Carotid body and glomus cells distributed in the wall of the common carotid artery in the bird

In the bird the carotid body is located between the distal (nodose) ganglion of the vagus nerve and the recurrent laryngeal nerve at the beginning of the common carotid artery, that is, the organ is located at the cervicothoracic border. The chicken carotid body receives numerous branches from the vagus and the recurrent laryngeal nerves. In addition, dense networks of the peptidergic nerve fibers immunoreactive for substance P, calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), galanin, and neuropeptide Y (NPY) are distributed in and around the carotid body parenchyma. The substance P- and CGRP-immunoreactive fibers are derived from both the superior and inferior ganglia of the vagus nerve. The VIP-, galanin-, and NPY-immunoreactive fibers originate from the 14th cervical ganglion of the sympathetic trunk. The endocrine organs including the thyroid gland, parathyroid glands, carotid body, and ultimobranchial gland are situated as a continuous series along the common carotid artery. The organs are supplied with arteries arising as one trunk from the common carotid artery. Glomus cells are widely distributed not only in the carotid body but also in the wall of the common carotid artery and around the common trunk and its branches. The glomus cells of the chicken carotid body exhibit intense immunoreactivity for serotonin, tyrosine hydroxylase, and chromogranin A. The cells located in the wall of the common carotid artery further express NPY mRNA and peptide. In the chickens exposed to isocapnic hypoxia for 35 days, 3-4-fold increase of the carotid body volume is induced and the carotid body glomus cells show enhanced synthetic and secretory activities. On the other hand, the cells in the wall of the common carotid artery display little changes after the long-term hypoxia, having different functions from the carotid body. The carotid body rudiment is formed in the lateral wall of the third branchial artery. The neural cells immunoreactive for TuJ1, PGP 9.5, and HNK-1, which are continuous with the inferior vagal (nodose) ganglion, first surround and then invade both the carotid body rudiment and the other portions of the third branchial artery, becoming glomus cells.     

Carotid labyrinth of amphibians

The amphibian carotid labyrinth is a characteristic maze-like vascular expansion at the bifurcation of the common carotid artery into the internal and external carotid arteries. The carotid labyrinths of anurans are spherical and those of urodeles are oblong. In the intervascular stroma of both anuran and urodelan carotid labyrinths, the glomus cells (type I cells, chief cells) are distributed singly or in clusters between connective tissue cells and smooth muscle cells. In fluorescence histochemistry, the glomus cells emit intense fluorescence for biogenic monoamines. In fine structure, the glomus cells are characterized by a number of dense-cored vesicles in their cytoplasm. The glomus cells have long, thin cytoplasmic processes, some of which are closely associated with smooth muscle cells, endothelial cells, and pericytes. Afferent, efferent, and reciprocal synapses are found on the glomus cells. The morphogenesis of the carotid labyrinth starts in the larvae at the point where the carotid arch descends to the internal gills. Through the early stages of larval development, the slightly expanded region of the external carotid artery becomes closely connected with the carotid arch. By the end of the foot stage, the expanded region becomes globular, and at the final stage of metamorphosis the carotid labyrinth is close to its adult form. In fine structure, the glomus cells appear as early as the initial stage of larval development. At the middle stages of development, the number of dense-cored vesicles increases remarkably. Distinct afferent synapses are found in juveniles, although efferent synapses can be seen during metamorphosis. The carotid labyrinth is innervated by nerve fibers containing several kinds of regulatory neuropeptides. Double-immunolabeling in combination with a multiple dye filter system demonstrates the coexistence of two different neuropeptides. The amphibian carotid labyrinth has been electrophysiologically confirmed to have arterial chemo- and baroreceptor functions analogous to those of the mammalian carotid body and carotid sinus. The ultrastructural characteristics of the glomus cells during and after metamorphosis suggest that the glomus cells contribute to the chemoreception after metamorphosis. The three-dimensional fine structure of vascular corrosion casts suggests that the amphibian carotid labyrinth has the appropriate architecture for controlling vascular tone and the findings throughout metamorphosis reveal that the vascular regulatory function begins at an early stage of metamorphosis. In addition, immunohistochemical studies suggest that the vascular regulation in the carotid labyrinth is under peptidergic innervation. Thus, the multiple functions of the carotid labyrinth underline the importance of this relatively small organ for maintenance of homeostasis and appropriate blood supply to the cephalic region.     

