Role of endothelin and endothelin A-type receptor in adaptation of the carotid body to chronic hypoxia

Abstract

Chronic exposure in a low-PO(2) environment (i.e., chronic hypoxia, CH) elicits an elevated hypoxic ventilatory response and increased hypoxic chemosensitivity in arterial chemoreceptors in the carotid body. In the present study, we examine the hypothesis that changes in chemosensitivity are mediated by endothelin (ET), a 21-amino-acid peptide, and ET(A) receptors, both of which are normally expressed by O(2)-sensitive type I cells. Immunocytochemical staining showed incremental increases in ET and ET(A) expression in type I cells after 3, 7, and 14 days of CH (380 Torr). Peptide and receptor upregulation was confirmed in quantitative RT-PCR assays conducted after 14 days of CH. In vitro recordings of carotid sinus nerve activity after in vivo exposure to CH for 1-16 days demonstrated a time-dependent increase in chemoreceptor activity evoked by acute hypoxia. In normal carotid body, the specific ET(A) antagonist BQ-123 (5 microM) inhibited 11% of the nerve discharge elicited by hypoxia, and after 3 days of CH the drug diminished the hypoxia-evoked discharge by 20% (P < 0.01). This inhibitory effect progressed to 45% at day 9 of CH and to nearly 50% after 12, 14, and 16 days of CH. Furthermore, in the presence of BQ-123, the magnitude of the activity evoked by hypoxia did not differ in normal vs. CH preparations, indicating that the increased activity was the result of endogenous ET acting on an increasing number of ET(A). Collectively, our data suggest that ET and ET(A) autoreceptors on O(2)-sensitive type I cells play a critical role in CH-induced increased chemosensitivity in the rat carotid body.

Molecular genetics of paragangliomas of the skull base and head and neck region: implications for medical and surgical management

“…2 Hypobaric pressure models of altitude hypoxia in rats also demonstrate carotid body hyperplasia, with a 3-to 4-fold increase in size within 12-16 days of exposure to chronic hypoxia. 25,26 Consequently, there is an increased incidence of extra-adrenal paraganglioma (including SHN-PG) in individuals living at higher altitudes. 4,12 Oxygen deprivation sensed by the carotid body leads to neurotransmitter release, altering cardiopulmonary function, as well as an upregulation of hypoxia-inducible factors that regulate oxygen-dependent gene expression and mitochondrial oxidative phosphorylation.…”

Arterial Chemoreceptors and Sympathetic Nerve Activity

“…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.…”

Adaptation to chronic hypoxia involves immune cell invasion and increased expression of inflammatory cytokines in rat carotid body

“…These include altered gene expression and increased chemosensitivity in the initial 1-3 days of exposure to hypobaric hypoxia (3,4,9). In the rat, exposure to hypobaric hypoxia (380 Torr) for 9 -14 days approximately doubles stimulus-evoked CSN activity in response to a standardized acute hypoxic challenge.…”

“…In the rat, exposure to hypobaric hypoxia (380 Torr) for 9 -14 days approximately doubles stimulus-evoked CSN activity in response to a standardized acute hypoxic challenge. Moreover, the resting nerve activity in these preparations is substantially elevated (3). Given their exquisite sensitivity to oxygen, it has long been assumed that type I cells initiate and regulate adaptive processes via the autocrine and paracrine action of their secretory products.…”