Sustained hypoxia promotes hyperactive response of carotid body in the cat

Carotid body chemosensory activities were measured before and after 0.2, 5,6 and 7 h of sustained isocapnic (PaCO(2) approximately equal to 30 Torr) hypoxia (PaO(2) approximately equal to 43 Torr) in the cats (n=7). The activity increased from 5.4 impsec(-1) at 0.2 h to about 13 impsec(-1) at 7 h. This increase in chemosensory activities were due to both an augmented sensitivity and to a long-term facilitation and not due to arterial [H(+)] changes.     

Distribution of carotid body type I cells and other periadventitial type I cells in the carotid bifurcation regions of the cat

Summary The bilateral distribution of carotid body type I cells was investigated in five non-pedigree cats by serially sectioning the carotid bifurcation regions. Carotid body type I cells occurred bilaterally in close proximity to the wall of the occipital artery or one of its proximal branches, and less frequently the ascending pharyngeal artery within a division of connective tissue with defineable but irregular borders. Caudally, and separate from the principal mass of carotid body type I cells, isolated groups of periadventitial type I cells were found in seven out of ten specimens lying freely in the connective tissues around the occipito-ascending pharyngeal trunk and the origin of the occipital artery immediately rostral to the carotid bifurcation. Periadventitial type I cells were not observed at the level of the carotid bifurcation but on one occasion these cells were noted caudal to the carotid bifurcation lying adjacent to the wall of the rostral end of the common carotid artery. From our data on four specimens, reconstructions were made of the carotid body. The occurrence and significance of the periadventitial type I cells is discussed.     

NO modulation of carotid body chemoreception in health and disease

Nitric oxide (NO), at physiological concentrations, is a tonic inhibitory modulator of carotid body (CB) chemosensory discharges. NO modulates the chemoreception process by several mechanisms, indirectly by modifying the vascular tone and oxygen delivery, and directly through the modulation of the excitability of glomus cells and petrosal neurons. In addition to the inhibitory effect, at high concentrations NO has a dual dose-dependent effect on CB chemoreception that depends on the P_O2${\text{P}}_{{\text{O}}_2}$. In hypoxic conditions, NO is primarily an inhibitory modulator of CB chemoreception, while in normoxia NO increases the chemosensory discharges. In this review, we will examine new evidence supporting the idea that NO is involved in the CB chemosensory potentiation induced by congestive heart failure (CHF) and chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea (OSA). Evidence from patients and experimental animal models indicates that CHF and OSA, as well as CIH, potentiate the carotid hypoxic chemoreflexes, contributing to enhance the sympathetic tone. Moreover, animals exposed to CIH or to pacing-induced CHF showed enhanced baseline CB discharges in normoxia and potentiated chemosensory responses to acute hypoxia. Several molecules and pathways are altered in CHF, OSA and CIH, but the available evidence suggests that a reduced NO production in the CB plays an essential role in both diseases, contributing to enhance the CB chemosensory discharges.     

A quantitative electron microscopic study of the effect of glucocorticoids in vivo on the early postnatal differentiation of paraneuronal cells in the carotid body and the adrenal medulla of the rat

Summary The postnatal differentiation of carotid body chief cells and endocrine adrenal medullary cells was comparatively examined during ontogenesis and in rats which were treated with dexamethasone for 7 days after birth. Ultrastructure and innervation of carotid body chief cells are mature in neonates according to the functional requirements of chemoreception. By the end of the first postnatal week, only an increase in number of dense core vesicles can be noticed, the concentration of which then will reach the adult level. Under the effect of dexamethasone most of the heterochromatin is transformed into finely dispersed euchromatin within the nuclei of carotid body chief cells. In the cytoplasm, the Golgi apparatus becomes larger and the granular endoplasmic reticulum hypertrophic. The number of catecholamines storing dense core vesicles increases considerably. The innervation density remains constant. In contrast to the carotid body chief cells, the adrenal medullary cells have not reached their definitive maturity at the time of birth. Besides phenotypes of adrenaline-cells, noradrenaline-cells and small granules containing cells, pheochromoblasts and intermediary cells can be seen as well. Their cytoplasm is sparse, the concentration of dense core vesicles and the innervation density very low. After 8 days of postnatal ontogenesis, pheochromoblasts and intermediary cells are no longer present in the adrenal medulla. In adrenaline-cells and noradrenaline-cells, important processes of growth can be noticed, the cytoplasm has grown in extent, the number of dense core vesicles doubled and the innervation density of single cells triplicated. Only the few small granules containing cells remain small. Under the effect of dexamethasone also in the nuclei of chromaffin cells a transformation of heterochromatin into euchromatin occurs. The increase in number of dense core vesicles is relatively lower than in carotid body chief cells. The significant growth of innervation density during the first postnatal week was inhibited. Our observations suggest that dexamethasone stimulates the synthesis of catecholamines in adrenal medullary cells of newborn rats less pronouncedly than in carotid body chief cells. This could be attributed to the inhibited formation of synapses of growing chromaffin cells and to the in vivo active endocrine counter-regulation.     