Electrical properties of chemoreceptor elements in the carotid body

The electrical properties of chemoreceptor afferent nerve fibers and glomus cells and the behavior of cytosolic Ca(2+) in glomus cells are reviewed. While this has not been confirmed, spontaneously depolarizing potentials (SDPs) recorded in a chemoreceptor afferent terminal may be the postsynaptic expression of presynaptic events. Glomus cells, which are presynaptic elements, either depolarized or hyperpolarized in response to natural and chemical stimulation. After-hyperpolarization following an initial depolarization and after-depolarization following an initial hyperpolarization were often seen. When a glomus cell depolarizes, voltage noise increases despite a decrease in input resistance in both intact and denervated carotid bodies. The voltage noise may be "receptor noise" generated in the glomus cell itself. The electrical properties of glomus cells change in the denervated carotid body, which suggests that the chemoreceptor afferent nerve exerts some trophic effect(s) on glomus cells. Hypoxia either increases or decreases cytosolic Ca(2+), while ACh or NaCN induces either an increase or no change in cytosolic Ca(2+) in glomus cells. There are at least two possible explanations for voltage changes in glomus cells: a chemical stimulus first depolarizes the glomus cell and induces Ca(2+) influx to release chemical substances, or a chemical stimulus induces an increase in [Ca(2+)](i) and then hyperpolarizes the glomus cell via potassium influx.     

Cellular distribution of oxygen sensor candidates-oxidases,cytochromes, K+-channels--in the carotid body

The specific tissue of the carotid body is built up of groups of glomus cells, enveloped by glial-type sustentacular cells, and innervated by sensory nerve fibers. These units sense arterial pO(2) and respond to hypoxia by a variety of reactions that include initiation of the arterial chemoreflex, i.e., increasing firing activity in the carotid sinus nerve. Until now, neither the cellular localization of the initial events that lead to stimulation of chemoreceptor afferents nor the molecular mechanism of oxygen sensing in the carotid body have been unequivocally identified. Proposed molecular candidates for the mechanism of oxygen sensing include: 1). components of the mitochondrial respiratory chain, 2). NADPH oxidases generating reactive oxygen species in an oxygen-dependent manner, 3). oxygen-regulated plasmalemmal K(+)-channels, and 4). nonoxidase iron-proteins. Our still limited knowledge on their cellular distribution within the carotid body is reviewed here. It is evident that: 1). the distribution of at least some oxygen sensor candidates is not ubiquitous but cell-type-specific, and 2). each specific parenchymal cell type of the carotid body contains at least one of the proposed oxygen sensor candidates. This applies also for the glial-type sustentacular cells that exhibit immunoreactivity to the two-pore domain K(+)-channel, TASK-1. These observations fit best with the assumption that each cell type within the carotid body is principally responsive to hypoxia. The differential equipping of glomus cells, nerve endings, and sustentacular cells with sensor proteins might serve to determine different thresholds of sensitivity and/or to connect the process of oxygen sensing to different signaling pathways. It also favors the assumption that several mechanisms of oxygen sensing may act simultaneously. The cellular identification of the cell type initiating the chemoreceptor reflex, however, has to await the molecular identification of the particular oxygen sensor molecule that initiates increased carotid sinus nerve activity.     

Gene expression in peripheral arterial chemoreceptors

The peripheral arterial chemoreceptors of the carotid body participate in the ventilatory responses to hypoxia and hypercapnia, the arousal responses to asphyxial apnea, and the acclimatization to high altitude. In response to an excitatory stimuli, glomus cells in the carotid body depolarize, their intracellular calcium levels rise, and neurotransmitters are released from them. Neurotransmitters then bind to autoreceptors on glomus cells and postsynaptic receptors on chemoafferents of the carotid sinus nerve. Binding to inhibitory or excitatory receptors on chemoafferents control the electrical activity of the carotid sinus nerve, which provides the input to respiratory-related brainstem nuclei. We and others have used gene expression in the carotid body as a tool to determine what neurotransmitters mediate the response of peripheral arterial chemoreceptors to excitatory stimuli, specifically hypoxia. Data from physiological studies support the involvement of numerous putative neurotransmitters in hypoxic chemosensitivity. This article reviews how in situ hybridization histochemistry and other cellular localization techniques confirm, refute, or expand what is known about the role of dopamine, norepinephrine, substance P, acetylcholine, adenosine, and ATP in chemotransmission. In spite of some species differences, review of the available data support that 1). dopamine and norepinephrine are synthesized and released from glomus cells in all species and play an inhibitory role in hypoxic chemosensitivity; 2). substance P and acetylcholine are not synthesized in glomus cells of most species but may be made and released from nerve fibers innervating the carotid body in essentially all species; 3). adenosine and ATP are ubiquitous molecules that most likely play an excitatory role in hypoxic chemosensitivity.     

