Chemoreceptor Sensitivity Research Articles

Recovery of peripheral chemoreceptor function after denervation in ponies.

Resting ventilation (PaCO2) and ventilatory responses to acute hypoxia and to intravenous NaCN were assessed over a 4-yr period following cutting of the carotid sinus nerves and stripping the adventitia of the aortic arch. The data indicated essentially complete loss of peripheral chemoreceptor function immediately after surgery and hypoventilation during normoxia (delta PaCO2 = +8.7 Torr). There was a time-dependent, partial recovery of peripheral chemoreceptor function between 2 and 22 mo after surgery. Approximately 10% of the ventilatory response to iv NaCN returned, and 30-40% of the normal response to acute hypoxia was restored. Resting PaCO2 was no longer significantly elevated above normal by 22 mo after surgery. Four years after surgery these animals were unable to sustain normal ventilatory acclimatization to chronic hypoxia just as in an earlier study in the same ponies. Experiments carried out under anesthesia showed that recovered peripheral chemoreceptor sensitivity was not present in the carotid chemoreceptor area. However, sectioning of the aortic nerve caused the animals to again hypoventilate during acute hypoxia, and it nearly eliminated the ventilatory response to NaCN, but normal eucapnic ventilation was retained. We conclude that in the pony aortic chemoreceptors become functional in a time-dependent manner following carotid body denervation.

Mechanisms of neurohumoral regulation of heart function in aging.

Changes in hemodynamics and myocardial contractile capacity following the stimulation of extracardial nerves and administration of various doses of acetylcholine, norepinephrine, propranolol, phentolamin, atropine, serpasil and benzohexonium were studied in albino rats, rabbits and cats of various age. The shifts in cardiac acetylcholine and norepinephrine content and the activity of some enzymes of their catabolism were determined as well. Functional changes were compared with the structural shifts in intramural nervous system. In old animals there was a rise in threshold of voltage, which induced threshold reaction at stimulation of n. vagus and n. sympaticus and there was a change in heart sensitivity to acetycholine and norepinephrine, propranolol, atropine, serpasil and benzohexonium. A relationship was shown between age changes in nervous regulation of heart and transmitter metabolism. The intensity of acetylcholine and norepinephrine synthesis was decreased in old age, the transmitter metabolism in various parts of the heart was not uniformly altered, the sensitivity of epicardial chemoreceptors to nicotine, veratrum, acetylcholine was increased. The reflexes from cardiac mechanoreceptors were diminished.

Carbon dioxide sensitivity of aortic chemoreceptors in the cat

Steady state CO 2 sensitiviy in the aortic chemoreceptors was variable. For 70.3% of the steady state response lines to increasing CO 2 the slope was not significantly different from zero. For 24.3% it was significantly positive and for 5.4% significantly negative. In contrast, in 86.7% of cases the oscillating response to alternate breaths of high and low CO 2 suggested a transient response line which was significantly steeper than the steady state line. Removing CO 2 from a high CO 2 content inspirate for one breath caused a distinct drop in discharge on 83.3% of occasions. The significance of such transient CO 2 sensitivity in the absence of clear steady state sensitivity is discussed.

The sensitivity of the labellar sugar receptors of Phormia regina in relation to feeding

The hypothesis that behavioural feeding threshold of P. regina modulates and is modulated by the sensitivity of the labellar contact chemoreceptors is not supported by the examination of individual flies. Sensitivity (number of impulses fired in the first second of stimulation) of the sugar receptors in selected labellar hairs of flies of known age was recorded periodically on a fixed schedule for up to 72 hr. Experimental flies were hand fed 2.0 M fructose once every 24 hr. No correlations between feeding or age and receptor sensitivity were found. Statistically significant changes in firing frequency did occur but were unrelated to feeding and age. The proboscis extension response, on which behavioural threshold measures are based, is known to be triggered by the first few sugar receptor spikes of sufficient frequency. Neither age nor feeding significantly affected the number or frequency of impulses during the first 50 msec of stimulation.

