Ang â…¡ In Paraventricular Nucleus Contribute To Chronic Intermittent Hypoxia Induced-hypertension In Rats

BackgroundSleep apnea syndrome(SAS) is closely connecting with high blood pressure. Chronic intermittent hypoxia(CIH) is the main pathophysiological characteristics and damage mechanism of SAS. The hypothalamic paraventricular(PVN) is an important site regulating arterial pressure and sympathetic activity. The PVN influences sympathetic activity via direct projections to sympathetic preganglionic neurons or via a synaptic relay with the rostral ventrolateral medulla(RVLM), another role in cardiovascular regulation. Angiotensin II(Ang Ⅱ) is considered a biologically active peptide of the RAS family in PVN,which can regulate sympathetic activity and arterial blood pressure as important neuromodulator and closely related to various development of hypertension.Objective1 To explore that the role of Angiotensin in PVN in Ⅱ mediating chronic intermittent hypoxia induced-hypertension and its mechanism in rats.2 To observe the therapeutic effect of chronic intermittent hypoxia induced hypertension by LOS, AT1 R antagonist and provide the basis for the treatment of SAS induced complications.MethodsThe conscious noninvasive method with tail cuff was performed in rats to record the systolic blood pressure during establishing the model of CIH induced-hypertension. Mean arterial pressure(MAP) and heart rate(HR) were recorded in vivo on aPower Lab data acquisition system after CIH. Rats were fixed on the stereotaxic instrument to conduct microinjection in the PVN.Using Western blot measure Ang Ⅱlevel and Ang type 1 receptor(ATⅡ 1R) protein expression in PVN.1 The influence of chronic intermittent hypoxia on blood pressure in ratsExperimental animals in adaptive breeding experiment after 1 w, randomly divided into Sham group and CIH group. Sham group except not filling the nitrogen and oxygen, the rest are the same as the CIH group for processing. By nitrogen dilution principle, with reference to our previous method, the CIH group into the intermittent hypoxia in rats, and to the low oxygen tank filled with nitrogen and oxygen, each cycle for 9 min, namely 4 min into nitrogen, with 5 min oxygen supply. Measuring oxygen monitoring instrument of intermittent low oxygen concentration of oxygen tank adjust the gas flow rate, low oxygen cabin to control the oxygen concentration(6% ~ 21%),making every minimum oxygen concentration of the cycle of intermittent hypoxia at 6%, duration of about 40 s, and then gradually returning to 21%. The cycle repeated every day 8 h(9:00 am ~ 5:00 PM), a total of 15 d. Through the software analysis SBP,MAP, and analysis of chronic intermittent hypoxia on rat SBP, the influence of the MAP.2 The effect of chronic intermittent hypoxia on Ang Ⅱ level and AT1 R protein expression in PVNWe randomly divided the rats into Sham group and CIH group. Using Western blot measure Ang levelⅡ and AT1 R protein expression in PVN.3 Effects of acutely changed the level of Ang Ⅱ in PVN on MAPWe randomly divided the rats into Sham group and CIH group, which were subjected to microinjection of Ang Ⅱ(0.03、0.3、3 nmol)in bilateral PVN.We observed the correspondent changes of Ang Ⅱ on MAP after injection.4 Microinjection of LOS(50 nmol) in PVN on MAPWe randomly divided the rats into Sham group and CIH group, which were subjected to microinjection of saline、 Ang Ⅱ(0.3 nmol)、LOS(50 nmol)or LOS(50 nmol)+Ang Ⅱ(0.3 nmol)in bilateral PVN. The correspondent changes of MAP and HR were observed after injection.5 The effect of long-term application of LOS on SBP and AT1 R protein expression in PVNRats were divided into Sham group, the CIH group and CIH + LOS three groups. The conscious noninvasive method with tail cuff was performed in rats to record the systolic blood pressure during establishing the model of CIH induced-hypertension for 5,10 and 15 day.Using Western blot measure Ang Ⅱlevel and Ang Ⅱtype 1 receptor(AT1R) protein expression in PVN and observed long-term lower levels of(AT1R) protein expression in rat PVN.Results1 Chronic intermittent hypoxia increased the SBP and MAP significantly in rats. SBP and MAP increased significantly after 5 days.2 The level of Ang Ⅱin PVN on CIH rats were significantly higher than those in Sham rats, along with increased AT1 R protein expression.3 Microinjection of Ang Ⅱ(0.03、0.3、3 nmol)in bilateral PVN dose-dependently increased MAP in both CIH and Sham rats, this response was significantly augmented in CIH rats.4 Losartan(50 nmol), AT1 R antagonist, had no effect on MAP and rate in Sham rats,but significant decreases MAP in CIH rats, and prevented Ang Ⅱ-induced increases in MAP in both CIH and Sham rats.5 Long-term application of LOS can partly reduce MAP.AT1 R expression was increased in CIH rats vs.Sham rats,this difference was not evident in rats treated with losartan.Conclusions1 The increased Ang Ⅱrelease and enhanced AT1 R activation in the PVN contribute to CIH induced-hypertension in rats.2 Long-term application of Ang Ⅱ type 1 receptor antagonist LOS can significantly inhibit the chronic intermittent hypoxia induced-hypertension rats blood pressure,and the inhibition may be related to the downgrade AT1 R protein expression in the PVN.