Cellular mechanisms involved in rabbit carotid body excitation elicited by endothelin peptides

Chen, J; He, Liang; Dinger, B.; Fidone, S.

doi:10.1016/s0034-5687(00)00113-4

Cited by 46 publications

(37 citation statements)

References 25 publications

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“…Over three dozen genes are targets for transactivation by HIF-1 (21), and several of these may be involved in O 2 sensing͞signal transduction by the carotid body, including endothelin-1 (22,23) and tyrosine hydroxylase (24). Expression of endothelin-1 is induced by hypoxia in the carotid body and augments chemoreceptor responses by enhancing intracellular Ca 2ϩ levels and stimulating proliferation of glomus cells (25,26). However, administration of an endothelin receptor antagonist did not block ventilatory responses to hypoxia (27).…”

Section: Discussionmentioning

confidence: 99%

Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

Kline

Peng

Manalo

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

238

216

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To investigate whether the transcriptional activator hypoxiainducible factor 1 (HIF-1) is required for ventilatory responses to hypoxia, we analyzed mice that were either wild type or heterozygous for a loss-of-function (knockout) allele at the Hif1a locus, which encodes the O 2-regulated HIF-1␣ subunit. Although the ventilatory response to acute hypoxia was not impaired in Hif1a ϩ/Ϫ mice, the response was primarily mediated via vagal afferents, whereas in wild-type mice, carotid body chemoreceptors played a predominant role. When carotid bodies isolated from wild-type mice were exposed to either cyanide or hypoxia, a marked increase in sinus nerve activity was recorded, whereas carotid bodies from Hif1a ϩ/Ϫ mice responded to cyanide but not to hypoxia. Histologic analysis revealed no abnormalities of carotid body morphology in Hif1a ϩ/Ϫ mice. Wild-type mice exposed to hypoxia for 3 days manifested an augmented ventilatory response to a subsequent acute hypoxic challenge. In contrast, prior chronic hypoxia resulted in a diminished ventilatory response to acute hypoxia in Hif1a ϩ/Ϫ mice. Thus partial HIF-1␣ deficiency has a dramatic effect on carotid body neural activity and ventilatory adaptation to chronic hypoxia.O xygen homeostasis is mediated by the combined physiologic functioning of the circulatory and respiratory systems. Recent studies have demonstrated that the transcriptional activator hypoxia-inducible factor 1 (HIF-1) is required for both the establishment of the circulatory system during embryonic development and physiologic responses in postnatal life. Analysis of Hif1a Ϫ/Ϫ knockout mice, which are homozygous for a lossof-function mutation in the Hif1a gene encoding the O 2 -regulated HIF-1␣ subunit, revealed that complete HIF-1␣ deficiency results in embryonic lethality at midgestation with major malformations of the heart and vasculature (1-3). Hif1a ϩ/Ϫ heterozygous mice, which are partially HIF-1␣ deficient, develop normally and are indistinguishable from their wild-type littermates under normoxic conditions. However, adult Hif1a ϩ/Ϫ mice manifest impaired physiological responses to chronic hypoxia including significantly reduced rates of erythropoiesis and pulmonary vascular remodeling (4). Thus HIF-1␣ plays essential roles in cardiac, erythroid, and vascular development and physiology, i.e., all three major components of the circulatory system.An essential adaptation to both acute and chronic hypoxia is an increase in ventilation that depends on the activity of peripheral chemoreceptors, particularly those within the carotid body, which detect changes in arterial blood O 2 concentration and relay sensory information to the brainstem neurons that regulate breathing (reviewed in ref. 5). Altered ventilatory responses to hypoxia may play a critical role in asthma, diabetes, Parkinson's disease, sleep-related breathing disorders, and sudden infant death syndrome (6-8). We hypothesized that HIF-1␣ is required for carotid body function and ventilatory adaptation to chronic hypoxia. To test this hyp...

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Section: Discussionmentioning

confidence: 99%

Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

Kline

Peng

Manalo

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

238

216

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“…ET-1 is expressed in the CB, 65 induces CB chemosensory excitation, 66 and potentiates the chemosensory response to acute hypoxia. 67 ET-1 immunostaining in the CB vasculature and glomus cells is increased in cats exposed to CIH, whereas ET-1 plasma levels are unchanged. 68 A nonselective ET receptor antagonist, bosentan, reduces the elevated normoxic and hypoxic CB discharge induced by CIH.…”

Section: Mechanisms Of Enhanced Arterial Chemoreflex In Hypertensionmentioning

confidence: 85%

“…68 A nonselective ET receptor antagonist, bosentan, reduces the elevated normoxic and hypoxic CB discharge induced by CIH. 67 Upregulation of both ET-1 expression and enhanced superoxide anion signaling in the CB in response to CIH appears to be related to activation of hypoxia-inducible factor-1 63,69 and/or activator protein-1. 63 These transcription factors, induced by hypoxic challenges to the CB by either periodic bouts of hypoxemia during apneas or chronically reduced blood flow, may be the common denominator for altered CB function in hypertensive and CHF states.…”

