Autonomic innervation of the carotid body as a determinant of its sensitivity: implications for cardiovascular physiology and pathology.

The motivation for this review comes from the emerging complexity of the autonomic innervation of the carotid body (CB) and its putative role in regulating chemoreceptor sensitivity. With the carotid bodies as a potential therapeutic target for numerous cardiorespiratory and metabolic diseases, an understanding of the neural control of its circulation is most relevant. Since nerve fibres track blood vessels and receive autonomic innervation, we initiate our review by describing the origins of arterial feed to the CB and its unique vascular architecture and blood flow. Arterial feed(s) vary amongst species and, unequivocally, the arterial blood supply is relatively high to this organ. The vasculature appears to form separate circuits inside the CB with one having arterial venous anastomoses. Both sympathetic and parasympathetic nerves are present with postganglionic neurons located within the CB or close to it in the form of paraganglia. Their role in arterial vascular resistance control is described as is how CB blood flow relates to carotid sinus afferent activity. We discuss non-vascular targets of autonomic nerves, their possible role in controlling glomus cell activity, and how certain transmitters may relate to function. We propose that the autonomic nerves sub-serving the CB provide a rapid mechanism to tune the gain of peripheral chemoreflex sensitivity based on alterations in blood flow and oxygen delivery, and might provide future therapeutic targets. However, there remain a number of unknowns regarding these mechanisms that require further research that is discussed.

Lower hypoxic ventilatory response in smokers compared to non-smokers during abstinence from cigarettes.

BACKGROUND: Carotid body O2-chemosensitivity determines the hypoxic ventilatory response (HVR) as part of crucial regulatory reflex within oxygen homeostasis. Nicotine has been suggested to attenuate HVR in neonates of smoking mothers. However, whether smoking affects HVR in adulthood has remained unclear and probably blurred by acute ventilatory stimulation through cigarette smoke. We hypothesized that HVR is substantially reduced in smokers when studied after an overnight abstinence from cigarettes i.e. after nicotine elimination. METHODS: We therefore determined the isocapnic HVR of 23 healthy male smokers (age 33.9 ± 2.0 years, BMI 24.2 ± 0.5 kg m-2, mean ± SEM) with a smoking history of >8 years after 12 h of abstinence and compared it to that of 23 healthy male non-smokers matched for age and BMI. RESULTS: Smokers and non-smokers were comparable with regard to factors known to affect isocapnic HVR such as plasma levels of glucose and thiols as well as intracellular levels of glutathione in blood mononuclear cells. As a new finding, abstinent smokers had a significantly lower isocapnic HVR (0.024 ± 0.002 vs. 0.037 ± 0.003 l min-1 %-1BMI-1, P = 0.002) compared to non-smokers. However, upon re-exposure to cigarettes the smokers' HVR increased immediately to the non-smokers' level. CONCLUSIONS: This is the first report of a substantial HVR reduction in abstinent adult smokers which appears to be masked by daily smoking routine and may therefore have been previously overlooked. A low HVR may be suggested as a novel link between smoking and aggravated hypoxemia during sleep especially in relevant clinical conditions such as COPD.

Hypertension: a problem of organ blood flow supply-demand mismatch.

This review introduces a new hypothesis that sympathetically mediated hypertensive diseases are caused, in the most part, by the activation of visceral afferent systems that are connected to neural circuits generating sympathetic activity. We consider how organ hypoperfusion and blood flow supply-demand mismatch might lead to both sensory hyper-reflexia and aberrant afferent tonicity. We discuss how this may drive sympatho-excitatory-positive feedback and extend across multiple organs initiating, or at least amplifying, sympathetic hyperactivity. The latter, in turn, compounds the challenge to sufficient organ blood flow through heightened vasoconstriction that both maintains and exacerbates hypertension.

Heart failure and carotid body chemoreception.

There is substantial evidence to implicate a role of the carotid body (CB) chemoreflex in sympathetic and breathing dysregulation in several cardio-respiratory diseases, drawing renewed interest in its potential implications for clinical treatment and management. Evidence from both chronic heat failure (CHF) patients and animal models indicates that the CB chemoreflex is enhanced in CHF and contributes to the tonic elevation in sympathetic nerve activity (SNA) and periodic breathing associated with the disease. Although this maladaptive change likely derives from altered function at all levels of the reflex arc, a change in afferent function of the CB is likely to be a main driving force. This review will focus on recent advances in our understanding of the physiological mechanisms that alter CB function in CHF and their potential translational impact on treatment of CHF.

Peripheral chemoreceptors: function and plasticity of the carotid body.

