Peripheral chemoreceptors in respiratory oscillations

The hypothesis that instability of cardiorespiratory control may depend on the response and sensitivity of carotid body chemoreceptors to arterial blood gases was studied in anesthetized cats under three different experimental conditions. 1) Following administration of the peripheral dopamine receptor blocker [domperidone (0.6-0.8 mg X kg-1, iv)], carotid chemoreceptor activity and its sensitivity to CO2 during hypoxia increased, leading to cardiorespiratory oscillations at low arterial PO2 in four of eight cats. Inhalation of 100% O2 promptly decreased chemoreceptor activity and eliminated the oscillations. Inhalation of CO2 stimulated the chemoreceptor activity and ventilation but did not eliminate the oscillations. Bilateral section of carotid sinus nerves abolished the cardiorespiratory oscillations. The implication is that the dopaminergic system in the carotid body keeps chemoreceptor responses to blood gas stimuli suppressed and hence cardiorespiratory oscillations damped. 2) Hypotension and circulatory delay induced by the partial occlusion of venous return led to cardiorespiratory oscillations at low but not at high arterial PO2. 3) A few cats developed cardiorespiratory oscillations without any particular experimental intervention. These oscillations were independent of arterial PO2 and chemoreceptor activity. Thus it is reasonable to conclude that the peripheral chemoreflex can play a critical role in developing cardiorespiratory oscillations in certain instances.     

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.     

Responses of ganglioglomerular nerve activity to respiratory stimuli in the cat

We studied the responses of the ganglioglomerular nerve (GGN) efferents to brief periods of hypoxia and hypercapnia and to several levels of steady-state arterial PO2 and PCO2 and to intravascular injection of cyanide in thirteen anesthetized cats. The cats breathed spontaneously. A branch of the GGN which was cut close to the carotid body was divided into several filaments, and the activity of each filament was tested until clean and identifiable action potentials were obtained. The GGN efferent activity, breath-by-breath inspiratory volume, tracheal PO2 and PCO2 and arterial blood pressure were recorded simultaneously. We found that the GGN contained spontaneously active fibers which showed a range of responses to the respiratory stimuli. Fifty-eight percent of the filaments with dominant cardiovascular rhythm showed the least response to blood gas stimuli. Forty-two percent showed clear responses to hypoxia and hypercapnia. These responses developed slowly with the onset of the stimulus but decreased promptly with the withdrawal of the stimulus. These GGN efferents were also promptly stimulated by sodium cyanide. The steady-state response curve to hypoxia was hyperbolic and to hypercapnia it was linear. Some of these fibers showed stronger respiratory rhythms than others. The responses of these GGN efferents were associated with the respiratory responses to hypoxia and hypercapnia. For the same respiratory drive, however, the steady-state hypoxic stimulus elicited a greater GGN response than did hypercapnia.     

Enhanced peripheral chemoreflex function in conscious rabbits with pacing-induced heart failure.

The present study aimed to determine whether peripheral and/or central chemoreflex function is altered in chronic heart failure (CHF) and whether altered chemoreflex function contributes to sympathetic activation in CHF. A rabbit model of pacing-induced CHF was employed. The development of CHF (3-4 wk of pacing) was characterized by an enlarged heart, an attenuated contractility, and an elevated central venous pressure. Renal sympathetic nerve activity (RSNA) and minute volume (MV) of ventilation in response to stimulation of peripheral chemoreceptors by isocapnic/hypoxic gases were measured in the conscious state. It was found that the baseline RSNA at normoxia was higher in CHF rabbits than in sham rabbits (35. 00 +/- 4.03 vs. 20.75 +/- 2.87% of maximum, P < 0.05). Moreover, the magnitudes of changes in RSNA and MV in response to stimulation of the peripheral chemoreceptors and the slopes of RSNA-arterial PO2 and MV-arterial PO2 curves were greater in CHF than in sham rabbits. Inhibition of the peripheral chemoreceptors by inhalation of 100% O2 decreased RSNA in CHF but not in sham rabbits. The central chemoreflex function, as evaluated by the responses of RSNA and MV to hyperoxic/hypercapnic gases, was not different between sham and CHF rabbits. These data suggest that an enhancement of the peripheral chemoreflex occurs in the rabbit model of pacing-induced CHF and that the enhanced peripheral chemoreflex function contributes to the sympathetic activation in the CHF state.     

Short-term intermittent hypoxia enhances sympathetic responses to continuous hypoxia in humans.