ブリ口蓋化学受容器の海水稀釈に対する高感受性

ブリ口蓋化学受容器の海水稀釈に対する高感受性

Chemoreflexive drive of ventilation and noradrenaline stimulus in man

O2 chemoreflex drive of ventilation was studied before and after an intravenous infusion of L-norepinephrine (9 microgram/min), inducing a plasmatic hormone concentration similar to that obtained during submaximal exercise. The ventilation increasing rapidly at the beginning of the infusion was stabilized after 30 min : the ventilation was two times the reference value. The O2 chemoreflex drive of ventilation increased during norepinephrine infusion. When man was transiently switched from hypoxia to pure O2 (O2 test) the maximal fall of ventilation was two times the reference response. This increase in the chemoreflex drive, although the physico-chemical blood state was unchanged, may be explained by a norepinephrine chemoreceptor sensitization. Such a mechanism could partly explain the increase of O2 chemoreflex drive observed during muscular exercise.

Primary role of respiratory afferents in sustaining breathing rhythm

We studied the effects on breathing rhythm of suppressing the major respiratory stimuli (wakefulness, vagal, peripheral and central chemoreceptors) in healthy, unanesthetized dogs. Respiratory frequency (f) was obtained with a pneumotachograph; the state of wakefulness (W) or sleep was determined by EEG and behavioral criteria. During quiet W, f averaged 17 breaths/min and minute volume of ventilation (VI), 8.4 l/min. In slow-wave sleep (SWS), f slowed to 14 breaths/min, and VI decreased to 6.8 l/min. Afferent vagal blockade during SWS slowed f to 4 breaths/min, due primarily to prolongation of expiratory duration (Te) to 13.3 s, and decreased VI to 4.8 l/min. One breath of 100% O2 prolonged Te further to 27.4 s. Central chemoreceptor sensitivity was then reduced by inducting a metabolic alkalosis that combined with SWS, vagal blockade, and hyperoxia prolonged Te to as long as 57 s and reduced f to as low as 1 breath/min. The results demonstrate that afferent respiratory stimuli are essential for sustaining adequate ventilation.

Depression of ventilation by dopamine in man. Evidence for an effect on the chemoreceptor reflex.

Dopamine is present in the carotid body and has been postulated to be an inhibitory neurotransmitter. The purpose of this study was to determine the effects of dopamine on ventilation in man and to examine its mechanism of action. Dopamine (0.5-10 mug/kg per min) was infused in eight normal men at different levels of arterial chemoreceptor activity, produced by varying the inspired Po(2). During normoxia dopamine produced a small decrease in minute ventilation (Ve) and an increase in arterial Pco(2). When arterial chemoreceptors were stimulated by hypoxia, infusion of dopamine produced a marked initial depression of Ve followed by a sustained although less pronounced decrease in Ve. An increase in Pa(co) (2) and a decrease in Pao(2) were also observed. When arterial chemoreceptor activity was suppressed by hyperoxia, infusion of dopamine did not affect ventilation. Subjects also breathed a hypercarbic, hyperoxic gas mixture. The hypercarbia produces hyperventilation by stimulating central chemoreceptors, whereas the hyperoxia suppresses peripheral chemoreceptors. Dopamine did not alter ventilation while the subjects were breathing this gas mixture. These studies suggest that dopamine suppresses ventilation in man through an action on the arterial chemoreceptor reflex. These findings support the hypothesis that dopamine is an inhibitory neurotransmitter in the carotid body, and that release of dopamine may modulate the sensitivity of peripheral arterial chemoreceptors.