The discovery of the sensory nature of the carotid body dates back to the beginning of the 20th century. Following these seminal discoveries, research into carotid body mechanisms moved forward progressively through the 20th century, with many descriptions of the ultrastructure of the organ and stimulus-response measurements at the level of the whole organ. The later part of 20th century witnessed the first descriptions of the cellular responses and electrophysiology of isolated and cultured type I and type II cells, and there now exist a number of testable hypotheses of chemotransduction. The goal of this article is to provide a comprehensive review of current concepts on sensory transduction and transmission of the hypoxic stimulus at the carotid body with an emphasis on integrating cellular mechanisms with the whole organ responses and highlighting the gaps or discrepancies in our knowledge. It is increasingly evident that in addition to hypoxia, the carotid body responds to a wide variety of blood-borne stimuli, including reduced glucose and immune-related cytokines and we therefore also consider the evidence for a polymodal function of the carotid body and its implications. It is clear that the sensory function of the carotid body exhibits considerable plasticity in response to the chronic perturbations in environmental O2 that is associated with many physiological and pathological conditions. The mechanisms and consequences of carotid body plasticity in health and disease are discussed in the final sections of this article.

Carotid body growth during chronic postnatal hyperoxia.

Rats reared in hyperoxia have smaller carotid bodies as adults. To study the time course and mechanisms underlying these changes, rats were reared in 60% O(2) from birth and their carotid bodies were harvested at various postnatal ages (P0-P7, P14). The carotid bodies of hyperoxia-reared rats were smaller than those of age-matched controls beginning at P4. In contrast, 7d of 60% O(2) had no effect on carotid body size in rats exposed to hyperoxia as adults. Bromodeoxyuridine (BrdU) and TdT-mediated dUTP nick end labeling (TUNEL) were used to assess cell proliferation and DNA fragmentation at P2, P4, and P6. Hyperoxia reduced the proportion of glomus cells undergoing cell division at P4; although a similar trend was evident at P2, hyperoxia no longer affected cell proliferation by P6. The proportion of TUNEL-positive glomus cells was modestly increased by hyperoxia. We did not detect changes in mRNA expression for proapoptotic (Bax) or antiapoptotic (Bcl-X(L)) genes or transcription factors that regulate cell cycle checkpoints (p53 or p21), although mRNA levels for cyclin B1 and cyclin B2 were reduced. Collectively, these data indicate that hyperoxia primarily attenuates postnatal growth of the carotid body by inhibiting glomus cell proliferation during the first few days of exposure.

Hypoxic ventilatory response of adult rats and mice after developmental hyperoxia.

Chronic postnatal hyperoxia attenuates the hypoxic ventilatory response (HVR) of rats. To determine whether the ability to detect deficits in the HVR depends on the degree of hypoxia, we assessed the HVR at several levels of hypoxia in adult rats reared in 60% O(2) for the first two postnatal weeks. Hyperoxia-treated rats exhibited smaller increases in ventilation than control rats at 12% O(2) (30±8 vs. 53±4% baseline, mean±SEM; P=0.02) but not at 10% O(2) (83±11 vs. 96±14% baseline; P=0.47). Interestingly, 10% O(2) was used as the test gas in the only study to assess HVR in mice exposed to developmental hyperoxia, and that study reported normal HVR (Dauger et al., Chest 123 (2003), 530-538). Therefore, we assessed the HVR at 12.5% O(2) in adult mice reared in 60% O(2) for the first two postnatal weeks. Hyperoxia-treated mice exhibited smaller increases in ventilation (28±7 vs. 58±8% baseline; P<0.01) and smaller carotid bodies than control mice. We conclude that hyperoxia impairs the HVR in both rats and mice, but this effect is most evident at moderate levels of hypoxia.

Position and blood supply of the carotid body in a Kenyan population / Posición y suministro sanguíneo del cuerpo carotídeo en una población de Kenia

Position and source of blood supply to the human carotid body displays population variations. These data are important during surgical procedures and diagnostic imaging in the neck but are only scarcely reported and altogether missing for the Kenyan population. The aim of this study was to describe the position and blood supply of the carotid body in a Kenyan population. A descriptive cross-sectional study at the Department of Human Anatomy, University of Nairobi, was designed. 136 common carotid arteries and their bifurcations were exposed by gross dissection. The carotid body was identified as a small oval structure embedded in the blood vessel adventitia. Position and source of blood supply were photographed. Data are presented by tables and macrographs. 138 carotid bodies were identified. Commonest position was carotid bifurcation (75.4 percent) followed by external carotid artery (10.2 percent), internal carotid artery (7.2 percent) and ascending pharyngeal artery (7.2 percent). Sources of arterial blood supply included the carotid bifurcation (51.4 percent), ascending pharyngeal (21.0 percent), external carotid (17.4 percent) and internal carotid (10.2 percent) arteries. Position and blood supply of the carotid body in the Kenyan population displays a different profile of variations from those described in other populations. Neck surgeons should be aware of these to avoid inadvertent injury.