Immunohistochemical distribution and colocalization of regulatory peptides in the carotid body

Current investigations on the immunohistochemical occurrence and co-occurrence of biogenic polypeptides in the mammalian carotid body were reviewed and extended by our own recent findings. The family of chromogranins and related peptides in glomus cells appears to have a widespread interspecies distribution, whereas other peptides investigated occur in a species-specific pattern. Immunoreactivity to antisera against opioids, which derive from the proenkephalin sequence, appears to be present in glomus cells of the rabbit, cat, dog, and a shrew. Conversely, glomus cells of pig and guinea pig predominantly are immunoreactive to cleavage products of prodynorphin, which co-occur in some cells with substance P and met-enkephalin-arg-phe, respectively. In the rat and Callithrix jacchus, opioid immunoreactivity is present in nerve fibres but not in glomus cells. Immunoreactivity to other peptides, such as neurotensin, cholecystokinin, neuropeptide Y, and galanin, is found only in one or two particular species. Neurotensin immunolabelling occurs in beagle dog glomus cells, which are known to lack substance P. Cholecystokinin immunoreactivity is present in glomus cells of dog and Callithrix, and co-exists with chromogranin A, neuropeptide Y, and substance P. Substance P appears to exist in both carotid body glomus cells and nerve fibres. Substance P immunoreactivity is present in glomus cells of all species investigated, except dog. Coexistence of substance P and calcitonin gene-related peptide (CGRP) is demonstrated in nerve fibres of the guinea pig carotid body, which originate in the petrosal and jugular ganglia. Other peptides visualized immunohistochemically in mammalian carotid body nerve fibres are vasoactive intestinal peptide and neuropeptide Y. The functional significance of the various peptides present in the carotid body is discussed.     

Development of spiral ganglion cells in mammalian cochlea

The development of the spiral ganglion in the cat, the rat, and the mouse was studied by electron microscopy, from fetal stages in the cat and from birth in the rodent. In the earliest stages, a single population of ganglion cells is present. Immature spiral ganglion neurons possess small perisomatic processes that seem to disappear with development, before the myelination ganglion cells are surrounded by one or two layers of Schwann cell processes. With maturation, the Schwann process increases in number around the perikaryon and its processes, which leads to the onset of myelination. The onset of myelination of the cell body processes is asynchronous. The perikaryon may be delayed in myelination by several days. Moreover, ganglion neurons from a given region of the cochlea do not myelinate simultaneously. The differentiation of two types of fibers in the intraganglionic spiral bundle and the first appearance of TII neurons occurs around birth in the cat and a few days after birth for the rat and the mouse. The distinction of TII cells is possible due to characteristic accumulation of neurofilamentous structures in the cytoplasm.     

Vagal paraganglia of the rat

Paraganglia are associated with every branch of the rat vagus nerve except the pharyngeal branch. Some of the paraganglia closely resemble the glomus caroticum, whereas others appear like small, intensely fluorescent (SIF) cells of autonomic ganglia. The paraganglionic cells of SIF cell-like bodies (SLB) store catecholamines (the most abundant is probably noradrenaline) and in some cases neurotensin. The innervation pattern of SLB is variable and their physiological role remains unclear. Paraganglionic cells of glomus-like bodies (GLB) predominantly store dopamine and probably also to a lesser extent noradrenaline. These putative chemoreceptor organs receive sensory innervation from nodose ganglion neurons as revealed by degeneration experiments and by anterograde neuronal tracing. Substance P- and calcitonin gene-related peptide-immunoreactive fibres seen in the region of vascular entry into the GLB may account for some of these sensory fibres, but the peptide/classical transmitter stored in sensory terminals synapsing on paraganglionic cells is unknown. Ultrastructural immunocytochemistry revealed vasoactive intestinal polypeptide (VIP)-immunoreactive fibres lying in the interstitial space between paraganglionic cells and large capillaries. These fibres may originate from VIP-immunoreactive neurons, being frequently attached to GLB. The major difference between GLB and the glomus caroticum concerns their blood supply and related innervation: Arteries and arterioles do not penetrate into GLB and, accordingly, noradrenaline- and neuropeptide Y-containing nerve fibres are lacking within GLB. This peculiar arrangement of paraganglionic parenchyma and arterial blood supply may be one of the reasons for the different physiological properties of vagal and carotid arterial chemoreceptors.     

