Knockdown of tyrosine hydroxylase in the nucleus of the solitary tract (NTS) reduces elevated blood pressure during chronic intermittent hypoxia (CIH)

Abstract

We tested the hypothesis that tyrosine hydroxylase (TH) knockdown in NTS reduces cardiovascular responses to CIH, a model of the arterial hypoxemia observed during sleep apnea. Adult male Sprague‐Dawley rats were implanted with radiotelemetry transmitters and AAV constructs with a GFP reporter having either short hairpin RNA for TH (shRNA) or scrambled virus (scrambled) were injected into caudal NTS. Virus injected rats were exposed to 7 days CIH (alternating 6 min periods of 10% O2 and 4 min of 21% O2 from 8am to 4pm; from 4pm to 8am rats were exposed to 21% O2). CIH increased MAP and HR during the day in both the scrambled (n= 14) and shRNA (n=13) groups (all p < 0.001). During the night MAP and HR remained elevated in the scrambled rats (both p<0.001) but not in the shRNA group. The number of TH‐immunoreactive neurons per section was reduced by 20% in sections with GFP fluorescence; shRNA 28±1 vs. scrambled 35±1 (p=.005) without altering the number of dopamine â‐hydroxylase (DBH) – immunoreactive neurons; shRNA 45±3 cells/section vs. scrambled 45±3 cells/section. Western blot analysis showed reductions in TH protein levels of 30% and 10% in caudal and sub‐postremal NTS respectively. Exposure to CIH increased MAP beyond the period of exposure to CIH. Knockdown of TH in the NTS reduces this persistent increase in MAP. This indicates that NTS A2 neurons play a role in the cardiovascular responses to CIH. Supported by HL‐088052