Ventilatory responses to CO 2 in the chicken: intrapulmonary and systemic chemoreceptors

The independent effects of pulmonary and arterial P co 2 on respiratory amplitude (RA) and respiratory frequency (f) were studied in unidirectionally ventilated chickens anesthetized with phénobarbital (160 mg · kg −). Pulmonary P co 2 was set by the level of PI co 2 ventilating the vascularly isolated right lung (VIL), whereas the systemic arterial P co 2 was set by the level of P co 2 ventilating thedenervated left or gas exchange lung (GEL). The following results were obtained: 1. 1) Increasing the PI co 2 to the VIL from 0 to 35 torr and maintaining Pa co 2 constant at 29 lorr increased RA from apnea to 76% of the animals maxima] hypercapnic response and decreased f: further increases in PI co 2 to VIL had only minimal effects on RA and f. 2. 2) Increasing Pa co 2, from 19 to 61 torr and maintaining pulmonary P co 2, constant increased RA and decreased f; further increases in Pa co 2, had only slight effects on RA and f. It is concluded that (1) intrapulmonary CO 2, -sensitive chemoreceptors mediate a pulmonary chemoreflex and can dominate the control of RA during hypocapnic conditions, and (2) systemic CO 2-sensitivc chemoreceptors dominate the control of RA during hypercapnic conditions. It is suggested that the intrapuimonary chemoreceptors may act as a sensory system which plays a pertinent role in the regulation of parabronchial ventilation.

Role of the carotid chemoreceptors in the hyperpnea of exercise in the cat

The role of the carotid chemoreceptors in the hyperpnea of exercise was investigated. The activity of the sinus nerve of the cat was monitored while the blood supply to the carotid body was controlled independently of the systemic circulation. By this technique, fluctuations in the arterial blood gases during a short interval of exercise induced by electrical stimulation of hindlimb muscles were unable to affect the chemoreceptor activity. While minute ventilation increased by an average of 51%, chemoreccptor discharge was found to be unchanged in 12 experiments, 6 while perfusing with normoxic blood and 6 while perfusing with hypoxic blood. Thus, it must be concluded that alteration of carotid chemoreceptor sensitivity does not occur during artificially induced exercise in anesthetized cats. However, the difference in the time course of ventilation following the initiation of artificially induced exercise between cats and other species does not allow it to be ruled out in other species, including man. Indirect evidence is against such a role.

Relationships between eupnoeic pattern of breathing and ventilatory control in man II. Early response to transient hypercapnia.

The individual importance of peripheral chemosensitive afferents was studied using a transient hypercapnia (inhalation of a 5% or a 10% CO2 in air gas mixture respectively during 4 or 2 breaths) in human conscious subjects chosen for their different eupnoeic ventilatory patterns. Calculation of the speed of change in end-tidal CO2 pressure in tracheal gas (sPETCO2) and of the rate of change in tidal volume (sVI) gave assessment for quantifying the sensitivity of arterial chemoreceptors to hypercapnia (sCO2=SVI/SPETCO2). Our results showed that, independently of any outside influence of the eupnoeic ventilatory pattern on the components of the chemical stimulus, sVI and sCO2 were found to be much smaller in subjects whose pattern of breathing was slow (i.e. having a large tidal volume). The possible causes of the weak importance of peripheral chemosensitive afferents in such subjects were discussed.

Effect of liver failure on the ventilatory response to hypoxia in man and the goat.

1. The ventilatory responses to transient and steady-state hypoxia were measured in ten patients with hepatic cirrhosis and in ten healthy control subjects. Successive measurements of these responses were also obtained in six goats before and after the experimental production of liver failure. Changes in the effect of steady-state hypoxia on the ventilatory response to hypercapnia were evaluated by successive studies in another goat. 2. In spite of a respiratory alkalosis during liver failure, the response to transient hypoxia was greater in the patients than in the control subjects. This response was increased after the onset of liver failure in all the goats. 3. In healthy humans and goats the responses to transient and steady-state hypoxia were similar in magnitude. During liver failure there was a disparity between the size of these responses, since the ventilatory increment evoked by steady-state hypoxia was unchanged in spite of the increase in response to transient hypoxia. Steady-state hypoxia consistently enhanced the ventilatory response to hypercapnia in a healthy goat, but frequently depressed the response to hypercapnia during liver failure. 4. The findings suggest that liver failure heightens the sensitivity of the peripheral chemoreceptors to the hypoxic stimulus, but may increase the tendency of the medullary centres to become depressed in hypoxia.

