Time-dependent effect of hypoxia on carotid body chemosensory function

The time-dependent effects of hypoxia on the discharge rate carotid chemoreceptors were measured in anesthetized cats. Hypoxic exposure of two different durations were used: a short-term exposure (2-3 h) was used to measure the response of the same carotid chemoreceptors; and a long-term exposure (28 days at inspired PO2 of 70 Torr) to study carotid chemoreceptor properties in one group of cats relative to those of a control group. In the chronically hypoxic and control groups, determinations were made of the 1) steady-state responses to four levels of arterial PO2 (PaO2) at constant levels of arterial PCO2; 2) steady-state responses to acute hypercapnia during hyperoxia; and 3) maximal discharge rates during anoxia. We found that the acute responses of carotid chemoreceptor afferents to a given level of hypoxia (PaO2 = 30-40 Torr) did not significantly change within 2-3 h. After long-term exposure the carotid chemoreceptor responses to hypoxia significantly increased, with no significant changes in the hypercapnic response and in the maximal discharge rate during anoxia. We conclude that isocapnic hypoxia may not elicit a sufficient cellular response within 2-3 h in the cat carotid body to sensitize the O2 responsive mechanism, but hypoxia of longer duration will sensitize such a mechanism, thereby augmenting the chemosensory activity.     

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.     

Lamotrigine and phenytoin, but not amiodarone, impair peripheral chemoreceptor responses to hypoxia.

Amiodarone, lamotrigine, and phenytoin, common antiarrhythmic and antiepileptic drugs, inhibit a persistent sodium current in neurons (I(NaP)). Previous results from our laboratory suggested that I(NaP) is critical for functionality of peripheral chemoreceptors. In this study, we determined the effects of therapeutic levels of amiodarone, lamotrigine, and phenytoin on peripheral chemoreceptor and ventilatory responses to hypoxia. Action potentials (APs) of single chemoreceptor afferents were recorded using suction electrodes advanced into the petrosal ganglion of an in vitro rat peripheral chemoreceptor complex. AP frequency (at Po(2) approximately 150 Torr and Po(2) approximately 90 Torr), conduction time, duration, and amplitude were measured before and during perfusion with therapeutic dosages of the drug or vehicle. Hypoxia-induced catecholamine secretion within the carotid body was measured using amperometry. With the use of whole body plethysmography, respiration was measured in unanesthesized rats while breathing room air, 12% O(2), and 5% CO(2), before and after intraperitoneal administration of amiodarone, lamotrigine, phenytoin, or vehicle. Lamotrigine (10 microM) and phenytoin (5 microM), but not amiodarone (5 microM), decreased chemoreceptor AP frequency without affecting other AP parameters or magnitude of catecholamine secretion. Similarly, lamotrigine (5 mg/kg) and phenytoin (10 mg/kg) blunted the hypoxic but not the hypercapnic ventilatory response. In contrast, amiodarone (2.5 mg/kg) did not alter the ventilatory response to hypoxia or hypercapnia. We conclude that lamotrigine and phenytoin at therapeutic levels impair peripheral chemoreceptor function and ventilatory response to acute hypoxia. These are consistent with I(NaP) serving an important function in AP generation and may be clinically important in the care of patients using these drugs.     

Are the carotid bodies of the guinea-pig functional?

We have previously observed that the guinea-pig appears to have a relatively poor ventilatory (V (E)) response to hypoxia, compared to other mammals. Therefore, in this study, we questioned the ability of the carotid bodies (primary peripheral chemoreceptors) in the guinea-pig to detect hypoxia. The ventilatory responses to poikilocapnic hypoxia (8% O(2)), poikilooxic hypercapnia (8% CO(2)), hyperoxia (100% O(2)) and cyanide (NaCN - 200 mug/kg, i.v.) were assessed before and after carotid body denervation (CBD) in anaesthetized guinea-pigs. Although CBD attenuated the V (E) responses to hypercapnia and cyanide, it had no effect on normoxic breathing or the V (E) responses to hypoxia or hyperoxia. In a separate group of guinea-pigs, nerve activity was recorded from single or few-fibre preparations of the carotid sinus nerve (CSN). Basal chemoreceptor activity could not be detected from any of the nerve preparations. NaCN and hypercapnia consistently provoked an increase in neural activity. In contrast, hypoxia never clearly increased activity in any of the single or few-fibre preparations isolated from the CSN. In conclusion, although the carotid bodies of the guinea-pig, like those of other mammals, are able to detect hypercapnia and histotoxic hypoxia and elicit a reflex increase in V (E), they are essentially hypoxia-insensitive. The latter may explain, at least in part, the relatively poor V (E) response to hypoxia shown by the guinea-pig.     