La posición y la fuente de suministro sanguíneo del cuerpo carotídeo humano muestra variaciones en la población. Estos datos son importantes durante los procedimientos quirúrgicos y de diagnóstico por imagen en el cuello, pero son poco informados e inclusive faltan por completo en la población de Kenia. El objetivo de este estudio fue describir la posición y el aporte sanguíneo del cuerpo carotídeo en una población de Kenia. Se diseñó un estudio descriptivo de corte transversal en el Departamento de Anatomía Humana de la Universidad de Nairobi. 136 arterias carótidas comunes y sus bifurcaciones fueron expuestas mediante disección simple. El cuerpo carotídeo fue identificado como una pequeña estructura oval ubicada en la adventicia del vaso sanguíneo. La posición y la fuente de suministro sanguíneo fueron fotografiados. Los datos obtenidos fueron presentados en las tablas y fotomacrografías. 138 cuerpos carotídeos fueron identificados. La posición más frecuente fue la bifurcación carotídea (75,4 por ciento), seguida de la arteria carótida externa (10,2 por ciento), arteria carótida interna (7,2 por ciento) y la arteria faríngea ascendente (7,2 por ciento). Las fuentes de suministro sanguíneo arterial incluyeron la bifurcación carotídea (51,4 por ciento), arteria faríngea ascendente (21,0 por ciento), arteria carótida externa (17,4 por ciento) y arterias carótidas internas (10,2 por ciento). La posición y el suministro sanguíneo del cuerpo carotídeo en la población de Kenia muestra un perfil de variaciones diferente a las descritos en otras poblaciones. Los cirujanos de cuello deben conocer estas variaciones para así evitar lesiones accidentales.

Angiotensin and carotid body chemoreception in heart failure.

The carotid body (CB) plays an important role in the control of breathing and in autonomic control of cardiovascular function. CB chemoreceptor activity is enhanced in chronic heat failure (CHF) and contributes to the sympathetic hyperactivity that exacerbates the progression of the disease. Studies in the past few years have revealed that a local angiotensin (Ang) system exists in the CB and plays an important role in altering CB function in CHF as well as other conditions, such as chronic hypoxia. This brief review highlights recent revelations that Ang I metabolites exert effects within the CB, and focuses on the influence of Ang II and Ang-(1-7) on CB function in CHF.

Carotid body function in aged rats: responses to hypoxia, ischemia, dopamine, and adenosine.

The carotid body (CB) is the main arterial chemoreceptor with a low threshold to hypoxia. CB activity is augmented by A(2)-adenosine receptors stimulation and attenuated by D(2)-dopamine receptors. The effect of aging on ventilatory responses mediated by the CB to hypoxia, ischemia, and to adenosine and dopamine administration is almost unknown. This study aims to investigate the ventilatory response to ischemia and to adenosine, dopamine, and their antagonists in old rats, as well as the effect of hypoxia on adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in the aged CB. In vivo experiments were performed on young and aged rats anesthetized with pentobarbitone and breathing spontaneously. CB ischemia was induced by bilateral common carotid occlusions. cAMP content was measured in CB incubated with different oxygen concentrations. Hyperoxia caused a decrease in cAMP in the CB at all ages, but no differences were found between normoxia and hypoxia or between young and old animals. The endogenous dopaminergic inhibitory tonus is slightly reduced. However, both the ventilation decrease caused by exogenous dopamine and the increase mediated by A(2A)-adenosine receptors are not impaired in aged animals. The bradycardia induced by adenosine is attenuated in old rats. The CB's peripheral control of ventilation is preserved during aging. Concerns have also arisen regarding the clinical usage of adenosine to revert supraventricular tachycardia and the use of dopamine in critical care situations involving elderly people.

Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO(2).

