ABSTRACT
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.
Subject(s)
Adrenergic Neurons/enzymology , Arterial Pressure , Gene Knockdown Techniques , Hypertension/prevention & control , Protein-Tyrosine Kinases/metabolism , Solitary Nucleus/enzymology , Animals , Chronic Disease , Circadian Rhythm , Dependovirus/genetics , Disease Models, Animal , Down-Regulation , Gene Expression Regulation, Enzymologic , Genetic Vectors , Heart Rate , Hypertension/enzymology , Hypertension/etiology , Hypertension/genetics , Hypertension/physiopathology , Hypoxia/complications , Hypoxia/enzymology , Hypoxia/genetics , Hypoxia/physiopathology , Male , Paraventricular Hypothalamic Nucleus/metabolism , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins c-fos/metabolism , RNA Interference , RNA, Small Interfering/metabolism , Rats , Rats, Sprague-Dawley , Solitary Nucleus/physiopathology , Time Factors , Transduction, GeneticABSTRACT
Chronic intermittent hypoxia (CIH) is a model of arterial hypoxemia that accompanies sleep apnea and increases resting arterial pressure (AP). We examined the effects of 7 days of exposure to CIH on arterial baroreflex control of renal sympathetic nerve activity (RSNA) and heart rate (HR) in rats. Sprague-Dawley rats (15±2 weeks old) were exposed to CIH (9% oxygen for 3 min every 10 min, 8 h per day) for 7 days (n=16) while control rats (n=18) were maintained in normoxia. Baroreflex regulation of RSNA and HR were estimated in Inactin anesthetized and artificially ventilated rats during infusions of phenylephrine and nitroprusside to manipulate AP. After exposure to CIH, resting mean AP was higher in CIH than that in control group (115±7 vs. 105±7, P<0.001). Resting HR did not differ between the two groups. Exposure to CIH shifted the AP-RSNA relationship rightward (approximately 10 mm Hg, P<0.01). CIH did not alter maximum gain of the baroreflex control of RSNA (-2.6±0.6 vs. -2.5±0.6 arbitrary units (a.u.)/mm Hg) and HR (-1.8±0.6 vs. -1.8±0.7 bpm/mm Hg, CIH vs. control). In addition, cardiac spontaneous baroreflex sensitivity in conscious rats (n=8) also did not change during exposure to CIH. These results indicate that resetting of the sympathetic baroreflex control, rather than an impairment of its sensitivity, is associated with an onset of hypertension induced by CIH.