Trigeminal ganglion morphology in human fetus

The morphology of the trigeminal ganglion in human fetus was investigated by means of the tract‐tracing method using the lipophilic dye DiI‐C18‐(3) (1,1′‐double octadecane 3,3,3′3′‐tetramethyl indole carbonyl cyanine‐perchlorate), hematoxylin–eosin (HE) stain, and three‐dimensional computer reconstruction models. The trigeminal ganglion was flat in the dorsoventral direction, and DiI staining revealed that the trigeminal ganglion cells were somatotopically distributed in the ganglion in a way that reflected the mediolateral order of the three branches. Ganglion cells of the ophthalmic nerve were distributed in the anteromedial part of the trigeminal ganglion, those of the mandibular nerve were in the posterolateral part, and those of the maxillary nerve were localized in the intermediate part. DiI labeled both ganglion cells and nerve fibers in the trigeminal ganglion; the ganglion cells varied in size and appeared as round‐ or oval‐shaped, the neurites connected the cell soma, and some bipolar neurons were also observed. The number of embryonic trigeminal ganglion cells did not significantly change with gestational age, but the cell diameter, area, and perimeter significantly increased. The motor root leaves the pons, runs along the sensory root, passes the ventral surface of the ganglion, and finally runs together with the mandibular nerve. The findings reported here elucidate the morphology, development, and somatotopic organization of the trigeminal ganglion and reveal the trigeminal nerve motor root pathway along the trigeminal ganglion and mandibular nerve in the human fetus. Microsc. Res. Tech. 76:598–605, 2013. © 2013 Wiley Periodicals, Inc.     

Origin and Co-localization of nitric oxide synthase, CGRP, PACAP, and VIP in the cerebral circulation of the rat

The origin of perivascular nerve fibres storing nitric oxide synthase (NOS) and co-localisation with perivascular neuropeptides were examined in the rat middle cerebral artery (MCA) by retrograde tracing with True Blue (TB) in combination with immunocytochemistry. Application of TB to the proximal part of the middle cerebral artery labelled nerve cell bodies ipsilaterally in the trigeminal, sphenopalatine, otic, and superior cervical ganglia. A few labelled cell bodies were seen contralaterally, suggesting bilateral innervation. In the parasympathetic sphenopalatine and otic ganglia, numerous TB-labelled cell bodies contained neuronal NOS (C- and N-terminal), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase activating peptide (PACAP). In the trigeminal ganglion, almost all TB-labelled cell bodies contained calcitonin gene-related peptide (CGRP) but only a few cells contained NOS. In the superior cervical ganglion, the majority of the TB-labelled nerve cells contained neuropeptide Y (NPY) but none of them contained NOS. Removal of the ipsilateral sphenopalatine ganglion caused a slight reduction in the number of perivascular VIP-, PACAP-, and NOS-containing fibres after 3 days in the MCA while there was no difference at 2 and 4 weeks after the denervation as compared to control. This indicates that the parasympathetic VIP-, PACAP-, and NOS-immunoreactive nerve fibres in the rat MCA originate from several sources.     

Fine structure of the pinealopetal innervation of the mammalian pineal gland.

The mammalian pineal gland is innervated by peripheral sympathetic and parasympathetic nerve fibers as well as by nerve fibers originating in the central nervous system (central innervation). The perikarya of the sympathetic fibers are located in the superior cervical ganglia, while the fibers terminate in boutons containing small granular vesicles and a few large granular vesicles. Both noradrenaline and neuropeptide Y are contained in these neurons. The parasympathetic fibers originate from perikarya in the pterygopalatine ganglia. The neuropeptides, vasoactive intestinal peptide and peptide histidine isoleucine, are present in these fibers, the boutons of which contain small clear transmitter vesicles and larger granular vesicles. The fibers of the central innervation originate predominantly from perikarya located in hypothalamic and limbic forebrain structures as well as from perikarya in the optic system. These fibers terminate in boutons containing small clear and, in certain fibers, an abundant number of large granular vesicles. In rodents, the majority of the central fibers terminate in the deep pineal gland and the pineal stalk. From these areas impulses might be transmitted further caudally to the superficial pineal gland via neuronal structures or processes from pinealocytes. Several hypothalamic neuropeptides and monoamines might be contained in the central fibers. The intrapineal nerve fibers are located both in the perivascular spaces and intraparenchymally. The majority of the intraparenchymally located fibers terminate freely between the pinealocytes. However, some nerve terminals make synaptic contacts with the pinealocytes and in some species with intrapineal neurons. In fetal mammals, sympathetic, parasympathetic, and central fibers are also present. In addition, an unpaired nerve, connecting the caudal part of the pineal gland with the extreme rostral part of the mesencephalon, is present. This nerve is a homologue to the pineal nerve (nervus pinealis) observed in lower vertebrates.     