We assessed the contribution of carotid body chemoreceptors to the ventilatory response to specific CNS hypercapnia in eight unanaesthetized, awake dogs. We denervated one carotid body (CB) and used extracorporeal blood perfusion of the reversibly isolated remaining CB to maintain normal CB blood gases (normoxic, normocapnic perfusate), to inhibit (hyperoxic, hypocapnic perfusate) or to stimulate (hypoxic, normocapnic perfusate) the CB chemoreflex, while the systemic circulation, and therefore the CNS and central chemoreceptors, were exposed consecutively to four progressive levels of systemic arterial hypercapnia via increased fractional inspired CO(2) for 7 min at each level. Neither unilateral CB denervation nor CB perfusion, per se, affected breathing. Relative to CB control conditions (normoxic, normocapnic perfusion), we found that CB chemoreflex inhibition decreased the slope of the ventilatory response to CNS hypercapnia in all dogs to an average of 19% of control values (range 0-38%; n = 6), whereas CB chemoreflex stimulation increased the slope of the ventilatory response to CNS hypercapnia in all dogs to an average of 223% of control values (range 204-235%; n = 4). We conclude that the gain of the CNS CO(2)/H(+) chemoreceptors in dogs is critically dependent on CB afferent activity and that CNS-CB interaction results in hyperadditive ventilatory responses to central hypercapnia.

Trophic factors in the carotid body.

The aim of the present study is to provide a review of the expression and action of trophic factors in the carotid body. In glomic type I cells, the following factors have been identified: brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, artemin, ciliary neurotrophic factor, insulin-like growth factors-I and -II, basic fibroblast growth factor, epidermal growth factor, transforming growth factor-alpha and -beta1, interleukin-1beta and -6, tumour necrosis factor-alpha, vascular endothelial growth factor, and endothelin-1 (ET-1). Growth factor receptors in the above cells include p75LNGFR, TrkA, TrkB, RET, GDNF family receptors alpha1-3, gp130, IL-6Ralpha, EGFR, FGFR1, IL1-RI, TNF-RI, VEGFR-1 and -2, ETA and ETB receptors, and PDGFR-alpha. Differential local expression of growth factors and corresponding receptors plays a role in pre- and postnatal development of the carotid body. Their local actions contribute toward producing the morphologic and molecular changes associated with chronic hypoxia and/or hypertension, such as cellular hyperplasia, extracellular matrix expansion, changes in channel densities, and neurotransmitter patterns. Neurotrophic factor production is also considered to play a key role in the therapeutic effects of intracerebral carotid body grafts in Parkinson's disease. Future research should also focus on trophic actions on carotid body type I cells by peptide neuromodulators, which are known to be present in the carotid body and to show trophic effects on other cell populations, that is, angiotensin II, adrenomedullin, bombesin, calcitonin, calcitonin gene-related peptide, cholecystokinin, erythropoietin, galanin, opioids, pituitary adenylate cyclase-activating polypeptide, atrial natriuretic peptide, somatostatin, tachykinins, neuropeptide Y, neurotensin, and vasoactive intestinal peptide.

Can carotid body perfusion act as a respiratory controller?

The carotid bodies contain chemoreceptor cells that respond to hypoxia and hypercapnia/acidosis of the arterial blood. Since the carotid bodies receive exceptionally high blood perfusion through branches of the external carotid artery, their impulse activity to the respiratory center is thought to be determined mainly by the arterial partial pressures of oxygen (O(2)) and carbon dioxide (CO(2)). However, this paradigm explains the observed increase in ventilation neither during mentally agitated states nor physical exercise. The objective of the work was to test whether physiologically feasible reductions in carotid body perfusion could explain such respiratory overdrive using a flow-sensitive mathematical model of the carotid body chemoreception. The model is based on the law of mass balance and on the description of the chemical reactions in the arterial blood and inside the receptor cells. The neural response to the arterial O(2) and CO(2) levels is assumed to be mediated via the controller's intracellular O(2) partial pressure and pH. The model predicts that the O(2) response is affected even by moderate changes in blood flow, whereas the CO(2) response is not altered until blood flow is severely limited. Reducing blood flow increases neural stimulus but decreases sensitivity to changes in the partial pressures of arterial O(2) and CO(2). An example is given in which relatively small changes in blood flow significantly modify the carotid body sensitivity to CO(2). These results suggest that limiting perfusion of the carotid bodies through vasoconstriction can offer a powerful mechanism to drive breathing beyond metabolic needs. This observation may provide important insight into the control of ventilation, e.g., during transition from wakefulness to sleep, before physical exercise or during panic attack.

Paradoxical effect of phentolamine on aqueous flow in the rabbit.

