1. AT1a-dependent GABA(A) inhibition in the MnPO following chronic intermittent hypoxia
- Author
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Joel T. Little, J. Thomas Cunningham, George E. Farmer, and Alexandria B. Marciante
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Time Factors ,Physiology ,Blood Pressure ,Receptor, Angiotensin, Type 1 ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Sleep Apnea Syndromes ,Physiology (medical) ,Internal medicine ,Renin–angiotensin system ,medicine ,Chronic intermittent hypoxia ,Animals ,GABAergic Neurons ,Phosphorylation ,Hypoxia ,Symporters ,GABAA receptor ,business.industry ,Sympathetic nerve activity ,Sleep apnea ,Neural Inhibition ,medicine.disease ,Receptors, GABA-A ,Angiotensin II ,Preoptic Area ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Chronic Disease ,Hypertension ,business ,030217 neurology & neurosurgery ,Research Article - Abstract
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 Cl− indicator ClopHensorN showed CIH was associated with Cl− efflux 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.
- Published
- 2021