Short-term intermittent hypoxia leads to sustained sympathetic activation and a small increase in blood pressure in healthy humans. Because obstructive sleep apnea, a condition associated with intermittent hypoxia, is accompanied by elevated sympathetic activity and enhanced sympathetic chemoreflex responses to acute hypoxia, we sought to determine whether intermittent hypoxia also enhances chemoreflex activity in healthy humans. To this end, we measured the responses of muscle sympathetic nerve activity (MSNA, peroneal microneurography) to arterial chemoreflex stimulation and deactivation before and following exposure to a paradigm of repetitive hypoxic apnea (20 s/min for 30 min; O(2) saturation nadir 81.4 +/- 0.9%). Compared with baseline, repetitive hypoxic apnea increased MSNA from 113 +/- 11 to 159 +/- 21 units/min (P = 0.001) and mean blood pressure from 92.1 +/- 2.9 to 95.5 +/- 2.9 mmHg (P = 0.01; n = 19). Furthermore, compared with before, following intermittent hypoxia the MSNA (units/min) responses to acute hypoxia [fraction of inspired O(2) (Fi(O(2))) 0.1, for 5 min] were enhanced (pre- vs. post-intermittent hypoxia: +16 +/- 4 vs. +49 +/- 10%; P = 0.02; n = 11), whereas the responses to hyperoxia (Fi(O(2)) 0.5, for 5 min) were not changed significantly (P = NS; n = 8). Thus 30 min of intermittent hypoxia is capable of increasing sympathetic activity and sensitizing the sympathetic reflex responses to hypoxia in normal humans. Enhanced sympathetic chemoreflex activity induced by intermittent hypoxia may contribute to altered neurocirculatory control and adverse cardiovascular consequences in sleep apnea.     

Adenosine stimulates breathing in fetal sheep with brain stem section.

Breathing responses to adenosine were determined in 12 chronically catheterized fetal sheep (greater than 0.8 term) in which hypoxic inhibition of breathing had been eliminated by brain stem section. The caudal extent of transection varied from the rostral midbrain to the pontomedullary junction. Isocapnic hypoxia [delta arterial PO2 (PaO2) of -12 Torr] doubled the incidence and depth of breathing activity and increased the incidence of eye movements. Intra-arterial infusion of adenosine (0.30 +/- 0.03 mg.min-1.kg fetal wt-1) increased the incidence and amplitude of breathing without affecting blood gases. Adenosine did not significantly alter the incidence of eye activity. Intra-arterial injection of oligomycin (120 +/- 26 micrograms/kg fetal wt), an inhibitor of mitochondrial oxidative phosphorylation, also stimulated breathing activity. In four fetuses with brain stem section, peripheral arterial chemodenervation blunted the stimulatory effects of hypoxia on breathing activity and abolished altogether the excitatory effects of adenosine. It is concluded that 1) hypoxia and adenosine likely inhibit breathing in normal fetuses by affecting similar areas of the brain stem and 2) in fetuses with brain section, hypoxic hyperpnea depends on peripheral and central mechanisms, whereas adenosine stimulates breathing via the peripheral arterial chemoreceptors.     

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.     

Mechanisms of respiratory response to isoproterenol in glomectomized cats

Effects of intravenous isoproterenol (2-3 micrograms) on arterial pressure, end-tidal CO2 partial pressure (PCO2), medullary extracellular fluid (ECF) pH, and phrenic activity were studied in 13 anesthetized paralyzed cats whose vagi and carotid sinus nerves were cut. The cats were servo-ventilated to keep PCO2 relatively constant. Injections of Ringer solution were without effect. Isoproterenol caused arterial pressure to fall, a transient small (1 Torr) increase of PCO2, increased venous CO2 return to the lungs, a medullary ECF acidosis, and a stimulation of respiration that continued to be elevated after arterial pressure, PCO2, and medullary ECF pH had returned to control. We show that the ECF acidosis is minimally due to the hypotension and to the small transient rise of PCO2. We also show that the respiratory response cannot be explained solely by the ECF acidosis. We conclude that, in addition to its known stimulation of peripheral chemoreceptors, isoproterenol causes medullary ECF to become acidic probably due to metabolic effects on neural tissue and has a separate direct stimulating effect on neurons in the brain.     

