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Department of Physiology, University of Utah School of Medicine, Salt Lake City, Utah 84108
Chronic exposure in a low-PO2 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 ETA receptors, both of which are normally expressed by O2-sensitive type I cells. Immunocytochemical staining showed incremental increases in ET and ETA 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 ETA antagonist BQ-123 (5 µM) 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 ETA. Collectively, our data suggest that ET and ETA autoreceptors on O2-sensitive type I cells play a critical role in CH-induced increased chemosensitivity in the rat carotid body.
chemoreceptor; chemosensitivity; chemotransduction; hypoxic ventilatory response; ventalitory acclimatization to hypoxia
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