Differential role of the paraventricular nucleus of the hypothalamus in modulating the sympathoexcitatory component of peripheral and central chemoreflexes

In the present study we investigated the involvement of the hypothalamic paraventricular nucleus (PVN) in the modulation of sympathoexcitatory reflex activated by peripheral and central chemoreceptors. We measured mean arterial blood pressure (MAP), heart rate (HR), renal sympathetic nerve activity (RSNA), and phrenic nerve activity (PNA) before and after blocking neurotransmission within the PVN by bilateral microinjection of 2% lidocaine (100 nl) during specific stimulation of peripheral chemoreceptors by potassium cyanide (KCN, 75 microg/kg iv, bolus dose) or stimulation of central chemoreceptors with hypercapnia (10% CO(2)). Typically stimulation of peripheral chemoreceptors evoked a reflex response characterized by an increase in MAP, RSNA, and PNA and a decrease in HR. Bilateral microinjection of 2% lidocaine into the PVN had no effect on basal sympathetic and cardiorespiratory variables; however, the RSNA and PNA responses evoked by peripheral chemoreceptor stimulation were attenuated (P < 0.05). Bilateral microinjection of bicuculline (50 pmol/50 nl, n = 5) into the PVN augmented the RSNA and PNA response to peripheral chemoreceptor stimulation (P < 0.05). Conversely, the GABA agonist muscimol (0.2 nmol/50 nl, n = 5) injected into the PVN attenuated these reflex responses (P < 0.05). Blocking neurotransmission within the PVN had no effect on the hypercapnia-induced central chemoreflex responses in carotid body denervated animals. These results suggest a selective role of the PVN in processing the sympathoexcitatory and ventilatory component of the peripheral, but not central, chemoreflex.     

Responses of bulbospinal and laryngeal respiratory neurons to hypercapnia and hypoxia

The purpose was to evaluate activities of medullary respiratory neurons during equivalent changes in phrenic discharge resulting from hypercapnia and hypoxia. Decerebrate, cerebellectomized, paralyzed, and ventilated cats were used. Vagi were sectioned at left midcervical and right intrathoracic levels caudal to the origin of right recurrent laryngeal nerve. Activities of phrenic nerve and single respiratory neurons were monitored. Neurons exhibiting antidromic action potentials following stimulations of the spinal cord and recurrent laryngeal nerve were designated, respectively, bulbospinal or laryngeal. The remaining neurons were not antidromically activated. Hypercapnia caused significant augmentations of discharge frequencies for all neuronal groups. Many of these neurons had no change or declines of activity in hypoxia. We conclude that central chemoreceptor afferent influences are ubiquitous, but excitatory influences from carotid chemoreceptors are more limited in distribution among medullary respiratory neurons. Hypoxia will increase activities of neurons that receive sufficient excitatory peripheral chemoreceptor afferents to overcome direct depression by brain stem hypoxia. The possibility that responses of respiratory muscles to hypoxia are programmed within the medulla is discussed.     

Interaction between vagal and chemoreceptors afferents in ventilatory response to transient hypercapnia (awake rabbits).

The ventilatory response to a transient hypercapnia was studied in four awake rabbits maintained in a volume displacement plethysmograph : the increase in inspiratory volume (VI) was associated or not with an increase in inspiratory and expiratory durations (TI and TE). These ventilatory variations were consistent with the activation of the peripheral chemoreceptors by carbon dioxide (short latency of the initial response). After vagal blockade by local anaesthesia, relative ventilatory variations were not significantly different from those previously measured. Central activity seems an important factor reducing inhibitory vagal input and favouring peripheral chemoreceptor afferents.     

Relative latency of responses of chemoreceptor afferents from aortic and carotid bodies

Discharges from aortic and carotid body chemoreceptor afferents were simultaneously recorded in 18 anesthetized cats to test the hypothesis that aortic chemoreceptors, because of their proximity to the heart, respond to changes in arterial blood gases before carotid chemoreceptors. We found that carotid chemoreceptor responses to the onset of hypoxia and hypercapnia, and to the intravenously administered excitatory drugs (cyanide, nicotine, and doxapram), preceded those of aortic chemoreceptors. Postulating that this unexpected result was due to differences in microcirculation and mass transport, we also investigated their relative speed of responses to changes in arterial blood pressure. The aortic chemoreceptors responded to decreases in arterial blood pressure before the carotid chemoreceptors, supporting the idea that the aortic body has microcirculatory impediments not generally present in the carotid body. These findings strengthened the concept that carotid bodies are more suited for monitoring blood gas changes due to respiration, whereas aortic bodies are for monitoring circulation.     

