Knockdown of tyrosine hydroxylase in the nucleus of the solitary tract reduces elevated blood pressure during chronic intermittent hypoxia.
Noradrenergic A2 neurons in nucleus tractus solitarius (NTS) respond to stressors such as hypoxia. We hypothesize that tyrosine hydroxylase (TH) knockdown in NTS reduces cardiovascular responses to chronic intermittent hypoxia (CIH), a model of the arterial hypoxemia observed during sleep apnea in humans. Adult male Sprague-Dawley rats were implanted with radiotelemetry transmitters and adeno-associated viral constructs with green fluorescent protein (GFP) reporter having either short hairpin RNA (shRNA) for TH or scrambled virus (scRNA) were injected into caudal NTS. Virus-injected rats were exposed to 7 days of CIH (alternating periods of 10% O2 and of 21% O2 from 8 AM to 4 PM; from 4 PM to 8 AM rats were exposed to 21% O2). CIH increased mean arterial pressure (MAP) and heart rate (HR) during the day in both the scRNA (n = 14, P < 0.001 MAP and HR) and shRNA (n = 13, P < 0.001 MAP and HR) groups. During the night, MAP and HR remained elevated in the scRNA rats (P < 0.001 MAP and HR) but not in the shRNA group. TH immunoreactivity and protein were reduced in the shRNA group. FosB/ΔFosB immunoreactivity was decreased in paraventricular nucleus (PVN) of shRNA group (P < 0.001). However, the shRNA group did not show any change in the FosB/ΔFosB immunoreactivity in the rostral ventrolateral medulla. Exposure to CIH increased MAP which persisted beyond the period of exposure to CIH. Knockdown of TH in the NTS reduced this CIH-induced persistent increase in MAP and reduced the transcriptional activation of PVN. This indicates that NTS A2 neurons play a role in the cardiovascular responses to CIH.
Department of Integrative Physiology, Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth, Texas.
Chandra Sekhar
CS
Bathina
Anuradha
A
Rajulapati
Michelle
M
Franzke
Kenta
K
Yamamoto
J Thomas
JT
Cunningham
Steve
S
Mifflin
D059331:Adrenergic Neurons / Q000201:enzymology*; D000818:Animals; D062186:Arterial Pressure; D002908:Chronic Disease; D002940:Circadian Rhythm; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors; D006339:Heart Rate; D006973:Hypertension / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D008297:Male; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017552:Solitary Nucleus / Q000201:enzymology* / Q000503:physiopathology; D013997:Time Factors; D014161:Transduction, Genetic
C483820:Fosb protein, rat; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D011505:Protein-Tyrosine Kinases
A2 neurons; nucleus of the solitary tract; tyrosine hydroxylase and chronic intermittent hypoxia