Capsaicin-sensitive nerve fibers: a potential extra-ACTH mechanism participating in adrenal regeneration in rats

Pituitary-derived factors, including ACTH, have been widely implicated in initiating adrenal regeneration. However, recent work has demonstrated that adrenal regeneration is also modulated by adrenal nerves that extensively reinnervate the regenerating adrenal. Moreover, transection of the splanchnic nerve removes sensory calcitonin gene-related peptide (CGRP) and preganglionic sympathetic vesicular acetylcholine transporter (VAChT)-positive fibers from the regenerating gland and delays regeneration. However, it is not known whether the splanchnic nerve effects on adrenal regeneration are mediated by the CGRP-positive or VAChT-positive innervation. The present studies use the drug capsaicin, a neurotoxin selective for a subset of primary afferent neurons, to specifically remove CGRP-positive fibers from the adrenal gland and assess subsequent effects on the recovery of adrenal mass and function after surgical enucleation. Male, Sprague-Dawley rats were anesthetized and treated with capsaicin (vs. vehicle) periaxonally to the thoracic splanchnic nerve (33 mM, 15 minutes) or systemically (30-100 mg/kg for 4 days, s.c.). After 7-12 days of recovery, rats received right adrenalectomy and left adrenal enucleation. At 14 and 21 days postenucleation, prestress and poststress plasma and adrenals glands were collected; adrenals were weighed and fixed for immunolabeling of CGRP-positive nerve fibers. Periaxonal capsaicin treatment decreased adrenal CGRP content prior to surgical enucleation; however, reinnervation by CGRP-positive fibers was not prevented and regeneration was not affected. Systemic capsaicin treatment attenuated the reinnervation by CGRP-positive fibers and increased the rate, but not extent, of adrenal regeneration. These results support the hypothesis that adrenal innervation represents an extra-ACTH mechanism to modulate the rate of adrenal regeneration.     

Functional immunohistochemistry of neuropeptides and nitric oxide synthase in the nerve fibers of the supratentorial dura mater in an experimental migraine model

The supratentorial cerebral dura of the albino rat is equipped with a rich sensory innervation both in the connective tissue and around blood vessels, which includes nociceptive axons and their terminals; these display intense calcitonin gene-related peptide (CGRP) immunoreactivity. Stereotactic electrical stimulation of the trigeminal (Gasserian) ganglion, regarded as an experimental migraine model, caused marked increase and disintegration of club-like perivascular CGRP-immunopositive nerve endings in the dura mater and induced an apparent increase in the lengths of CGRP-immunoreactive axons. Intravenous administration of sumatriptan or eletriptan, prior to electrical stimulation, prevented disintegration of perivascular terminals and induced accumulation of CGRP in terminal and preterminal portions of peripheral sensory axons. Consequently, immunopositive terminals and varicosities increased in size; accumulation of axoplasmic organelles resulted in the "hollow" appearence of numerous varicosities. Since triptans exert their anti-migraine effect by virtue of agonist action on 5-HT(1D/B) receptors, we suggest that these drugs prevent the release of CGRP from perivascular nerve terminals in the dura mater by an action at 5-HT(1D/B) receptors. Nitroglycerine (NitroPOHL), given subcutaneously to rats, induces increased beading of nitric oxide synthase (NOS)-immunoreactive nerve fibers in the supratentorial cerebral dura mater, and an apparent increase in the number of NOS-immunoreactive nerve fibers in the dural areas supplied by the anterior and middle meningeal arteries, and the sinus sagittalis superior. Structural alterations of nitroxidergic axons innervating blood vessels of the dura mater support the idea that nitric oxide (NO) is involved in the induction of headache, a well-known side effect of coronary dilator agents.     

