title: Role of oxidative stress-induced endothelin-converting enzyme activity in the alteration of carotid body function by chronic intermittent hypoxia.
abstract: Chronic intermittent hypoxia (CIH) leads to remodelling of the carotid body function, manifested by an augmented sensory response to hypoxia and induction of sensory long-term facilitation (LTF). It was proposed that endothelin-1 (ET-1) contributes to CIH-induced hypoxic hypersensitivity of the carotid body. The objectives of the present study were as follows: (i) to delineate the mechanisms by which CIH upregulates ET-1 expression in the carotid body; and (ii) to assess whether ET-1 also contributes to sensory LTF. Experiments were performed on adult, male rats exposed to alternating cycles of 5% O2 (15 s) and room air (5 min), nine episodes per hour and 8 h per day for 10 days. Chronic intermittent hypoxia increased ET-1 levels in glomus cells without significantly altering prepro-endothelin-1 mRNA levels. The activity of endothelin-converting enzyme increased with concomitant elevation of ET-1 levels in CIH-exposed carotid bodies, and MnTMPyP, a membrane-permeable antioxidant, prevented these effects. Hypoxia facilitated ET-1 release from CIH-treated carotid bodies, which is a prerequisite for activation of ET receptors; however, hypoxia had no effect on ET-1 release from control carotid bodies. In CIH-exposed carotid bodies, mRNAs encoding ETA receptor were upregulated, and an ETA receptor-specific antagonist abolished CIH-induced hypersensitivity of the hypoxic response, whereas it had no effect on the sensory LTF. These results suggest that ECE-dependent increased production of ET-1 coupled with hypoxia-evoked ET-1 release and the ensuing ETA receptor activation mediate the CIH-induced carotid body hypersensitivity to hypoxia, but the ETA signalling pathway is not associated with sensory LTF elicited by CIH.
authors.affiliation: N. R. Prabhakar: Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, Biological Sciences Division, MC 5068, 5841 South Maryland Avenue, Chicago, IL 60637, USA. nanduri@uchicago.edu.
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Peng
authors.forename: Jayasri
authors.initials: J
authors.lastname: Nanduri
authors.forename: Gayatri
authors.initials: G
authors.lastname: Raghuraman
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Ganesh K
authors.initials: GK
authors.lastname: Kumar
authors.forename: Nanduri R
authors.initials: NR
authors.lastname: Prabhakar
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D002344:Carotid Body / Q000503:physiopathology*; D019332:Endothelin-1 / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D004789:Enzyme Activation; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism*; D008665:Metalloporphyrins / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects; D018384:Oxidative Stress / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000235:genetics
chemical_list: D000975:Antioxidants; D019332:Endothelin-1; D008665:Metalloporphyrins; C502230:Mn(III) 5,10,15,20-tetrakis(N-methylpyridinium-2-yl)porphyrin; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes
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