Abstract
A striking feature of the carotid body (CB) is its remarkable degree of plasticity in a variety of neurotransmitter/modulator systems in response to environmental stimuli, particularly following hypoxic exposure of animals and during ascent to high altitude. Current evidence suggests that acetylcholine and adenosine triphosphate are two major excitatory neurotransmitter candidates in the hypoxic CB, and they may also be involved as co-transmitters in hypoxic signaling. Conversely, dopamine, histamine and nitric oxide have recently been considered inhibitory transmitters/modulators of hypoxic chemosensitivity. It has also been revealed that interactions between excitatory and inhibitory messenger molecules occur during hypoxia. On the other hand, alterations in purinergic neurotransmitter mechanisms have been implicated in ventilatory acclimatization to hypoxia. Chronic hypoxia also induces profound changes in other neurochemical systems within the CB such as the catecholaminergic, peptidergic and nitrergic, which in turn may contribute to increased ventilatory and chemoreceptor responsiveness to hypoxia at high altitude. Taken together, current data suggest that complex interactions among transmitters markedly influence hypoxia-induced transmitter release from the CB. In addition, the expression of a wide variety of growth factors, proinflammatory cytokines and their receptors have been identified in CB parenchymal cells in response to hypoxia and their upregulated expression could mediate the local inflammation and functional alteration of the CB under hypoxic conditions.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Atanasova DY, Lazarov NE (2014) Expression of neurotrophic factors and their receptors in the carotid body of spontaneously hypertensive rats. Respir Physiol Neurobiol 202:6–15
Atanasova DY, Dandov AD, Dimitrov ND, Lazarov NE (2020) Histochemical and immunohistochemical localization nitrergic structures in the carotid body of spontaneously hypertensive rats. Acta Histochem 122:151500
Atanasova DY, Dandov AD, Lazarov NE (2023) Neurochemical plasticity of the carotid body in hypertension. Anat Rec 306:2366–2377
Bavis RW, Olson EB Jr, Vidruk EH, Bisgard GE, Mitchell GS (2003) Level and duration of developmental hyperoxia influence impairment of hypoxic phrenic responses in rats. J Appl Physiol 95:1550–1559
Bavis RW, Young KM, Barry KJ, Boller MR, Kim E, Klein PM, Ovrutsky AR, Rampersad DA (2010) Chronic hyperoxia alters the early and late phases of the hypoxic ventilatory response in neonatal rats. J Appl Physiol 109:796–803
Bavis RW, Dirstine T, Lachance AD, Jareno A, Reynoso Williams M (2023) Recovery of the biphasic hypoxic ventilatory response in neonatal rats after chronic hyperoxia. Respir Physiol Neurobiol 307:103973
Bisgard GE (2000) Carotid body mechanisms in acclimatization to hypoxia. Respir Physiol 121:237–246
Burlon DC, Jordan HL, Wyatt CN (2009) Presynaptic regulation of isolated neonatal rat carotid body type I cells by histamine. Resp Physiol Neurobiol 168:218–223
Buttigieg J, Nurse CA (2004) Detection of hypoxia-evoked ATP release from chemoreceptor cells of the rat carotid body. Biochem Biophys Res Commun 322:82–87
Chavez-Valdez R, Mason A, Nunes AR, Northington FJ, Tankersley C, Ahlawat R, Johnson SM, Gauda EB (2012) Effect of hyperoxic exposure during early development on neurotrophin expression in the carotid body and nucleus tractus solitarii. J Appl Physiol 112:1762–1772