Expression of high-molecular-mass neurofilament protein in horse (Equus caballus) spinal ganglion neurons

Spinal ganglion (SG) neurons are subdivided, on the basis of their cytoplasmic aspect at light and electron microscopy, into dark (D) and light (L) neurons. Numerous efforts have been made to find specific markers able to identify D and L neuronal cytotypes. The isolectin B4 (IB4), utilized to identify nonpeptidergic D neurons in mice, unfortunately, has not proved as effective in other species. The 200-kDa neurofilament protein (NF200) is considered as a typical marker of L neurons in the rat, cat, and chick. The aim of this study was to analyze the histological, morphometric, and neurochemical characteristic of NF200-immunoreactive (IR) horse SG neurons, to better characterize them morphologically and functionally. NF200-IR neurons showed two levels (strong and weak) of staining intensity. Most (84%) strongly stained NF200-IR neurons corresponded to L neurons, and showed similar bimodality as in the size distribution study, which seems to indicate a third population of neurons, in addition to the two populations (small and large) previously identified. In triple-staining experiments where NF200 was colocalized with IB4, substance P (SP), and neuronal nitric oxide synthase (nNOS) neuronal markers, most NF200-IR neurons were single stained. On the contrary, most IB4-, SP-, and nNOS-stained neurons were triple labeled and almost equally subdivided between strong and weak NF200-IR with the latter being always smaller in size than strong NF200-IR neurons. In conclusion, horse SG neurons display significant morphometric and neurochemical differences compared with those of rodents.     

Freeze-fracture and immunomorphological analysis of spiral ganglion cells

Freeze-fracture analysis of adult spiral ganglion cells of CBA/CBA mice revealed two types of membrane specializations. Most cells (type I) had a smooth surface and were surrounded by Schwann cells. Type II spiral ganglion cells showed numerous membrane specializations with well-delineated indentations similar to those previously found on hair cells adjacent to afferent and efferent nerve endings. Immunomorphological analysis (using well-defined monoclonal antibodies directed against different subclasses of intermediate filament proteins) revealed a unique co-expression of neurofilaments, vimentin and cytokeratins in spiral ganglion cells of 8-to 22-week human fetuses.     

The terminal nerve and its relation with extrabulbar "olfactory" projections: lessons from lampreys and lungfishes

The definition of the terminal nerve has led to considerable confusion and controversy. This review analyzes the current state of knowledge as well as diverging opinions about the existence, components, and definition of terminal nerves or their components, with emphasis on lampreys and lungfishes. I will argue that the historical terminology regarding this cranial nerve embraces a definition of a terminal nerve that is compatible with its existence in all vertebrate species. This review further summarizes classical and more recent anatomical, developmental, neurochemical, and molecular evidence suggesting that a multitude of terminalis cell types, not only those expressing gonadotropin-releasing hormone, migrate various distances into the forebrain. This results in numerous morphological and neurochemically distinct phenotypes of neurons, with a continuum spanning from olfactory receptor-like neurons in the olfactory epithelium to typical large ganglion cells that accompany the classical olfactory projections. These cell bodies may lose their peripheral connections with the olfactory epithelium, and their central projections or cell bodies may enter the forebrain at several locations. Since "olfactory" marker proteins can be expressed in bona fide nervus terminalis cells, so-called extrabulbar "olfactory" projections may be a collection of disguised nervus terminalis components. If we do not allow this pleiomorphic collection of nerves to be considered within a terminal nerve framework, then the only alternative is to invent a highly species- and stage-specific, and, ultimately, thoroughly confusing nomenclature for neurons and nerve fibers that associate with the olfactory nerve and forebrain.     

Chronic hypoxia-induced morphological and neurochemical changes in the carotid body

The carotid body (CB) plays an important role in the control of ventilation. Type I cells in CB are considered to be the chemoreceptive element which detects the levels of PO(2), PCO(2), and [H(+)] in the arterial blood. These cells originate from the neural crest and appear to retain some neuronal properties. They are excitable and produce a number of neurochemicals. Some of these neurochemicals, such as dopamine and norepinephrine, are considered to be primarily inhibitory to CB function and others, such as adenosine triphosphate, acetylcholine, and endothelin, are thought to be primarily excitatory. Chronic hypoxia (CH) induces profound morphological as well as neurochemical changes in the CB. CH enlarges the size of CB and causes hypertrophy and mitosis of type I cells. Also, CH changes the vascular structure of CB, including inducing marked vasodilation and the growth of new blood vessels. Moreover, CH upregulates certain neurochemical systems within the CB, e.g., tyrosine hydroxylase and dopaminergic activity in type I cells. There is also evidence that CH induces neurochemical changes within the innervation of the CB, e.g., nitric oxide synthase. During CH the sensitivity of the CB chemoreceptors to hypoxia is increased but the mechanisms by which the many CH-induced structural and neurochemical changes affect the sensitivity of CB to hypoxia remains to be established.     