Regulation of chemoreceptor sensitivity in the carotid body: the role of presynaptic sensory nerves

Several neural and vascular mechanisms regulate the sensitivity of carotid body chemoreceptors to hypoxia, hypercapnia, and acidosis. Factors that control blood flow and oxygen delivery in the carotid body along with those that augment or diminish catecholamine release from glomus cells can have major effects on chemoreceptor function. In addition, the sensory nerves themselves may participate in the regulation of chemoreceptor sensitivity. A portion of the carotid body's sensory nerves are presynaptic to glomus cells. In response to stimulation, the sensory nerve terminals exhibit ultrastructural changes that resemble changes associated with increased release of transmitter from motor nerves: 1) the number of small (synaptic) vesicles decreases; and 2) coated vesicles and coated regions of cisternal membrane increase in number during stimulation. If sensory nerves of the carotid body release a neurotransmitters, sensory nerve activity could influence glomus cell secretion of catecholamines or other substances tha modify chemoreceptor sensitivity. Such an effect could be produced in the carotid body by hypoxia and other conditions that stimulate the sensory nerves or it could result from antidromic activity evoked in the sensory nerves by primary afferent depolarization of their terminals in the CNS.     

Ventilatory response to hyperoxia in the chick embryo

In the avian embryo at term we measured the ventilatory response to hyperoxia, which lowers the chemoreceptor activity, to test the hypothesis that the peripheral chemoreceptors are tonically functional. Measurements of pulmonary ventilation (VE) were conducted in chicken embryos during the external pipping phase, at 38 degrees C, during air and hyperoxia, and during hypercapnia in air or in hyperoxia. Hyperoxia (95% O2) maintained for 30 min lowered VE by 15-20%, largely because of a reduction in breathing frequency (f). The oxygen consumption and carbon dioxide production of the embryo were not altered. The hyperoxic drop of VE was more marked in those embryos, which had higher values of normoxic VE. Hypercapnia, whether 2 or 5% CO2, increased VE, almost exclusively because of the increase in tidal volume (VT). The increase in VT was less pronounced when hypercapnia was associated with hyperoxia, and f slightly decreased. Hence, in hyperoxia, the VE response to CO2 was less than in air. The results are in support of the hypothesis that in the avian embryo, after the onset of breathing, the peripheral chemoreceptors exert a tonic facilitatory input on . This differs from neonatal mammals, where the chemoreceptors have minimal or no activity at birth, presumably because the increased arterial oxygenation with the onset of air breathing is a much more sudden phenomenon in mammals than it is in birds.     

Almitrine mimics hypoxia in fetal sheep with lateral pontine lesions

Almitrine bimesylate is a potent and long-lasting respiratory stimulant in adult species. It acts by stimulating the peripheral chemoreceptors, where it has been shown to accumulate specifically, although its exact mechanism of action is uncertain. In the fetal lamb, however, it produces a profound inhibition of breathing even after denervation of the peripheral chemoreceptors. In this respect its action is similar to hypoxia. To investigate whether almitrine is hypoxia mimetic, we examined the effect of almitrine in nine fetal lambs of 120-130 days gestation. Five had lesions in the lateral pons that changed the fetal depressive response to hypoxia to one of stimulation. In the remaining four fetuses, the lesions did not bilaterally encompass the appropriate area of the pons; thus they still showed the normal fetal depressive response to hypoxia and so acted as controls. Almitrine (10 mg iv) caused a pronounced stimulation of breathing that lasted 406 +/- 26 min in all five fetuses with lesions that caused a stimulatory response to hypoxia. However, in the remaining four fetuses, in which the response to hypoxia was inhibitory, almitrine caused an inhibition of breathing that lasted 184 +/- 28 min. We conclude that the action of almitrine is like that of hypoxia and that, because it acts specifically on the chemoreceptors, it may prove to be a useful tool in the study of possible central chemoreceptor mechanisms.     

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.     

