Chronic intermittent hypoxia impairs heart rate responses to AMPA and NMDA and induces loss of glutamate receptor neurons in nucleus ambiguous of F344 rats

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2009-02, Vol.296 (2), p.R299-R308
• Main Authors: Yan, Binbin, Li, Lihua, Harden, Scott W, Gozal, David, Lin, Ying, Wead, William B, Wurster, Robert D, Cheng, Zixi Jack
• Format: Article
• Language: English
• Subjects: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - administration & dosage; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - pharmacology; Animals; Baroreflex - drug effects; Blood Pressure - drug effects; Brain Stem - drug effects; Brain Stem - metabolism; Brain Stem - physiopathology; Disease Models, Animal; Down-Regulation; Excitatory Amino Acid Agonists - administration & dosage; Excitatory Amino Acid Agonists - pharmacology; Heart - innervation; Heart Rate - drug effects; Hypoxia - metabolism; Hypoxia - physiopathology; Microinjections; Motor Neurons - drug effects; Motor Neurons - metabolism; N-Methylaspartate - administration & dosage; N-Methylaspartate - pharmacology; Nerve Degeneration - physiopathology; Rats; Rats, Inbred F344; Receptors, AMPA - agonists; Receptors, Glutamate - drug effects; Receptors, Glutamate - metabolism; Receptors, N-Methyl-D-Aspartate - agonists
• ISSN: 0363-6119
• DOI: 10.1152/ajpregu.90412.2008

Chronic intermittent hypoxia (CIH), as occurs in sleep apnea, impairs baroreflex-mediated reductions in heart rate (HR) and enhances HR responses to electrical stimulation of vagal efferent. We tested the hypotheses that HR responses to activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the nucleus ambiguous (NA) are reduced in CIH-exposed rats and that this impairment is associated with degeneration of glutamate receptor (GluR)-immunoreactive NA neurons. Fischer 344 rats (3-4 mo) were exposed to room air (RA) or CIH for 35-50 days (n = 18/group). At the end of the exposures, AMPA (4 pmol, 20 nl) and NMDA (80 pmol, 20 nl) were microinjected into the same location of the left NA (-200 microm to +200 microm relative to caudal end of area postrema; n = 6/group), and HR and arterial blood pressure responses were measured. In addition, brain stem sections at the level of -800, -400, 0, +400, and +800 microm relative to obex were processed for AMPA and NMDA receptor immunohistochemistry. The number of NA neurons expressing AMPA receptors and NMDA receptors (NMDARs) was quantified. Compared with RA, we found that after CIH 1) HR responses to microinjection of AMPA into the left NA were reduced (RA -290 +/- 30 vs. CIH -227 +/- 15 beats/min, P < 0.05); 2) HR responses to microinjection of NMDA into the left NA were reduced (RA -302 +/- 16 vs. CIH -238 +/- 27 beats/min, P < 0.05); and 3) the number of NMDAR1, AMPA GluR1, and AMPA GluR2/3-immunoreactive cells in the NA was reduced (P < 0.05). These results suggest that degeneration of NA neurons expressing GluRs contributes to impaired baroreflex control of HR in rats exposed to CIH.