DL-propranolol inhibits the vascular changes in the rat carotid body induced by long-term hypoxia

Summary Two groups of rats were exposed to hypoxia (10% O₂) for 1 and 3 weeks with or without daily injections of DL-propranolol (0.66 mg·kg^–1 ip). The structure of the carotid body was analyzed by light microscopical morphometry and the catecholamine content was assayed by high performance liquid chromatography. Exposure to hypoxia induced enlargement of the carotid body due to enhanced vascularity and hypertrophy of glomic and interstitial tissues. The dopamine and norepinephrine content were increased at both 1 and 3 weeks of hypoxia and reached levels 40–50 times those of the controls. The DL-propranolol treatment abolished the vasodilatory effect of hypoxia within the first week but did not prevent the other structural changes or the rise in catecholamine content. The data suggest that 1. the vasodilation elicited by long-term hypoxia may be controlled by-adrenoceptors and 2. the structural and biochemical events occurring in rat carotid body during long-term hypoxia do not influence each other and thus seem to be controlled by different mechanisms.     

Specific localization of manserin peptide in the rat carotid body

The carotid body, located at the bifurcation of the common carotid artery, is a small sensory organ that detects changes in oxygen concentration and plays a vital role in controlling respiration. Although several molecules, such as neurotransmitters and neuropeptides, are involved in the regulation of the respiratory system, their detailed mechanisms have not been established yet. This study identifies that the presence of manserin, a neuropeptide, in the carotid body may play a crucial role in regulating respiration.The carotid bodies of adult Wistar rats were perfused with paraformaldehyde, and the frozen sections were subjected to immunohistochemical analyses. The carotid body comprises two distinct types of cells, neuron-like glomus cells and glial-like sustentacular cells. We used specific antibodies to distinguish the specific location of manserin in the carotid body, which included a tyrosine hydroxylase-positive antibody for glomus cells and an S100 protein antibody for sustentacular cells. Immunofluorescence analysis revealed that while tiny, round signals were exclusively observed in the cytoplasm of glomus cells, no signals were observed in sustentacular cells.Because manserin is believed to be secreted from precursor proteins by the endoproteolytic processing of a large precursor protein called secretogranin II, manserin secretion systems may exist in the carotid body, and thus, behave as potential regulators of respiration in the carotid body.     

Postnatal development of carotid body glomus cell response to hypoxia

This study examines developmental changes in CB glomus cell depolarization, intracellular calcium ([Ca(2+)](i)) and the magnitude of an O(2)-sensitive background ionic conductance that may play roles in the postnatal increase in oxygen sensitivity of glomus cells isolated from rats of 1-3 days and 11-14 days postnatal age. Using fura-2 and perforated patch whole cell recordings, we simultaneously measured [Ca(2+)](i) and membrane potential (E(m)) during normoxia and hypoxia. Resting E(m) in normoxia was similar at both ages. Hypoxia caused a larger E(m) depolarization and correspondingly larger [Ca(2+)](i) response in glomus cells from 11- to 14-day-old rats compared to 1-3-day-old rats. E(m) and [Ca(2+)](i) responses to 40mM K(+) were identical between the two age groups. Under normoxic conditions both age groups had similar background conductances. Under anoxic conditions (at resting membrane potential) background K(+) conductance decreased significantly more in cells from 11- to 14-day-old rats compared to cells from 1- to 3-day-old rats. Glomus cells from newborns therefore have less O(2)-sensitive background K(+) conductance. These results support the hypothesis that postnatal maturation of glomus cell O(2) sensitivity involves developmental regulation of the expression and/or O(2)-sensitivity of background ionic conductances.     

Comparative embryology of the carotid body

Vertebrate carotid bodies and related structures (branchial arch oxygen chemoreceptors in fishes, carotid labyrinth in amphibians, chemoreceptors in the wall of the common carotid and its branches in birds) develop in embryos when neural crest cells, blood vessels, and nerve fibers from sympathetic and cranial nerve ganglia invade mesenchymal primordia in the wall of the 3rd branchial arch. This review focuses on literature published since the 1970s investigating similarities and differences in the embryological development of 3rd arch oxygen chemoreceptors, especially between mammals and birds, but also considering reptiles, amphibians and fishes.     