Hypoxia inhibits abdominal expiratory nerve activity

Our purpose was to examine the influence of steady-state changes in chemical stimuli, as well as discrete peripheral chemoreceptor stimulation, on abdominal expiratory motor activity. In decerebrate, paralyzed, vagotomized, and ventilated cats that had bilateral pneumothoraces, we recorded efferent activity from a phrenic nerve and from an abdominal nerve (cranial iliohypogastric nerve, L1). All cats showed phasic expiratory abdominal nerve discharge at normocapnia [end-tidal PCO2 38 +/- 2 Torr], but small doses (2-6 mg/kg) of pentobarbital sodium markedly depressed this activity. Hyperoxic hypercapnia consistently enhanced abdominal expiratory activity and shortened the burst duration. Isocapnic hypoxia caused inhibition of abdominal nerve discharge in 11 of 13 cats. Carotid sinus nerve denervation (3 cats) exacerbated the hypoxic depression of abdominal nerve activity and depressed phrenic motor output. Stimulation of peripheral chemoreceptors with NaCN increased abdominal nerve discharge in 7 of 10 cats, although 2 cats exhibited marked inhibition. Four cats with intact neuraxis, but anesthetized with ketamine, yielded qualitatively similar results. We conclude that when cats are subjected to steady-state chemical stimuli in isolation (no interference from proprioceptive inputs), hypercapnia potentiates, but hypoxia attenuates, abdominal expiratory nerve activity. Mechanisms to explain the selective inhibition of expiratory motor activity by hypoxia are proposed, and physiological implications are discussed.     

Role of substance P in hypercapnic excitation of carotid chemoreceptors

Experiments were performed on 17 anesthetized, paralyzed, and artificially ventilated cats to evaluate the importance of substance P-like peptide (SP) on the carotid body responses to CO2. Single or paucifiber carotid chemoreceptor activity was recorded from the peripheral end of the cut carotid sinus nerve. In eight of the cats the influence of SP on hyperoxic hypercapnic responses was studied. While the animals breathed 100% O2, intracarotid infusion of SP (1 microgram.kg-1.min-1, 3 min) increased chemoreceptor activity by +4.8 +/- 0.3 impulses/s. After SP infusion, inhalation of CO2 in O2 caused a rapid increase in activity that reached a peak and then adapted to a lower level, whereas similar levels of CO2 before SP caused only a gradual increase in carotid body discharge rate without any overshoot in response. Furthermore SP significantly increased the magnitude and slope of the CO2 response. In the other nine cats the effect of intracarotid infusion of an SP antagonist, [D-Pro2,D-Trp7,9] SP (10-15 micrograms.kg-1.min-1), on carotid body responses to 1) hyperoxic hypercapnia (7% CO2-93% O2), 2) isocapnic hypoxia (11% O2-89% N2), and 3) hypoxic hypercapnia (11% O2-7% CO2-82% N2) was examined. SP antagonist had no effect on carotid body response to hyperoxic hypercapnia but significantly attenuated the chemoreceptor excitation caused by isocapnic hypoxia and hypoxic hypercapnia. These results suggest that 1) SP may play an important role in carotid body responses to hypoxia but not to CO2, and 2) the mechanisms of stimulation of the carotid body by hypercapnia and by hypoxia differ.     

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.     

A mathematical model of CO2 effect on cardiovascular regulation

The effect of changes in arterial CO2 tension on the cardiovascular system is analyzed by means of a mathematical model. The model is an extension of a previous one that already incorporated the main reflex and local mechanisms triggered by O2 changes. The new aspects covered by the model are the O2-CO2 interaction at the peripheral chemoreceptors, the effect of local CO2 changes on peripheral resistances, the direct central neural system (CNS) response to CO2, and the control of central chemoreceptors on ventilation and tidal volume. A statistical comparison between model simulation results and various experimental data has been performed. This comparison suggests that the model is able to simulate the acute cardiovascular response to changes in blood gas content in a variety of conditions (normoxic hypercapnia, hypercapnia during artificial ventilation, hypocapnic hypoxia, and hypercapnic hypoxia). The model ascribes the observed responses to the complex superimposition of many mechanisms simultaneously working (baroreflex, peripheral chemoreflex, CNS response, lung-stretch receptors, local gas tension effect), which may be differently activated depending on the specific stimulus under study. However, although some experiments can be reproduced using a single basal set of parameters, reproduction of other experiments requires a different combination of the mechanism strengths (particularly, a different strength of the local CO2 mechanism on peripheral resistances and of the CNS response to CO2). Starting from these results, some assumptions to explain the striking differences reported in the literature are presented. The model may represent a valid support for the interpretation of physiological data on acute cardiovascular regulation and may favor the synthesis of contradictory results into a single theoretical setting.     

Is urea pulsing in toadfish related to environmental O2 or CO2 levels?