三种自然刺激对家兔颈动脉体化学感受器活动的影响

在游离灌流的颈动脉体窦神经标本,观察了ＰＯ２降低、ＰＣ２增加和ＰＨ降低对化学感受性单位放电的影响。共记录了３２个有自发放电的化学感受性单位对三种自然刺激的反应。所得结果如下：（１）只对ＰＯ２降低有反应的化学感受性单位（对ＰＣＯ２增加及ＰＨ降低均无反应）有１０例＊（占总数的３１％）,对三种自然刺激均有反应的化学感受性单位有９例（占２８％）,对ＰＯ２降低和ＰＣＯ２增加有反应的化学感受性单位有９例,（占     

Carotid chemoreceptor activity during acute and sustained hypoxia in goats

The role of carotid body chemoreceptors in ventilatory acclimatization to hypoxia, i.e., the progressive, time-dependent increase in ventilation during the first several hours or days of hypoxic exposure, is not well understood. The purpose of this investigation was to characterize the effects of acute and prolonged (up to 4 h) hypoxia on carotid body chemoreceptor discharge frequency in anesthetized goats. The goat was chosen for study because of its well-documented and rapid acclimatization to hypoxia. The response of the goat carotid body to acute progressive isocapnic hypoxia was similar to other species, i.e., a hyperbolic increase in discharge as arterial PO2 (PaO2) decreased. The response of 35 single chemoreceptor fibers to an isocapnic [arterial PCO2 (PaCO2) 38-40 Torr)] decrease in PaO2 of from 100 +/- 1.7 to 40.7 +/- 0.5 (SE) Torr was an increase in mean discharge frequency from 1.7 +/- 0.2 to 5.8 +/- 0.4 impulses. During sustained isocapnic steady-state hypoxia (PaO2 39.8 +/- 0.5 Torr, PaCO2, 38.4 +/- 0.4 Torr) chemoreceptor afferent discharge frequency remained constant for the first hour of hypoxic exposure. Thereafter, single-fiber chemoreceptor afferents exhibited a progressive, time-related increase in discharge (1.3 +/- 0.2 impulses.s-1.h-1, P less than 0.01) during sustained hypoxia of up to 4-h duration. These data suggest that increased carotid chemoreceptor activity contributes to ventilatory acclimatization to hypoxia.     

Cardiovascular responses to peripheral chemoreflex activation and comparison of different methods to evaluate baroreflex gain in conscious mice using telemetry

Peripheral chemoreceptors located in the carotid bodies are the primary sensors of systemic hypoxia. Although the pattern of responses elicited by peripheral chemoreceptor activation is well established in rats, lambs, and rabbits, the cardiovascular responses to peripheral chemoreflex activation in conscious mice have not been delineated. Here we report that stimulation of peripheral chemoreceptors by potassium cyanide (KCN) in conscious mice elicits a unique biphasic response in blood pressure that is characterized by an initial and robust rise followed by a decrease in blood pressure, which is accompanied by a marked reduction in heart rate. The depressor and bradycardic responses to KCN were abolished by muscarinic receptor blockade with atropine, and the pressor response was abolished by alpha-adrenergic receptor blockade with prazosin, suggesting that vagal and sympathetic drive to the heart and sympathetic drive to the vasculature mediate these cardiovascular responses. These studies characterized the chemoreflex in conscious mice and established the reliability of using them for studying hypoxia-related diseases such as obstructive sleep apnea. In another series of experiments, two methods for analyzing baroreflex sensitivity were compared: the classical pharmacological approach using phenylephrine and sodium nitroprusside (i.e., the Oxford technique) or the sequence method for analyzing spontaneous baroreflex activity. Our findings indicate that both methods are reliable, and the sequence method certainly has its benefits as a predictive tool in the context of long-term noninvasive studies using telemetry. However, for absolute determination of baroreflex function, analysis of spontaneous baroreflex activity should be complemented by the classical pharmacological method.     

Carotid body function and ventilatory responses in intermittent hypoxia. Evidence for anomalous brainstem integration of arterial chemoreceptor input

Obstructive sleep apnea is a frequent medical condition consisting in repetitive sleep-related episodes of upper airways obstruction and concurrent events of arterial blood hypoxia. There is a frequent association of cardiovascular diseases and other pathologies to this condition conforming the obstructive sleep apnea syndrome (OSAS). Laboratory models of OSAS consist in animals exposed to repetitive episodes of intermittent hypoxia (IH) which also develop cardiovascular pathologies, mostly hypertension. The overall OSAS pathophysiology appears to be linked to the repetitive hypoxia, which would cause a sensitization of carotid body (CB) chemoreflex and chemoreflex-driven hyperreactivity of the sympathetic nervous system. However, this proposal is uncertain because hyperventilation, reflecting the CB sensitization, and increased plasma CA levels, reflecting sympathetic hyperreactivity, are not constant findings in patients with OSAS and IH animals. Aiming to solve these uncertainties we have studied the entire CB chemoreflex arch in a rat model of IH, including activity of chemoreceptor cells and CB generated afferent activity to brainstem. The efferent activity was measured as ventilation in normoxia, hypoxia, and hypercapnia. Norepinephrine turnover in renal artery sympathetic endings was also assessed. Findings indicate a sensitization of the CB function to hypoxia evidenced by exaggerated chemoreceptor cell and CB afferent activity. Yet, IH rats exhibited marked hypoventilation in all studied conditions and increased turnover of norepinephrine in sympathetic endings. We conclude that IH produces a bias in the integration of the input arising from the CB with a diminished drive of ventilation and an exaggerated activation of brainstem sympathetic neurons.     