Histological changes associated with ageing of the human carotid body

A qualitative and quantitative histological study was made of the carotid bodies obtained at necropsy from 47 subjects ranging in age from 14 to 100 years. With increasing age there is a loss of more than a third of the amount of glomic tissue with a diminution in the size of the lobules. In young people the basic histological pattern of clusters, composed of cores of chief cells with surrounding rims of sustentacular cells, has commonly superimposed on it prominence of the dark variant of chief cells. In middle-aged subjects there is proliferation of sustentacular cells which appear to merge imperceptibly into fibrosis of the lobules and becomes associated with diffuse or focal infiltrates of lymphocytes.     

Expression of HIF-1alpha, VEGF and VEGF receptors in the carotid body of chronically hypoxic rat

We examined the protein expression and localization of HIF-1alpha, VEGF, VEGF receptors in the carotid body (CB) of rats breathing 10% inspired oxygen for up to 4 weeks. The immunoreactivity (IR) of HIF-1alpha was distributed numerously in the nuclei of glomus (type-I) and other cells since hypoxia for 1 day, but was faint and scattered in the normoxic CBs. Cytoplasmic staining of the VEGF was intense in glomus cells of the hypoxic but not the normoxic group. The IR levels of HIF-1alpha and VEGF reached plateau at 4 weeks, and the IRs of VEGFR-1 and VEGFR-2 were strongly positive in the hypoxic group. Yet, the expression of VEGFR-1-IR was mild, whereas the VEGFR-2-IR was intense in normoxic CBs, suggesting an upregulation of VEGFR-1 but not VEGFR-2 in hypoxia. Hence, HIF-1 may activate the expression of VEGF and VEGFR-1 in the CB and the expression of VEGF in the chemoreceptors may play a paracrine role in the vascular remodeling during chronic hypoxia.     

Monoamines and their catabolites in the rabbit carotid body

Monoamines and their metabolites have been measured by high performance liquid chromatography with electrochemical detection, in control rabbit carotid bodies and under several experimental conditions: 1) at different times (3 h, 6 h, 24 h, 48 h) after intravenous injection of reserpine (5 mg/kg); 2) 14 days after sympathectomy; 3) 14 days after section of the carotid sinus nerve. The results were analyzed with probability plotting methods. Dopamine was the most important monoamine in the carotid body (CB) and its variations were very large. It was almost entirely depleted by reserpinization without simultaneous increase in 3,4-dihydroxyphenylacetic acid. Sympathectomy increased dopamine content but did not change noradrenaline content. However data analysis suggested that noradrenaline might be compartmented in two pools: one with a large variance, located in the type I cells was increased after sympathectomy, the other, more constant, located in the sympathetic nerve endings was entirely depleted after sympathectomy. Section of the carotid sinus nerve increased dopamine and noradrenaline and quadrupled the serotonin content of the CB. It is proposed that carotid sinus and sympathetic innervations regulate the monoamine metabolism of the CB.     

The carotid body of the harbour seal (Phoca vitulina richardsi)

Summary The bilateral distribution of carotid body type 1 and 11 cells was investigated in five harbour seals (Phoca vitulina richardsi), by serially sectioning the carotid bifurcation regions. The cells occurred bilaterally in the animals and were also present in one specimen from a sixth animal available for study. The type 1 and 11 cells were located in the space between the internal and external carotid arteries and had a varied relationship to the occipital and condyloid arteries. They lay within a division of connective tissue with irregular but defineable borders and this combination of connective tissue and type 1 and 11 cells constituted the principal mass of the carotid body. The carotid body occurred in a variety of forms: wedge-shaped, crescentic or horse-shoe shaped, or as a discrete oval structure. In some specimens the carotid body had a central neurovascular core of small blood vesels and nerves. The artery to the organ originated from either the external carotid, internal carotid or common carotid arteries. Using an interactive image analysis system in eight specimens, which had been perfusion-fixed at a normal arterial pressure, the mean volume of the carotid body was 1.666±0.45 (SD) mm³. Caudally and separate from the principal mass of the carotid body periadyentitial type 1 and 11 cells were noted in 4 out of 11 specimens in the connective tissues adjacent to the external carotid artery, origin of the occipital, and the rostral part of the common carotid artery and its bifurcation.     

