Submitted on June 12, 2008
Revised on December 17, 2008
Accepted on December 17, 2008
REACTIVE OXYGEN SPECIES-DEPENDENT ENDOTHELIN SIGNALING IS REQUIRED FOR AUGMENTED HYPOXIC SENSORY RESPONSE OF THE NEONATAL CAROTID BODY BY INTERMITTENT HYPOXIA
Anita Pawar1, Jayasri Nanduri1, Guoxiang Yuan1, Shakil A Khan1, Ning Wang1, Ganesh K. Kumar1, and Nanduri R. Prabhakar2*
1 University of Chicago
2 Case Western Reserve University
* To whom correspondence should be addressed. E-mail: nanduri{at}uchicago.edu.
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 hypoxic sensory response (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 up-regulation of ETA but not an ETB receptor mRNA without altering the ET-1 content. An ETA but not ETB 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, up-regulation of ETA 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 involves a ROS-mediated increase in basal ET-1 release as well as up-regulation of ETA receptor mRNA.