Chen J, He L, Dinger B, Stensaas L, Fidone S (2002) Role of endothelin and endothelin A-type receptor in adaptation of the carotid body to chronic hypoxia. Am J Physiol Lung Cell Mol Physiol 282:L1314–L1323
Conde SV, Monteiro EC (2004) Hypoxia induces adenosine release from the rat carotid body. J Neurochem 89:1148–1156
Conde SV, Ribeiro MJ, Obeso A, Rigual R, Monteiro EC, González C (2012) Chronic caffeine intake in adult rat inhibits carotid body sensitization produced by chronic sustained hypoxia but maintains intact chemoreflex output. Mol Pharmacol 82:1056–1065
Czyzyk-Krzeska MF, Bayliss DA, Lawson EE, Millhorn DE (1992) Regulation of tyrosine hydroxylase gene expression in the rat carotid body by hypoxia. J Neurochem 58:1538–1546
De Caro R, Macchi V, Sfriso MM, Porzionato A (2013) Structural and neurochemical changes in the maturation of the carotid body. Resp Physiol Neurobiol 185:9–19
Del Rio R, Moya EA, Iturriaga R (2011a) Differential expression of pro-inflammatory cytokines, endothelin-1 and nitric oxide synthases in the rat carotid body exposed to intermittent hypoxia. Brain Res 1395:74–85
Del Rio R, Muñoz C, Arias P, Court FA, Moya EA, Iturriaga R (2011b) Chronic intermittent hypoxia-induced vascular enlargement and VEGF upregulation in the rat carotid body is not prevented by antioxidant treatment. Am J Physiol Lung Cell Mol Physiol 301:L702–L711
Del Rio R, Moya EA, Iturriaga R (2012) Contribution of inflammation on carotid body chemosensory potentiation induced by intermittent hypoxia. Adv Exp Med Biol 758:199–205
Di Giulio C, Di Muzio M, Sabatino G, Spoletini L, Amicarelli F, Di Ilio C, Modesti A (1998) Effect of chronic hyperoxia on young and old rat carotid body ultrastructure. Exp Gerontol 33:319–329
Di Giulio C, Zara S, Mazzatenta A, Verratti V, Porzionato A, Cataldi A, Pokorski M (2023) Aging and the carotid body: a scoping review. Respir Physiol Neurobiol 313:104063
Dmitrieff EF, Wilson JT, Dunmire KB, Bavis RW (2011) Chronic hyperoxia alters the expression of neurotrophic factors in the carotid body of neonatal rats. Respir Physiol Neurobiol 175:220–227
Donnelly DF (1996) Chemoreceptor nerve excitation may be not proportional to catecholamine secretion. J Appl Physiol 81:2330–2337
Erickson JT, Mayer C, Jawa A, Ling L, Olson EB Jr, Vidruk EH, Mitchell GS, Katz DM (1998) Chemoafferent degeneration and carotid body hypoplasia following chronic hyperoxia in newborn rats. J Physiol 509:519–552
Fitzgerald RS, Shirahata M, Ide T (1997) Further cholinergic aspects of carotid body chemotransduction of hypoxia in cats. J Appl Physiol 82:819–827
Fitzgerald RS, Eyzaguirre C, Zapata P (2009) Fifty years of progress in carotid body physiology. In: González C, Nurse CA, Peers C (eds) Arterial chemoreceptors, vol 648. Springer, Dordrecht, pp 19–28
González C, Almaraz L, Obeso A, Rigual R (1994) Carotid body chemoreceptors: from natural stimuli to sensory discharges. Physiol Rev 74:829–898
Hanson G, Jones L, Fidone S (1986) Physiological chemoreceptor stimulation decreases enkephalin and substance P in the carotid body. Peptides 7:767–769
Hertzberg T, Fan G, Finley JCW, Erickson JT, Katz DM (1994) BDNF supports mammalian chemoafferent neurons in vitro and following peripheral target removal in vivo. Dev Biol 166:801–811
Iturriaga R (2018) Translating carotid body function into clinical medicine. J Physiol 596:3067–3077