A theoretical analysis of the carotid body chemoreceptor response to O2 and CO2 pressure changes

A simple mathematical model of the carotid body chemoreceptor response is presented. The model assumes that the static chemoreceptor characteristic depends on oxygen saturation in the arterial blood and on CO2 arterial concentration. The values of O2 saturation and of CO2 concentration are computed, from pressure, using blood dissociation curves, which include both the Bohr and Haldane effects. Moreover, the O2-CO2 static responses interact via a multiplicative term followed by an upper saturation. The dynamic response includes a term depending on the time derivative of CO2 concentration and a low-pass filter, which accounts for the time required to reach the steady state level. With a suitable choice of its parameters, the model reproduces the carotid chemoreceptor response under a variety of combined O2 and CO2 stimuli, both in steady state conditions and in the transient period following acute CO2 or O2 pressure changes. In particular, simulations show that if two hypercapnic stimuli are given in rapid succession, the response to the second stimulus is weaker than the first. Moreover, during transient conditions the effect of CO2 pressure changes prevail over the effect of O2 changes, due to the intrinsic derivative component of the response to CO2. In conclusion, the model allows present knowledge about chemoreceptor activity to be summarized in a single theoretical framework. In perspective, it may be used as an afferent block within large-scale models of the overall cardio-respiratory control system.     

The spatial relationship between type I glomus cells and arteriolar myocytes in the mouse carotid body

The structural relationship between type I glomus cells and the vascular smooth muscle was investigated by electron microscopy in the mouse carotid body. A close apposition (<0.1 μm) between the glomus parenchyma and the neighbouring arterioles was regularly present. Profiles of type I glomus cells were found to be exposed to the vascular smooth muscle without any supporting cell investment. In circumscribed areas of these profiles, type I glomus cells and the vascular smooth muscle cells made contact by fusion of their basal laminae. These glomus-cell-myocyte junctions structurally resemble vascular neuromuscular junctions of sympathetic nerve terminals. In addition to the occurrence of such glomus cell-myocyte contacts, myoendothelial junctions also appeared frequently. On the basis of these observations, it is suggested that type I glomus cells play a role in the regulation of the vascular tone in the carotid body and that a physiological interaction between the endothelial cells, the vascular smooth muscle cells and the type I glomus cells exists.     

Ultrastructure of the glomus cells in the carotid body of chronically hypoxic rats: With special reference to the similarity of amphibian glomus cells

The ultrastructural characteristics of the glomus cells in the rat carotid body exposed to extremely long-term hypoxia (10–12 weeks) were investigated. The glomus cells could be classified into four distinct types according to the shape of dense-cored vesicles in the glomus cell cytoplasm: (1) small vesicle cells (SVCs, 50 nm in mean diameter), (2) large vesicle cells (LVCs, 80 nm in mean diameter), (3) dilated eccentric vesicle cells (EVCs, 400–800 nm in diameter), and (4) mixed vesicle cells (MVCs, large and eccentric vesicles). Many clusters of glomus cells were found to contain all four categories of cell types. The appearance of EVCs was a unique and common characteristic of glomus cells in this long-term hypoxia model. We also noted other ultrastructural features with chronic hypoxia which are characteristic of the amphibian carotid labyrinth glomus cells: (1) incomplete covering of glomus cells with the supporting cell missing over a wide area, (2) long thin cytoplasmic projections in the intervascular stroma, and (3) intimate apposition of the glomus cells and pericytes (g-p connection), endothelial cells (g-e connection), plasma cells, and fibrocytes. Because arterial PO₂ is generally low in amphibia, these may be general features of hypoxic adaptation and facilitate both uptake of oxygen from blood and release of catecholamine into the blood. The g-p and g-e connections may take part in the regulation of the microcirculation in the enlarged carotid body. © 1993 Wiley-Liss Inc.     

The effects of blood osmolality changes on cat carotid body chemoreceptors in vivo

The possibility that carotid chemoreceptors respond to changes in plasma osmolality was investigated in the cat, perfusing the carotid artery with blood made hyper- or hypo-osmotic and recording chemoreceptor activity from carotid nerve fibers. Blood made hyperosmotic with sucrose or NaCl reduced the chemoreceptor discharge, while hypoosmotic blood increased chemoreceptor activity. The minimal osmolality variation necessary to obtain a detectable frequency change was 3–8% of the control. Frequency changes of 30% of the control were obtained with a 20% variation in osmolality. The frequency variations produced by the osmotic changes lasted as long as the infusion was maintained (up to 15 min). In some instances a rebound was observed when iso-osmotic saline was perfused again. A transient change in frequency and a clear rebound were obtained when blood made hyperosmotic with glycerol was perfused. These effects probably reflect a rapid change in intracellular osmolality due to the free passage of glycerol across cellular membranes.The modifications in chemoreceptor activity consecutive to osmolality variations are the opposite of those observed in isolated and superfused carotid bodies. As it is known that osmolality values affect the smooth muscle of the blood vessels, we conclude that our results are mainly produced by changes in carotid body blood flow due to a direct effect of hyper- and hypo-osmotic solutions on vascular muscle tone. Chemoreceptor excitation during a decrease in blood osmolality may contribute reflexly to the increased vascular resistance observed during acute osmolality reductions in man.     

