Neonatal intermittent hypoxia impairs neuronal nicotinic receptor expression and function in adrenal chromaffin cells.
We recently reported that adrenomedullary chromaffin cells (AMC) from neonatal rats treated with intermittent hypoxia (IH) exhibit enhanced catecholamine secretion by hypoxia (Souvannakitti D, Kumar GK, Fox A, Prabhakar NR. J Neurophysiol 101: 2837-2846, 2009). In the present study, we examined whether neonatal IH also facilitate AMC responses to nicotine, a potent stimulus to chromaffin cells. Experiments were performed on rats exposed to either IH (15-s hypoxia-5-min normoxia; 8 h/day) or to room air (normoxia; controls) from ages postnatal day 0 (P0) to P5. Quantitative RT-PCR analysis revealed expression of mRNAs alpha(3-), alpha(5-), alpha(7-), and beta(2-) and beta(4-)nicotinic acetylcholine receptor (nAChR) subunits in adrenal medullae from control P5 rats. Nicotine-elevated intracellular Ca(2+) concentration ([Ca(2+)](i)) in AMC and nAChR antagonists prevented this response, suggesting that nAChRs are functional in neonatal AMC. In IH-treated rats, nAChR mRNAs were downregulated in AMC, which resulted in a markedly attenuated nicotine-evoked elevation in [Ca(2+)](i) and subsequent catecholamine secretion. Systemic administration of antioxidant prevented IH-evoked downregulation of nAChR expression and function. P35 rats treated with neonatal IH exhibited reduced nAChR mRNA expression in adrenal medullae, attenuated AMC responses to nicotine, and impaired neurogenic catecholamine secretion. Thus the response to neonatal IH lasts for at least 30 days. These observations demonstrate that neonatal IH downregulates nAChR expression and function in AMC via reactive oxygen species signaling, and the effects of neonatal IH persist at least into juvenile life, leading to impaired neurogenic catecholamine secretion from AMC.
Souvannakitti
Dangjai
D
Department of Medicine, The Center for Systems Biology of O(2) Sensing, University of Chicago, Chicago, Illinois, USA.
Kuri
Barbara
B
Yuan
Guoxiang
G
Pawar
Anita
A
Kumar
Ganesh K
GK
Smith
Corey
C
Fox
Aaron P
AP
Prabhakar
Nanduri R
NR
D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000378:metabolism* / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology; D010100:Oxygen / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
D000975:Antioxidants; D011978:Receptors, Nicotinic; D009538:Nicotine; D010100:Oxygen; D002118:Calcium