Mathematical simulation of the respiratory system (author's transl)

The respiratory system is described as a feedback control system. The controller consists of the peripheral chemoreceptors and the central chemosensitive structures, the respiratory centre in the medulla oblongata and the thorax-lung pump which they drive. The controlled system is comprised of three compartments (lung, brain and the remaining tissue) connected by the blood circulation. The controlled values are arterial pH and arterial O2 partial pressure and cerebral extracellular pH. Earlier models have been improved by: (1) the dead space description, (2) the thermodynamic formulation of the CO2 dissociation equation and the simple but accurate O2 dissociation equation of the blood, (3) the alteration of the CO2 dissociation equation for the brain and the remaining tissue to accommodate recent results, (4) the application of the one-receptor-theory of central chemosensitivity, (5) the pH dependence of brain circulation, (6) the bicarbonate exchange between blood and extracellular fluid of the brain and (7) the introduction of variable circulation times. Respiratory and metabolic disturbances of the respiratory system are analyzed. The mathematical formulation of the respiratory system is a differential difference equation system. In the steady state the experimental results are reproduced fairly well. A slight discrepancy is found in the simulation of metabolic acidosis. Apparently we have assumed the sensitivity of the peripheral chemoreceptors to be too large so that the respiratory response is not correctly predicted. In the numerical solution there is an overshoot in the on-transient and a damped oscillation in the off-transient of the alveolar CO2 partial pressure during respiratory acidosis. We have varied the parameters to make deviations small. The best agreement seems to result, if the central threshold is near the normal extracellular pH of the brain. A further deviation from experimental findings is that the cerebral CO2 and H+ concentration, the blood circulation of the brain, the alveolar O2 partial tension and the ventilation show a slight oscillation in the off-transient. Except for these discrepancies the experimental results, especially the stability of the extracellular pH of the brain, are reproduced fairly well. During hypoxia there are deviations form the experimental results if the central residual activity is constant and the central threshold deviates from the normal extracellular pH of the brain. But if the central residual activity is pH dependent and if the central threshold is equal to the normal extracellular pH of the brain, then the time course of VE and the other variables agree fairly well with experimental results. There is also a good correspondence between the theoretical and experimental data during hyperoxia. During metabolic acidosis the time constant of the bicarbonate exchange between blood and extracellular fluid of the brain is important. If a time constant of one minute is assumed, then the predicted and the experimental results correspond sufficiently well.

The action of 5-hydroxytryptamine on chemoreceptor discharges of the cat's carotid body.

1 Chemoreceptor discharges were recorded in vivo from fine filaments of the carotid sinus nerve containing a single or several active units; their frequency was used as an index of receptor activity. The effects of 5-hydroxytryptamine (5-HT) on chemoreceptors were studied in 26 adult cats. At times, sinus baroreceptor discharges were recorded from the carotid nerve and the effect of 5-HT on the discharges was examined. 2 Intra-carotid injections of 5-HT (2-20 mug) induced a sharp and brief increase in chemoreceptor discharges, followed by depression or block which lasted for several seconds. Repeated injections at short intervals, and a small dose after a large dose of 5-HT resulted in depressed or blocked response to 5-HT. 3 5-HT in high doses (10-20 mug, i.a.) slightly depressed the chemoreceptor discharges induced by either acetylcholine (ACh) or NaCN, when these substances were applied within 20 s after 5-HT. 5-HT (5-20 mug, i.a.) applied during asphyxia induced a further increase in chemoreceptor discharges, soon followed by block of the discharges lasting for several seconds. 4 Atropine or hexamethonium in high doses did not change the chemoreceptor response to 5-HT, while that to ACh was markedly depressed. 5 (+)-Lysergic diethylamide (LSD), methysergide or gramine did not alter the response to 5-HT, while LSD in low doses produced a marked increase in chemoreceptor discharges. 6 Acute and chronic treatment with reserpine (5-10 mg/kg, i.v.) of the animals did not change the sensitivity and the reactivity of the chemoreceptor to ACh and NaCN, while the chemoreceptor response to 5-HT was augmented, indicating an increase in the sensitivity of chemoreceptors to 5-HT. 7 5-HT in small doses (2-10 mug, i.a.) induced a marked increase in sinus baroreceptor discharges; subsequently discharges were depressed or blocked for several seconds. 8 The results are discussed in relation to possible mechanism of action of 5-HT on the chemoreceptors. It is concluded that the exogenous 5-HT probably acts directly on the chemosensory nerve endings and depolarizes them, but 5-HT contained in the carotid body does not play a significant role in the generation of chemoreceptor discharges.