The carotid body and arousal in the fetus and neonate

Arousal from sleep is a major defense mechanism in infants against hypoxia and/or hypercapnia. Arousal failure may be an important contributor to SIDS. Areas of the brainstem that have been found to be abnormal in a majority of SIDS infants are involved in the arousal process. Arousal is sleep state dependent, being depressed during AS in most mammals, but depressed during QS in human infants. Repeated exposure to hypoxia causes a progressive blunting of arousal that may involve medullary raphe GABAergic mechanisms. Whereas CB chemoreceptors contribute heavily to arousal in response to hypoxia, serotonergic central chemoreceptors have been implicated in the arousal response to CO₂. Pulmonary or chest wall mechanoreceptors also contribute to arousal in proportion to the ventilatory response and decreases in their input may contribute to depressed arousal during AS. Little is known about specific arousal pathways beyond the NTS. Whether CB chemoreceptor stimulation directly stimulates arousal centers or whether this is done indirectly through respiratory networks remains unknown. This review will focus on arousal in response to hypoxia and CO₂ in the fetus and newborn and will outline what we know (and do not know) about the involvement of the carotid body in this process.     

内皮素-1介导循环间歇性低氧影响大鼠颈动脉体可塑性的机制

目的 探讨内皮素-1（ET-1）介导循环间歇性低氧（CIH）影响颈动脉体可塑性的潜在分子机制。 方法（1）动物实验：将32只雄性SD大鼠随机分为2组,常氧对照组（Con）和循环间歇性低氧模型组（CIH）,每组16只。模型制作21d后,将每组（Con和CIH）16只大鼠再分为2组,分别予尾静脉注射ET-1（1×10^-6 mol/kg体重）或按照上述剂量计算的等体积生理盐水。30 min后,收集颈动脉体,采用Western blotting检测相关信号通路分子蛋白水平的变化。（2）器官培养：离体培养颈动脉体组织,ET-1（1×10^-4 mol /L）处理不同时间（0 min、10 min、60 min）,通过Western blotting检测p38丝裂原活化蛋白激酶（p38 MAPK）磷酸化水平。 结果 （1）CIH上调颈动脉体内皮素受体A（ET-A）和ET-B蛋白的表达;（2）与其他各组相比,ET-1可显著上调CIH大鼠颈动脉体磷酸化蛋白激酶A（p-PKA）、p-p38 MAPK、磷酸化的钙调蛋白激酶Ⅱ（p-CaMKⅡ）、磷酸化的环磷腺苷效应元件结合蛋白 （p-CREB）磷酸化水平和RhoA蛋白表达水平;（3）ET-1上调离体器官培养的颈动脉体p-p38 MAPK磷酸化水平,10 min较60 min明显。 结论 ET-1可能通过PKA/p38 MAPK/CaMKⅡ/CREB和RhoA信号通路调控CIH诱导的颈动脉体可塑性。     

Modulatory effects of histamine on cat carotid body chemoreception

Histamine has been proposed to be an excitatory transmitter between the carotid body (CB) chemoreceptor (glomus) cells and petrosal ganglion (PG) neurons. The histamine biosynthetic pathway, its storage and release, as well as the presence of histamine H1, H2 and H3 receptors have been found in the CB. However, there is only indirect evidence showing the presence of histamine in glomus cells, or weather its application produces chemosensory excitation. Thus, we studied the histamine immunocytochemical localization in the cat CB, and the effects of histamine, and H1, H2 and H3 receptor blockers on carotid sinus nerve (CSN) discharge, using CB and PG preparations in vitro. We found histamine immunoreactivity in dense-cored vesicles of glomus cells. Histamine induced dose-dependent increases in CSN discharge in the CB, but not in the PG. The H1-antagonist pyrilamine reduced the CB responses induced by histamine, the H2-antagonists cimetidine and ranitidine had no effect, while the H3-antagonist thioperamide enhanced histamine-induced responses. Present data suggests that histamine plays an excitatory modulatory role in the generation of cat CB chemosensory activity.     

Rate of dopamine metabolism in the rabbit carotid body in vivo

In the rabbit carotid body (CB) in vivo, the rate of dopamine metabolism was estimated to 44.4±3.9 (SD) pmol/CB/h from the decrease in dihydroxyphenylacetic acid content after pargyline inhibition of monoamine oxidase.