. 5. The oscillations in discharge to simultaneous alternations of PO2 and PCO2 were not significantly different from the sum of individual oscillations to alternations of PCO2 and of PO2 alone. This was true with respect to timing and to amplitude of the oscillation. 6. Usually the amplitude of the chemoreceptor discharge oscillation in response to an asphyxial alternation was greater than the amplitude of the oscillation to either its PCO2 or its PO2 component alone. However, at the highest frequencies used, the phase relation between the PCO2 and PO2 components of the response could lead to the summed asphyxial response being less than its individual components. 7. The amplitudes and shapes of the oscillations in response to 4 s PCO2 alternations were not affected by changing either the steady-background PO2 or PCO2, but the amplitudes of the oscillations to pure PO2 alternations were enhanced by hypoxia and by hypercapnia. The importance of PO2 and PCO2 in giving rise to the natural respiratory oscillations in chemoreceptor discharge depends on the mean levels of the two gases. In normocapnic hypoxia (PO2 ca. 50 Torr) they are equally important but when PO2 is raised it becomes less important.

The Chemoreceptor Response to Hypoxia is Independent of the Rate of Onset of Stimulus Both before and after Almitrine

The Chemoreceptor Response to Hypoxia is Independent of the Rate of Onset of Stimulus Both before and after Almitrine