The neurochemical, serotonin (5-hydroxytryptamine; 5-HT) is involved in the regulation of toadfish pulsatile urea excretion as well as the teleost hypoxia response. Thus, the goal of this study was to determine whether environmental conditions that activate branchial chemoreceptors also trigger pulsatile urea excretion in toadfish, since environmental dissolved oxygen levels in a typical toadfish habitat show significant diel fluctuations, often reaching hypoxic conditions at dawn. Toadfish were fitted with arterial, venous and/or buccal catheters and were exposed to various environmental conditions, and/or injected with the O(2) chemoreceptor agonist NaCN or the 5-HT(2) receptor agonist alpha-methyl-5HT. Arterial PO(2), as well as ammonia and urea excretion were monitored. Natural fluctuations in arterial PO(2) levels in toadfish did not correlate with the occurrence of a urea pulse. Chronic exposure (24 h) of toadfish to hyperoxia was without effect on nitrogen excretion, however, exposure to hypoxia caused a significant reduction in the frequency of urea pulses, and exposure to hypercapnia resulted in a reduction in the percentage of nitrogen waste excreted as urea. Of toadfish exposed acutely to hypoxia, 20% pulsed within 1 h, whereas none pulsed after normoxic or hypercapnic treatments. Furthermore, 20% of fish injected intravenously with NaCN pulsed within 1 h of injection, but no fish pulsed after injection of NaCN into the buccal cavity. To test whether environmental conditions affected 5-HT(2) receptors, toadfish were injected with alpha-methyl-5HT, which elicits urea pulses in toadfish. No significant differences in pulse size occurred among the various environmental treatments. Our findings suggest that neither the environmental conditions of hypoxia, hyperoxia or hypercapnia, nor direct branchial chemoreceptor activation by NaCN play a major role in the regulation of pulsatile urea excretion in toadfish.     

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.     

Carotid body chemosensory function in prolonged normobaric hyperoxia in the cat

The effects of normobaric hyperoxia on carotid body chemosensory function in the cat were studied. The hypothesis was that carotid body chemosensory function would be affected by chronic exposure to 100% O2 at sea level. It was based on the assumptions that carotid body tissue is exposed to high PO2 because of its high blood flow and that its O2 chemosensing mechanism is sensitive to O2 radical-induced reactions. Twelve cats were exposed to 100% O2 for 60-67 h, and 10 control cats were maintained in room air at sea level. They were anesthetized with pentobarbital sodium (Nembutal), and chemosensory afferents from a cut carotid sinus nerve were isolated and identified. The responses of single or a few clearly identifiable chemoreceptor afferents to isocapnic hypoxia and hypercapnia during hyperoxia and to the bolus injections of cyanide, nicotine, and dopamine were studied. We found that chronic hyperoxia severely blunted or eliminated the O2-sensitive response of the carotid chemoreceptors while augmenting the hypercapnic response. The response to cyanide but not to nicotine and dopamine were attenuated. Thus the hypoxic and hypercapnic responses that normally interact were separable. The lack of the cyanide response was consistent with the lack of the hypoxic response, suggesting a possible shared mechanism of carotid chemoreceptor response. Qualitatively normal responses to dopamine and nicotine indicated that the respective receptors were relatively intact after chronic exposure to hyperoxia and that the sensory nerves themselves were not affected by the prolonged O2 exposure.     

Function of the rat carotid body chemoreceptors in ageing

Some age-related deficits in the ventilatory responses have been attributed to a decline in the functionality of the carotid body (CB) arterial chemoreceptors, but a systematic study of the CB function in ageing is lacking. In rats aged 3-24 months, we have performed quantitative morphometry on specific chemoreceptor tissue, assessed the function of chemoreceptor cells by measuring the content, synthesis and release of catecholamines (a chemoreceptor cell neurotransmitter) in normoxia and hypoxia, and determined the functional activity of the intact organ by measuring chemosensory activity in the carotid sinus nerve (CSN) in normoxia, hypoxia and hypercapnic acidosis. We found that with age CBs enlarge, but at the same time there is a concomitant decrease in the percentage of chemoreceptor tissue. CB content and turnover time for their catecholamines increase with age. Hypoxic stimulation of chemoreceptor cells elicits a smaller release of catecholamines in rats after 12 months of age, but a non-specific depolarizing stimulus elicits a comparable release at all ages. In parallel, there was a marked decrease in the responsiveness to hypoxia, but not to an acidic-hypercapnic stimulus, assessed as chemosensory activity in the CSN. We conclude that in aged mammals chemoreceptor cells become hypofunctional, leading to a decreased peripheral drive of ventilation.