TY - JOUR
T1 - AT1a-dependent GABAA inhibition in the MnPO following chronic intermittent hypoxia
AU - Farmer, George E.
AU - Little, Joel T.
AU - Marciante, Alexandria B.
AU - Cunningham, J. Thomas
N1 - Funding Information:
This study was supported by National Heart, Lung, and Blood Institute grants P01 HL088052 and R01 155977, and National Institute for Aging grant T32 AG020494.
Publisher Copyright:
Copyright © 2021 the American Physiological Society.
PY - 2021/9
Y1 - 2021/9
N2 - Chronic intermittent hypoxia (CIH) is associated with diurnal hypertension, increased sympathetic nerve activity (SNA), and increases in circulating angiotensin II (ANG II). In rats, CIH increases angiotensin type 1 (AT1a) receptor expression in the median preoptic nucleus (MnPO), and pharmacological blockade or viral knockdown of this receptor prevents CIH-dependent increases in diurnal blood pressure. The current study investigates the role of AT1a receptor in modulating the activity of MnPO neurons following 7 days of CIH. Male Sprague-Dawley rats received MnPO injections of an adeno-associated virus with an shRNA against the AT1a receptor or a scrambled control. Rats were then exposed to CIH for 8 h a day for 7 days. In vitro, loose patch recordings of spontaneous action potential activity were made from labeled MnPO neurons in response to brief focal application of ANG II or the GABAA receptor agonist muscimol. In addition, MnPO K-Cl cotransporter isoform 2 (KCC2) protein expression was assessed using Western blot. CIH impaired the duration but not the magnitude of ANG II-mediated excitation in the MnPO. Both CIH and AT1a knockdown also impaired GABAA-mediated inhibition, and CIH with AT1a knockdown produced GABAA-mediated excitation. Recordings using the ratiometric Clindicator ClopHensorN showed CIH was associated with Clefflux in MnPO neurons that was associated with decreased KCC2 phosphorylation. The combination of CIH and AT1a knockdown attenuated reduced KCC2 phosphorylation seen with CIH alone. The current study shows that CIH, through the activity of AT1a receptors, can impair GABAA-mediated inhibition in the MnPO and contribute to sustained hypertension.
AB - Chronic intermittent hypoxia (CIH) is associated with diurnal hypertension, increased sympathetic nerve activity (SNA), and increases in circulating angiotensin II (ANG II). In rats, CIH increases angiotensin type 1 (AT1a) receptor expression in the median preoptic nucleus (MnPO), and pharmacological blockade or viral knockdown of this receptor prevents CIH-dependent increases in diurnal blood pressure. The current study investigates the role of AT1a receptor in modulating the activity of MnPO neurons following 7 days of CIH. Male Sprague-Dawley rats received MnPO injections of an adeno-associated virus with an shRNA against the AT1a receptor or a scrambled control. Rats were then exposed to CIH for 8 h a day for 7 days. In vitro, loose patch recordings of spontaneous action potential activity were made from labeled MnPO neurons in response to brief focal application of ANG II or the GABAA receptor agonist muscimol. In addition, MnPO K-Cl cotransporter isoform 2 (KCC2) protein expression was assessed using Western blot. CIH impaired the duration but not the magnitude of ANG II-mediated excitation in the MnPO. Both CIH and AT1a knockdown also impaired GABAA-mediated inhibition, and CIH with AT1a knockdown produced GABAA-mediated excitation. Recordings using the ratiometric Clindicator ClopHensorN showed CIH was associated with Clefflux in MnPO neurons that was associated with decreased KCC2 phosphorylation. The combination of CIH and AT1a knockdown attenuated reduced KCC2 phosphorylation seen with CIH alone. The current study shows that CIH, through the activity of AT1a receptors, can impair GABAA-mediated inhibition in the MnPO and contribute to sustained hypertension.
KW - AV3V
KW - Angiotensin
KW - Hypertension
KW - Sleep apnea
UR - http://www.scopus.com/inward/record.url?scp=85115755090&partnerID=8YFLogxK
U2 - 10.1152/AJPREGU.00030.2021
DO - 10.1152/AJPREGU.00030.2021
M3 - Article
C2 - 34189959
AN - SCOPUS:85115755090
SN - 0363-6119
VL - 321
SP - R469-R481
JO - American Journal of Physiology - Regulatory Integrative and Comparative Physiology
JF - American Journal of Physiology - Regulatory Integrative and Comparative Physiology
IS - 3
ER -