Ventilatory interaction between hypoxia and [H+] at chemoreceptors of man

By measuring ventilation during isocapnic progressive hypoxia, peripheral chemoreceptor sensitivity to acute hypoxia (deltaV40) was measured in five normal young men under four sets of conditions: 1) at sea level at the subject's resting PCO2, 2) at sea level with PCO2 5 Torr above resting PCO2, 3) after 24 h at a simulated altitude of 4,267 m (PB = 447 Torr) at the subject's resting PCO2 measured during acute hyperoxia, and 4) after 24 h at high altitude, with PCO2 elevated to the subject's sea-level resting PCO2. With this experimental design, we were able to systematically vary the PCO2 and [H+] at the peripheral and central chemoreceptors of man. When mean pHa was decreased from 7.424 to 7.377 without significant change in PACO2, the mean deltaV40 increased from 18.0 to 55.9 1/min. Conversely, when mean PACO2 was altered between 33.8 and 41.6 Torr with pHa held relatively constant, the mean deltaV40 did not change. This suggests that it is the H+ and not CO2 which interacts with hypoxia in stimulating the ventilation of man. An additional finding was that the intrinsic sensitivity of the peripheral chemoreceptors to acute hypoxia did not change during 24 h of acclimatization to high altitude.

Ventilatory response of goats to transient changes in CO 2 and O 2 during acute hypoxia

The authors assessed the relative sensitivity of the peripheral chemoreceptors of 4 goats to a transient decrease in inspired CO 2 using a 2-breath test. This test provides a steady-state background of hypoxia ana hypercapnia and then, for 2 breaths, an equally hypoxic gas mixture containing no CO 2. Another type of 2-breath test, providing 2 breaths of a hyperoxic gas mixture against a background of hypoxia, was used to establish the time course of a response known to come from peripheral chemoreceptors. Seven human subjects were studied in a similar fashion to establish the validity of the procedure. Except for 2 responses, the author's human data agree with those reported previously by others. All 4 goats resembled man in responding to removal of hypoxia with a significant decrease in ventilation, but 3 of the 4 goats, unlike man, showed no significant decrease in ventilation when CO 2 was removed. The authors conclude that the peripheral chemoreceptors of goats are commonly insensitive to transient changes in inspired CO 2 during acute hypoxia.

Sensitivity of central chemoreceptors controlling blood glucose and body temperature during glucose deprivation.

1. The rise in blood glucose and the fall in body temperature which follows the injection of a glucose analogue, 2-deoxy-D-glucose (2-DG) into the lateral cerebral ventricle (I.C.V) of unanaesthetized rats were studied and found to be dose-dependent. These 2-DG induced responses are elicited by the impairment of glucose metabolism within central "glucoreceptors'. 2. 2DG induced hyperglycaemia and hypothermia were completely prevented and even the converse effects occurred when fivefold equimolar amounts of D-fructose were simultaneously injected I.C.V.; fructose, at equimolar doses, did not modify the effects of 2-DG. 3. D-xylose and D-ribose, even at high doses, did not influence 2-DG hyperglycaemia, but increased slightly the 2-DG induced hypothermia. This suggests that the pentose phosphate pathway is unable to support the metabolism within the glucoreceptors. 4. Pyruvate suppressed the 2-DG induced hyperglycaemia with a marked delay, while acetate (as ethyl ester) and a mixture of malate plus oxaloacetate did not prevent 2-DG induced effects. These results may be accounted for by the low dosage used. 5. Acetoacetate and 3-hydroxybutyrate did not prevent 2-DG hypothermia and hyperglycaemia. 6. An effective prevention of the 2-DG induced hyperglycaemia and hypothermia was achieved with fumarate and glutamate, indicating that the stimulation of the Krebs cycle within "glucoreceptors' removes the glucoprivic effects. 7. The results indicate that prevention of 2-DG induced effects occurred only with alternate source of metabolic fuel which can support high respiratory rates in brain tissue. It is concluded that central chemoreceptors are not specifically responsive to glucose, or hexoses, but to the rate of oxidative metabolism.