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.     

Effect of a synthetic progestin on ventilatory response to hypoxia in anesthetized rats

Effects on ventilatory responses to progressive isocapnic hypoxia of a synthetic potent progestin, chlormadinone acetate (CMA), were determined in the halothane-anesthetized male rat. Ventilation during the breathing of hyperoxic gas was largely unaffected by treatment with CMA when carotid chemoreceptor afferents were kept intact. The sensitivity to hypoxia evaluated by hyperbolic regression analysis of the response curve did not differ between the control and CMA groups. The reduction of ventilation after bilateral section of the carotid sinus nerve (CSN) in hyperoxia was less severe in CMA-treated than in untreated animals. Furthermore, the CMA-treated rats showed a larger increase in ventilation during the hypoxia test and a lower PO2 break point for ventilatory depression. Inhibition of hypoxic ventilatory depression by CMA persisted even after the denervation of CSN. We conclude that exogenous progestin likely protects regulatory mechanism(s) for respiration against hypoxic depression through a stimulating action independent of carotid chemoreceptor afferents and without a change in the sensitivity of the ventilatory response to hypoxia.     

Hypoxic modulation of systolic blood pressure and urinary sodium excretion in spontaneously hypertensive rats after carotid body denervation

To explore the role of arterial chemoreceptors, the effect of hypobaric hypoxia on urinary sodium excretion and systolic blood pressure was investigated in conscious spontaneously hypertensive rats (SHR) with carotid body denervation (CBD) or after sham-operation (SO). Denervation of the carotid bodies was performed by section of the carotid sinus nerves. Exposure to hypobaric hypoxia equivalent to high altitude of 4000 m led to a more pronounced decrease in systolic blood pressure in CBD-rats than in SO-rats. The pattern of urinary sodium excretion observed on the first two days of hypoxia in both groups was not affected by the chemodenervation. It is being suggested that arterial chemoreceptors do not play a critical role in blood pressure and natriuretic responses to hypobaric hypoxia in conscious SHR.     

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

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

Chemoreceptor reflexes and cardiovascular control

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

Ventilatory responses to specific CNS hypoxia in sleeping dogs.

Our study was concerned with the effect of brain hypoxia on cardiorespiratory control in the sleeping dog. Eleven unanesthetized dogs were studied; seven were prepared for vascular isolation and extracorporeal perfusion of the carotid body to assess the effects of systemic [and, therefore, central nervous system (CNS)] hypoxia (arterial PO(2) = 52, 45, and 38 Torr) in the presence of a normocapnic, normoxic, and normohydric carotid body during non-rapid eye movement sleep. A lack of ventilatory response to systemic boluses of sodium cyanide during carotid body perfusion demonstrated isolation of the perfused carotid body and lack of other significant peripheral chemosensitivity. Four additional dogs were carotid body denervated and exposed to whole body hypoxia for comparison. In the sleeping dog with an intact and perfused carotid body exposed to specific CNS hypoxia, we found the following. 1) CNS hypoxia for 5-25 min resulted in modest but significant hyperventilation and hypocapnia (minute ventilation increased 29 +/- 7% at arterial PO(2) = 38 Torr); carotid body-denervated dogs showed no ventilatory response to hypoxia. 2) The hyperventilation was caused by increased breathing frequency. 3) The hyperventilatory response developed rapidly (<30 s). 4) Most dogs maintained hyperventilation for up to 25 min of hypoxic exposure. 5) There were no significant changes in blood pressure or heart rate. We conclude that specific CNS hypoxia, in the presence of an intact carotid body maintained normoxic and normocapnic, does not depress and usually stimulates breathing during non-rapid eye movement sleep. The rapidity of the response suggests a chemoreflex meditated by hypoxia-sensitive respiratory-related neurons in the CNS.     

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.     

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.