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This Article Full Text Full Text (PDF) All Versions of this Article: 296/3/R735    most recent 90490.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pawar, A. Articles by Prabhakar, N. R. Search for Related Content PubMed PubMed Citation Articles by Pawar, A. Articles by Prabhakar, N. R.

EXERCISE AND RESPIRATORY PHYSIOLOGY

Reactive oxygen species-dependent endothelin signaling is required for augmented hypoxic sensory response of the neonatal carotid body by intermittent hypoxia

¹Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio; and ²Center for Systems Biology of O₂ Sensing, Department of Medicine, University of Chicago, Chicago, Illinios

Submitted 12 June 2008 ; accepted in final form 17 December 2008

We previously reported that intermittent hypoxia (IH) augments hypoxic sensory response (HSR) and increases the number of glomus cells in neonatal carotid bodies. In the present study, we tested the hypothesis that recruitment of endothelin-1 (ET-1) signaling by reactive oxygen species (ROS) plays a critical role in IH-evoked changes in neonatal carotid bodies. Experiments were performed on neonatal rats exposed either to 10 days of IH (P0–P10; 8 h/day) or to normoxia. IH augmented HSR of the carotid bodies ex vivo and resulted in hyperplasia of glomus cells. The effects of IH were associated with enhanced basal release of ET-1 under normoxia, sensitization of carotid body response to exogenous ET-1, and upregulation of ET_A but not an ET_B receptor mRNA without altering the ET-1 content. An ET_A but not ET_B receptor antagonist prevented augmented HSR by IH. ROS levels were elevated in carotid bodies from IH-treated rat pups as evidenced by increased levels of malondialdehyde. Systemic administration of manganese (III) tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP; 5 mg/kg ip), a scavenger of O₂^–, prevented IH-induced elevation of ROS, basal release of ET-1, upregulation of ET_A mRNA, and augmented HSR. In striking contrast, MnTMPyP treatment had no significant effect on IH-induced hyperplasia of glomus cells. These results demonstrate that IH-evoked increase in HSR involve a ROS-mediated increase in basal ET-1 release and upregulation of ET_A receptor mRNA.

recurrent apneas; premature infants; chemoreflex; arterial chemoreceptors; chronic intermittent hypoxia