PURPOSE: The aim of this study was to assess the effects of acute systemic, nonselective alpha-adrenergic blockade on aqueous flow. METHODS: This study used pentobarbital-anesthetized rabbits (n=7), in which the following parameters were measured: mean arterial pressure, carotid blood flow, heart rate, intraocular pressure (IOP), orbital venous pressure (OVP), ciliary blood flow, and aqueous flow (AqFlow). Measurements were made before and after an intravenous administration of phentolamine (0.1 mg/kg). RESULTS: Phentolamine caused significant decreases in IOP -23%+/-2%; P<0.01), OVP (-28%+/-12%; P<0.05), and AqFlow (-33%+/-6%; P<0.01). The other parameters were not significantly altered. The rapidity of the OVP and IOP responses were noteworthy, being essentially complete 60 s after the phentolamine injection. CONCLUSIONS: A subpressor dose of phentolamine has complex effects on ocular hydrodynamics. The initial IOP decrease is too fast to be explained by aqueous dynamics or ocular rigidity, and so is most likely a result of the disgorgement of choroidal blood volume caused by decreased venous pressure outside the eye. The more prolonged ocular hypotensive effect is explained by the decrease in AqFlow, and perhaps a decrease in episcleral venous pressure or increase in uveoscleral outflow. However, the inhibition of aqueous production is odd, as lost prejunctional inhibition of norepinephrine release and unopposed beta-receptor activation should have increased aqueous production.

Expression and immunolocalization of endothelin peptides and its receptors, ETA and ETB, in the carotid body exposed to chronic intermittent hypoxia.

Increased levels of endothelin-1 (ET-1) in the carotid body (CB) contribute to the enhancement of chemosensory responses to acute hypoxia in cats exposed to chronic intermittent hypoxia (CIH). However, it is not known if the ET receptor types A (ETA-R) and B (ETB-R) are upregulated. Thus, we studied the expression and localization of ETA-R and ETB-R using Western blot and immunohistochemistry (IHC) in CBs from cats exposed to cyclic hypoxic episodes, repeated during 8 hr for 4 days. In addition, we determined if ET-1 is expressed in the chemoreceptor cells using double immunofluorescence for ET-1 and tyrosine hydroxylase (TH). We found that ET-1 expression was ubiquitous in the blood vessels and CB parenchyma, although double ET-1 and TH-positive chemoreceptor cells were mostly found in the parenchyma. ETAR was expressed in most chemoreceptor cells and blood vessels of the CB vascular pole. ETB-R was expressed in chemoreceptor cells, parenchymal capillaries, and blood vessels of the vascular pole. CIH upregulated ETB-R expression by approximately 2.1 (Western blot) and 1.6-fold (IHC) but did not change ETA-R expression. Present results suggest that ET-1,ETA-R, and ETB-R are involved in the enhanced CB chemosensory responses to acute hypoxia induced by CIH.

Carotid body tumor resection: does the need for vascular reconstruction worsen outcome?

We evaluated outcomes after carotid body tumor resection (CBR) requiring vascular reconstruction. Patients undergoing CBR at an academic medical center between 1990 and 2005 were identified. Medical records were retrospectively reviewed for clinical data, operative details, Shamblin's classification, tumor pathology, complications, and mortality. Comparisons were performed between those undergoing CBR alone and CBR requiring vascular reconstruction (CBR-VASC). Of the 71 CBRs performed in 62 patients, 16 required vascular reconstruction (23%). Although there was no difference in mean tumor size (CBR 29.1 +/- 11.9 mm, CBR-VASC 32.5 +/- 9.9 mm; p = 0.133), carotid body tumors were more commonly Shamblin's I when CBR was performed alone (CBR 53% vs. CBR-VASC 25%, p = 0.045) and Shamblin's II/III when vascular reconstruction was required (CBR 47% vs. CBR-VASC 75%, p = 0.045). There was also a significant difference in malignant tumor pathology when vascular reconstruction was required (CBR 4.4% vs. CBR-VASC 25%, p = 0.034). Cranial nerve dysfunction was higher in patients requiring vascular repair (CBR 27% vs. CBR-VASC 63%, p = 0.012), but there was no difference in baroreflex failure (CBR 7.27% vs. CBR-VASC 0%, p = 0.351), Horner's syndrome (CBR 5.5% vs. CBR-VASC 6.25%, p = 0.783), or first bite syndrome (CBR 7.27% vs. CBR-VASC 12.5%, p = 0.877). There were no perioperative strokes in either group, and one death was unrelated to operation. When required, carotid artery reconstruction at the time of CBR can be performed safely. Although cranial nerve dysfunction is more common when vascular repair is required, this is more likely related to locally advanced disease and tumor pathology rather than operative techniques.