Role of Alpha‐1 Adrenergic Receptors (α1AR) and Norepinephrine Transporter in Parvocellular Neurons of the Hypothalamic Paraventricular Nucleus (PVN) After Chronic Intermittent Hypoxia Exposure

Abstract

The Paraventricular nucleus (PVN) of the hypothalamus is critical for autonomic homeostasis and cardiorespiratory reflex responses to a variety of stimuli and stressors. This is accomplished, in part, via dense catecholaminergic and norepinephrine (NE) projections from nucleus tractus solitarii (nTS) and ventrolateral medulla (VLM). NE signaling is balanced by the uptake of NE by transporters (NET's) and the activation of one or more adrenergic receptor (AR). Within the PVN, stimulation of aAR's increases the frequency of spontaneous excitatory postsynaptic currents (sEPSCs), decreases the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and depolarizes resting membrane potential (RMP) which elevates blood pressure (BP) and sympathetic outflow. Chronic intermittent hypoxia (CIH) is a model for obstructive sleep apnea (OSA) that elevates respiration, BP, sympathoexcitation and circulating NE levels. CIH activates not only PVN neurons but also the catecholaminergic neurons in the VLM and nTS. However, the contribution of aAR and NET in PVN neurons after CIH exposure remains elusive. In the present work, we determined the electrophysiological properties of PVN parvocellular neurons in response to a1AR activation and NET inhibition after normoxia (Norm) and CIH. Male Sprague‐Dawley rats (110–150g) were exposed to either 10 days normoxia (Norm, FiO2 = 21%) or CIH (alternating FiO2 = 21% and 6%, 8 hr/day). PVN slices (~280 μm) were generated and cell capacitance (Cm), initial input resistance (Rin), and sEPSCs were examined by whole cell patch clamp. sEPSCs were recorded under aCSF baseline or in the presence of one or more of the following: NE (10–100 μM, general AR agonist), phenylephrine (Phe, a1AR agonist, 100 μM), prazosin (a1AR antagonist, 10 μM), or NET inhibitor (desipramine, 100 μM). The Cm of Norm neurons was smaller than CIH, but CIH decreased Rin. Between Norm and CIH, baseline sEPSC frequency and amplitude were similar. Phe and NE significantly increased sEPSC frequency in Norm but not in CIH. Block of the a1AR with prazosin alone did not alter sEPSC frequency or amplitude in Norm (n=10) or CIH (n=6). NE in the presence of prazosin (n=7) prevented the increase in sEPSC frequency in Norm. In Norm (n=5) and CIH (n=6), NET block with desipramine increased sEPSC frequency but did not alter amplitude. However, the magnitude of increase in sEPSC frequency was comparable. These results demonstrate that a1AR activation participate of neuronal responses in Norm, but are minimized in CIH. NET function may be elevated after CIH exposure. The latter may contribute to reduced neuronal responses evoked by Phe after CIH, as well as compensatory mechanism caused by over sympathetic activity.Support or Funding InformationHL 098602 and HL128454This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.