Iturriaga R, Alcayaga J (2004) Neurotransmission in the carotid body: transmitters and modulators between glomus cells and petrosal ganglion nerve terminals. Brain Res Rev 47:46–53
Iturriaga R, Alcayaga J, Zapata P (1996) Dissociation of hypoxia-induced chemosensory responses and catecholamine efflux in cat carotid body superfused in vitro. J Physiol 497(Pt 2):551–564
Iturriaga R, Villanova S, Mosqueivar M (2000) Dual effects of nitric oxide on cat carotid body chemoreception. J Appl Physiol 89:1005–1012
Janssen PL, O’Halloran KD, Pizarro J, Dwinell MR, Bisgard GE (1998) Carotid body dopaminergic mechanisms are functional after acclimatization to hypoxia in goats. Resp Physiol 111:25–32
Joseph V, Soliz J, Soria R, Pequignot J, Favier R, Spielvogel H, Pequignot JM (2002) Dopaminergic metabolism in carotid bodies and high-altitude acclimatization in female rats. Am J Physiol Regul Integr Comp Physiol 282:R765–R773
Kåhlin J, Mkrtchian S, Ebberyd A, Hammarstedt-Nordenvall L, Nordlander B, Yoshitake T, Kehr J, Prabhakar P, Poellinger L, Fagerlund MJ, Eriksson LI (2014) The human carotid body releases acetylcholine, ATP and cytokines during hypoxia. Exp Physiol 99:1089–1098
Kato K, Yamaguchi-Yamada M, Yamamoto Y (2010) Short-term hypoxia increases tyrosine hydroxylase immunoreactivity in rat carotid body. J Histochem Cytochem 58:839–846
Kim D-K, Oh EK, Summers BA, Prabhakar NR, Kumar GK (2001) Release of substance P by low oxygen in the rabbit carotid body: evidence for the involvement of calcium channels. Brain Res 892:359–369
Kim D-K, Prabhakar NR, Kumar GK (2004) Acetylcholine release from the carotid body by hypoxia: evidence for the involvement of autoinhibitory receptors. J Appl Physiol 96:376–383
Koerner P, Hesslinger C, Schaefermeyer A, Prinz C, Gratzl M (2004) Evidence for histamine as a transmitter in rat carotid body sensor cells. J Neurochem 91:493–500
Kumar P, Prabhakar NR (2012) Peripheral chemoreceptors: function and plasticity of the carotid body. Compr Physiol 2:141–219
Kusakabe T, Matsuda H, Harada H, Hayashida Y, Gono Y, Kawakami T, Takenaka T (1998a) Changes in the distribution of nitric oxide synthase immunoreactive nerve fibers in the chronically hypoxic rat carotid body. Brain Res 795:292–296
Kusakabe T, Hayashida Y, Matsuda H, Gono Y, Powell FL, Ellisman MH, Kawakami T, Takenaka T (1998b) Hypoxic adaptation of the peptidergic innervation in the rat carotid body. Brain Res 806:165–174
Kusakabe T, Matsuda H, Hirakawa H, Hayashida Y, Ichikawa T, Kawakami T, Takenaka T (2000) Calbindin D-28k immunoreactive nerve fibers in the carotid body of normoxic and chronically hypoxic rats. Histol Histopathol 15:1019–1025
Lahiri S, Roy A, Baby SM, Hoshi T, Semenza GL, Prabhakar NR (2006) Oxygen sensing in the body. Prog Biophys Mol Biol 91:249–286
Lam SY, Leung PS (2002) A locally generated angiotensin system in rat carotid body. Regul Pept 107:97–103
Lam SY, Liu Y, Ng KM, Lau CF, Liong EC, Tipoe GL, Fung ML (2012) Chronic intermittent hypoxia induces local inflammation of the rat carotid body via functional upregulation of proinflammatory cytokine pathways. Histochem Cell Biol 137:303–317
Lazarov N, Atanasova D (2012) The human carotid body in health and disease. Acta Morphol Anthropol 19:135–140
Lazarov N, Atanasova D (2022) The human carotid body and its role in ventilatory acclimatization to hypoxia. Acta Morphol Anthropol 29:63–68
Lazarov N, Atanasova D, Reindl S, Gratzl M (2011) Dopamine and histamine: two major transmitters in hypoxic chemosensitivity in the human carotid body. Clujul Med 2(Suppl 2):84–88