Studies on the importance of sympathetic innervation, adrenergic receptors, and a possible local catecholamine production in the development of patellar tendinopathy (tendinosis) in man

Changes in the patterns of production and in the effects of signal substances may be involved in the development of tendinosis, a chronic condition of pain in human tendons. There is no previous information concerning the patterns of sympathetic innervation in the human patellar tendon. In this study, biopsies of normal and tendinosis patellar tendons were investigated with immunohistochemical methods, including the use of antibodies against tyrosine hydroxylase (TH) and neuropeptide Y, and against alpha1-, alpha2A-, and beta1-adrenoreceptors. It was noticed that most of the sympathetic innervation was detected in the walls of the blood vessels entering the tendon through the paratendinous tissue, and that the tendon tissue proper of the normal and tendinosis tendons was very scarcely innervated. Immunoreactions for adrenergic receptors were noticed in nerve fascicles containing both sensory and sympathetic nerve fibers. High levels of these receptors were also detected in the blood vessel walls; alpha1-adrenoreceptor immunoreactions being clearly more pronounced in the tendinosis tendons than in the tendons of controls. Interestingly, immunoreactions for adrenergic receptors and TH were noted for the tendon cells (tenocytes), especially in tendinosis tendons. The findings give a morphological correlate for the occurrence of sympathetically mediated effects in the patellar tendon and autocrine/paracrine catecholamine mechanisms for the tenocytes, particularly, in tendinosis. The observation of adrenergic receptors on tenocytes is interesting, as stimulation of these receptors can lead to cell proliferation, degeneration, and apoptosis, events which are all known to occur in tendinosis. Furthermore, the results imply that a possible source of catecholamine production might be the tenocytes themselves     

Etiopathogenesis and clinical presentation of carotid body tumors

The carotid body (CB) is a highly specialized small organ located at the bifurcation of the common carotid artery in the neck and plays an important role in acute adaptation to hypoxia. The most common diseased state of the carotid body is its enlargement (i.e., the CB paraganglioma), which can be caused by a genetic predisposition (hereditary paraganglioma, PGL) and by chronic hypoxic stimulation. The CB is the most common tumor site in head and neck paragangliomas. Currently, inactivating germline mutations in the mitochondrial complex II subunits SDHB, SDHC, and SDHD have been identified as genetic risk factors for CB tumors (CBTs). Another locus at chromosome 11q13, identified by linkage analysis in a single family, may harbor a fourth susceptibility gene. Although CBTs are mostly slow-growing and benign, they can cause significant morbidity because of their proximity to major arteries and nerves in the head and neck. Here, we review the etiological factors implicated in the development of CBTs and provide information pertaining to their clinical presentation. Although CBTs are rare, they have the potential to provide unique insights for tumorigenesis and oxygen sensing and signaling mechanisms.     

Are there gap junctions between chief (glomus,type I) cells in the carotid body chemoreceptor? A review

Since the dye- and electronic couplings between the carotid body chief cells have been demonstrated, the detection and localization of the gap junctions in the carotid body is crucial to understanding the functional mechanism of chemoreception. However, conventional electron microscopy has been unsuccessful in unquestionably detecting ultrastructural features equivalent to the gap junctions, such as close (2 nm in width) membrane appositions in ultrathin sections and aggregations of intramembranous particles in freeze-fracture replicas of the carotid body. We previously reported using a modified electron microscopic study by chemically fixed and subsequent rapid freezing and freeze-substitution method a number of close membrane appositions comparable to the gap junctions. However, we later found that the freeze-substitution also induces numerous close apposition of the membrane in sites where the gap junctions are not known to occur, indicating that the modified electron microscopy by freeze-substitution is not always confirmative in the detection of the gap junction. With regard to the molecular evidence for the gap junction in the carotid body, there have so far been few data on the immunohistochemical demonstration on connexin 32 and 43 in cultured chief cells, but not in the in situ cells.