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

Abstract

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.

Alterations in Carotid Body Morphology and Cellular Mechanism Under the Influence of Intermittent Hypoxia

“…The chronic hypoxia induced morphological changes in mammalian CB included enlargement of CB and chief cells, hyperplasia and mitosis of type I cells along with congestion of blood capillaries, marked vasodilation and neovascularisation. It has also been established that there is an increase in the number and diameter of glomus cells on chronic exposure to simulated HA and rapid enlargement of the rat CBs on AH exposure that appeared to be simply due to vascular congestion [3,4]. On the other hand, IH with shorter hypoxic bouts as seen in OSA model, though sustained for 10 days, showed an increase in the CB's sensitivity and toxic sympathetic activation without obvious morphological alterations [12].…”

“…Various morphological changes have been reported in mammalian CB on chronic as well as on acute hypoxic exposure. CBs protect the organs from hypoxic damage by releasing neurotransmitters (NTs) and instantaneously signaling the brainstem respiratory centre via the carotid body nerve, resulting in hyperventilation that is an integral part of altitude acclimatization [2][3][4]. Currently, models of oxygen sensing are based on either a heme protein or the production of reactive oxygen species (ROS) by NAD(P)H oxidases and mitochondria [5].…”

Differences in tyrosine hydroxylase expression after short-term hypoxia, hypercapnia or hypercapnic hypoxia in rat carotid body

“…Hyperventilation induced by hypoxia and/or hypercapnia is mediated by the glomus cells, which transmit information concerning PaO 2 and PaCO 2 to primary sensory afferent terminals by the release of excitatory neurotransmitters, such as acetylcholine and ATP (Zhang 55 and Nurse, 2004;Nurse, 2005;Gourine, 2005;Fitzgerald et al, 2006). It has also been reported that dopamine, which is secreted by the glomus cells, has an inhibitory role in CB excitation (Docherty and McQueen, 1978;Lahiri et al, 1984;Wang and Bisgard, 2002;Nurse, 2005;Powell, 2007). Dopamine binds to D 2 receptors to inhibit L-type Ca 2+ channels in rat isolated glomus cells and to 60 decrease acetylcholine release from rabbit CBs (Benot and López-Barneo, 1990; Kim et al, 2004).…”

“…Moreover, in vivo experiments demonstrated that dopamine is released from glomus cells during Page 4 of 30 A c c e p t e d M a n u s c r i p t Wakai J. et al,Page 4 hypoxia (Fidone et al, 1982;Iturriaga and Alcayaga, 1998;Buerk et al, 1998;65 Wang and Bisgard, 2002;Powell, 2007), and dopamine content in the CB is increased by exposure to sustained hypoxia for 2-28 days (Hanbauer et al, 1981;Olson et al, 1983;Pequignot et al, 1987;Hui et al, 2003). In the CB, both short-term (within 24 hours) and long-term (for over a week) hypoxia enhances expression of the rate-limiting enzyme for catecholamine synthesis, tyrosine 70 hydroxylase (TH), at mRNA and protein levels (Czyzyk-Kruzeska et al, 1992;Wang et al, 1998;Wang and Bisgard, 2002;Hui et al, 2003;Kato et al, 2010).…”

“…This delay is probably related to the suppression of the enhancement of TH mRNA. TH regulates dopamine synthesis and dopamine inhibits the activation of glomus cells (Wang and Bisgard, 2002). Zhang and Nurse (2004) reported that action potential frequency 325 was higher in the glomus cells of rats exposed to hypercapnic hypoxia than in cells exposed to hypoxia or hypercapnia.…”