Leonard EM, Salman S, Nurse CA (2018) Sensory processing and integration at the carotid body tripartite synapse: neurotransmitter functions and effects of chronic hypoxia. Front Physiol 9:225
Leung PS, Fung ML, Tam MS (2003) Renin-angiotensin system in the carotid body. Int J Biochem Cell Biol 35:847–854
Liu X, He L, Stensaas L, Dinger B, Fidone S (2009) Adaptation to chronic hypoxia involves immune cell invasion and increased expression of inflammatory cytokines in rat carotid body. Am J Physiol Lung Cell Mol Physiol 296:L158–L166
Liu X, He L, Dinger B, Stensaas L, Fidone S (2013) Sustained exposure to cytokines and hypoxia enhances excitability of oxygen-sensitive type I cells in rat carotid body: correlation with the expression of HIF-1α protein and adrenomedullin. High Alt Med Biol 14:53–60
López-Barneo J, Ortega-Sáenz P, Pardal R, Pascual A, Piruat JI (2008) Carotid body oxygen sensing. Eur Respir J 32:1386–1398
Mosqueira M, Iturriaga R (2019) Chronic hypoxia changes gene expression profile of primary rat carotid body cells: consequences on the expression of NOS isoforms and ET-1 receptors. Physiol Genomics 51:109–124
Nurse CA (2005) Neurotransmission and neuromodulation in the chemosensory carotid body. Auton Neurosci 120:1–9
Nurse CA, Zhang M (1999) Acetylcholine contributes to hypoxic chemotransmission in co-cultures of rat type 1 cells and petrosal neurons. Respir Physiol 115:189–199
Olson EB Jr, Vidruk EH, McCrimmon DR, Dempsey JA (1983) Monoamine neurotransmitter metabolism during acclimatization to hypoxia in rats. Resp Physiol 54:79–96
Pedersen MEF, Dorrington KL, Robbins PA (1999) Effects of dopamine and domperidone on ventilatory sensitivity to hypoxia after 8 h of isocapnic hypoxia. J Appl Physiol 86:222–229
Pequignot JM, Cottet-Emard JM, Dalmaz Y, Peyrin L (1987) Dopamine and norepinephrine dynamics in rat carotid body during long-term hypoxia. J Auton Nerv Syst 21:9–14
Porzionato A, Macchi V, Parenti A, De Caro R (2008) Trophic factors in the carotid body. Int Rev Cell Mol Biol 269:1–58
Porzionato A, Macchi V, De Caro R, Di Giulio C (2013) Inflammatory and immunomodulatory mechanisms in the carotid body. Respir Physiol Neurobiol 187:31–40
Powell FL, Milsom WK, Mitchell GS (1998) Time domains of the hypoxic ventilatory response. Respir Physiol 112:123–134
Prabhakar NR (2001) Oxygen sensing during intermittent hypoxia: cellular and molecular mechanisms. J Appl Physiol 90:1986–1994
Prabhakar NR, Kumar GK, Chang CH, Agani FH, Haxhiu MA (1993) Nitric oxide in the sensory function of the carotid body. Brain Res 625:16–22
Prabhakar NR, Peng YJ, Kumar GK, Nanduri J (2015) Peripheral chemoreception and arterial pressure responses to intermittent hypoxia. Compr Physiol 5:561–577
Rey S, Corthorn J, Chacon C, Iturriaga R (2007) Expression and immunolocalization of endothelin peptides and its receptors, ETA and ETB, in the carotid body exposed to chronic intermittent hypoxia. J Histochem Cytochem 55:167–174
Rey S, Del Rio R, Iturriaga R (2008) Contribution of endothelin-1 and endothelin A and B receptors to the enhanced carotid body chemosensory responses induced by chronic intermittent hypoxia. Adv Exp Med Biol 605:228–232
Ryan ML, Hedrick MS, Pizarro J, Bisgard GE (1993) Carotid body noradrenergic sensitivity in ventilatory acclimatization to hypoxia. Resp Physiol 92:77–90