Ventilatory Response to Inhaled CO<sub>2</sub> at High Altitude

Central and peripheral chemoreceptor response to stimulation by carbon dioxide was assessed in 20 lowlanders studied at sea level as well as during the first and second weeks of their arrival at an altitude of 3,658 m. 13 permanent highlanders were also studied at the same altitude. The lowlanders exhibited an increase in the central as well as peripheral chemoreceptor response at high altitude. The high-landers, on the other hand, had a markedly blunted peripheral chemoreceptor response, although their central chemoreceptor sensitivity was normal. It appears that the high-landers exhibit a profound insensitivity to hypercapnia in addition to hypoxia at the peripheral chemoreceptor level.

Chemoreception in the antennule of the lobster,Homarus americanus

Chemoreceptors in the lobster antennule respond electrophysiologically to a large range of pure chemical substances including amino acids, sugars, alcohols, amines and fatty acids, in several cases down to thresholds below 10−6 or 10−7 M. Test substances were introduced by pipette into a current of sea water flowing over the isolated antennule and responses were recorded by hook electrode from small nerve fibre bundles in the antennular nerve. In many nerve bundles the responses consisted of multiunit activity, no individual nerve spikes being identifiable, while in other bundles large spikes due to one or more single receptor neurones were present. There are striking differences in response spectrum between the single and multiunit responses, which with other evidence suggest the presence of two major classes of antennular chemoreceptor. The results support the idea that in the lobster and other Crustacea the antennules are the site of sensitive chemoreceptors mediating such distance chemoreception responses as seen in trapping behaviour.

Vital capacity breaths of 5% or 15% CO 2 in N 2 or O 2 to test carotid chemosensitivity

To measure peripheral chemoreceptor sensitivity in man, we trained subjects to inspire a vital capacity breath of 5% or 15% CO 2 in either N 2 or O 2, to exhale rapidly to FRC, and then to breathe “spontaneously”. The stimulus was considered to be the P a O 2 or P a CO 2 measured at end expiration of the test breath. By evaluating various combinations of the first four spontaneous breaths we determined that the response was best defined as the average minute ventilation of the second and third spontaneous breaths. Fourteen normal men after 15% CO 2 in N 2 had a mean (± S.E.) stimulus of P a O 2 = 39.5±3.0 torr and P a CO 2 = 68.1±0.8 torr and a mean (± S.E.) response of 36.5±1.4 liters/(min × m 2). Following 5% CO 2 in N 2 the P a O 2 = 30.5±1.4 torr , P a CO 2 was normal, and ventilation was 14.7±2.6 liters/(min × m 2). A vital capacity of 15% CO 2 in O 2 raised P a co 2 to 68.7±1.3 torr and drove ventilation to 17.9±3.3 liters/ (min × m 2). The control, 5% CO 2 in O 2, produced no rise in P a CO 2 but was followed by a ventilation of 6.8±0.8 liters/(min × m 2), about twice normal ventilation. Arterial blood sampled at roughly two-second intervals from six of the subjects following test breaths of 15% CO 2 in N 2 showed that mean (± S.E.) maximum P a CO 2 was 9.9±0.8 torr higher than the corresponding P a CO 2 , and mean (± S.E.) minimum P a O 2 was 7.3±0.8 torr lower than the corresponding Pa O 2 Requirements of subject training and cooperation are offset by the test's brevity and lack of central hypoxic depression or hypercapnic stimulation, permitting evaluation of pure peripheral chemoreceptor drive.