Section: Mechanisms Of Enhanced Arterial Chemoreflex In Hypertensionmentioning

confidence: 99%

“…ET-1 itself has little effect on chemoreceptor activity under normoxic conditions in the superfused CB preparation, which is devoid of vascular effects. 67 Nevertheless, ET-1 can enhance CB responses to hypoxia in superfused CB preparations, possibly by enhancing voltage-gated (L-type) calcium current in CB glomus cells in response to hypoxia via a cAMP/inositol triphosphate pathway. 67 However, because CB chemoreceptor activity is elevated under normoxic conditions in CIH animals, the vascular effects of the peptide are likely to play a major role in this tonic activation of afferent input.…”

Section: Vascular Effects On Cb Function In Hypertensionmentioning

confidence: 99%

“…67 Nevertheless, ET-1 can enhance CB responses to hypoxia in superfused CB preparations, possibly by enhancing voltage-gated (L-type) calcium current in CB glomus cells in response to hypoxia via a cAMP/inositol triphosphate pathway. 67 However, because CB chemoreceptor activity is elevated under normoxic conditions in CIH animals, the vascular effects of the peptide are likely to play a major role in this tonic activation of afferent input. The sympathetic innervation of the CB and/or circulating catecholamines could conceivably play a role in enhanced CB excitability in certain hypertensive states by way of ␣ 1 adrenergic vasoconstriction with reduction of CB blood flow.…”

Section: Vascular Effects On Cb Function In Hypertensionmentioning

confidence: 99%

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Arterial Chemoreceptors and Sympathetic Nerve Activity

2007

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C hronic elevation in sympathetic nerve activity (SNA) is associated with the development and maintenance of certain types of hypertension 1 and contributes to the progression of chronic heart failure (CHF). 2 The mechanisms involved in sympathetic dysfunction in these disorders appear to be complex and multifactorial. A unified hypothesis is likely to encompass alterations in multiple autonomic reflex pathways, central integratory sites, and chemical mediators that control sympathetic outflow. For example, tonic restraint of sympathetic outflow by arterial and cardiopulmonary baroreflexes is depressed in CHF 2 and depressed or reset in hypertension. 3 Moreover, maladaptive changes also occur in the central nervous system at integrative sites for autonomic control in both disease processes. 4,5 It is also clear that sympathoexcitatory cardiac, 6 somatic, 7 and central/peripheral chemoreceptor reflexes 8 are enhanced in CHF and hypertension.Arterial chemoreceptors serve an important regulatory role in the control of alveolar ventilation, but they also exert a powerful influence on cardiovascular function. 9 Activation of arterial chemoreceptors by hypoxemia increases sympathetic outflow to systemic vascular beds to compensate for the direct vasodilating effects of hypoxia on these vessels and to redistribute blood flow to essential organs. In this review, we highlight relevant information that implicates the arterial chemoreflex as a contributory mechanism for the sympathetic hyperactivity in CHF and hypertension and illustrate proposed mechanisms for this altered function. The Sympathetic Response to Arterial Chemoreceptor ActivationArterial chemoreceptors located in the aortic and carotid bodies (CBs) respond to hypoxemia and hypercapnia. Because central chemoreceptors also respond to hypercapnia, hypoxia is typically used as a specific stimulus to arterial chemoreceptors. In some mammals, such as rats and rabbits, reflex responses to hypoxemia arise solely from the CB, whereas in other species, the aortic chemoreceptor contribution can be significant. However, it is not possible to experimentally separate the relative contribution of the aortic and CBs to reflex responses in conscious animals or humans. For these reasons, discussions on the arterial chemoreflex generally relate functionality to that of the CB, which has been more extensively studied. Glomus cells in the CB depolarize in response to hypoxia and release multiple putative neurotransmitters (including acetylcholine, serotonin, ATP, and substance P) that activate impulses in afferent fibers traveling to the medulla via the carotid sinus nerve. 10 Arterial chemoreceptor stimulation in freely breathing humans and conscious animals increases sympathetic vasoconstrictor outflow to muscle, splanchnic, and renal beds to elevate arterial pressure, and, in humans, increases cardiac sympathetic activity to increase heart rate and contractility. 9 There is preferential activation of sympathetic fibers going to the adrenal gland to increase norepinephrine but...

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Peripheral Chemoreceptors: Function and Plasticity of the Carotid Body

Kumar

Prabhakar

2012

Comprehensive Physiology

465

572

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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.

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Cellular mechanisms involved in rabbit carotid body excitation elicited by endothelin peptides

Cited by 46 publications

References 25 publications

Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

Arterial Chemoreceptors and Sympathetic Nerve Activity

Peripheral Chemoreceptors: Function and Plasticity of the Carotid Body

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