Saito H, Yokoyama T, Nakamuta N, Yamamoto Y (2023) Immunohistochemical distribution of Ca2+/calmodulin-dependent protein kinase II subunits in the rat carotid body. Acta Histochem 125:152043
Salman S, Vollmer C, McClelland GB, Nurse CA (2017) Characterization of ectonucleotidase expression in the rat carotid body: regulation by chronic hypoxia. Am J Physiol Cell Physiol 313:C274–C284
Schamel A, Chaouti A, Douma M, Sabour B (2016) Morphological and neurochemical plasticity of the carotid body after long-term hypoxia: vascular and cellular involvement, morphometric study in Meriones shawi rats. Der Pharma Chem 8:82–98
Stocco E, Barbon S, Tortorella C, Macchi V, De Caro R, Porzionato A (2020) Growth factors in the carotid body—an update. Int J Mol Sci 21:E7267
Stocco E, Sfriso MM, Borile G, Contran M, Barbon S, Romanato F, Macchi V, Guidolin D, De Caro R, Porzionato A (2021) Experimental evidence of A2A–D2 receptor–receptor interactions in the rat and human carotid body. Front Physiol 12:645723
Stocco E, Sfriso MM, Barbon S, Emmi A, Guidolin D, Di Giulio C, Macchi V, De Caro R, Porzionato A (2022) D2–H3 receptor-receptor interactions in the carotid body: a descriptive multispecies study. Ital J Anat Embryol 126(Suppl 1):52
Tatsumi K, Pickett CK, Weil JV (1995) Possible role of dopamine in ventilatory acclimatization to high altitude. Respir Physiol 99:63–73
Verna A, Schamel A, Pequignot JM (1993a) Noradrenergic glomus cells in the carotid body: an autoradiographic and immunocytochemical study in the rabbit and rat. Adv Exp Med Biol 337:93–100
Verna A, Schamel A, Pequignot JM (1993b) Long-term hypoxia increases the number of norepinephrine-containing glomus cells in the rat carotid body: a correlative immunocytochemical and biochemical study. J Auton Nerv Syst 44:171–177
Vizek M, Pickett CK, Weil JV (1987) Increased carotid body hypoxic sensitivity during acclimatization to hypobaric hypoxia. J Appl Physiol 63:2403–2410
Wang Z-Y, Bisgard GE (2002) Chronic hypoxia-induced morphological and neurochemical changes in the carotid body. Microsc Res Tech 59:168–177
Wang Z-Y, Bisgard GE (2005) Postnatal growth of carotid body. Respir Physiol Neurobiol 149:181–190
Wang ZZ, Dinger B, Fidone SJ, Stensaas LJ (1998) Changes in tyrosine hydroxylase and substance P immunoreactivity in the cat carotid body following chronic hypoxia and denervation. Neuroscience 83:1273–1281
Xu J, Xu F, Tse FW, Tse A (2005) ATP inhibits the hypoxia response in type I cells of rat carotid bodies. J Neurochem 92:1419–1430
Zhang M, Zhong H, Vollmer C, Nurse CA (2000) Co-release of ATP and ACh mediates hypoxic signalling at rat carotid body chemoreceptors. J Physiol 525:143–158
Zhao C, Li C, Zhao B, Liu Y (2022) Expression of group II and III mGluRs in the carotid body and its role in the carotid chemoreceptor response to acute hypoxia. Front Physiol 13:1008073
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
Copyright information
© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Lazarov, N.E., Atanasova, D.Y. (2023). Neurochemical Plasticity of the Carotid Body. In: Morphofunctional and Neurochemical Aspects of the Mammalian Carotid Body. Advances in Anatomy, Embryology and Cell Biology, vol 237. Springer, Cham. https://doi.org/10.1007/978-3-031-44757-0_7
Download citation
DOI: https://doi.org/10.1007/978-3-031-44757-0_7
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-44756-3
Online ISBN: 978-3-031-44757-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)