| Objective: Hypertension is one of the leading causes of death from cardiovascular disease.Hypertension in children and adolescents is a risk factor for adult hypertension and is closely related to the morbidity and mortality of cardiovascular diseases in adulthood.In recent years,the incidence of hypertension in children and adolescents is on the rise.More and more attention has been paid to the prevention and treatment of hypertension in children and adolescents.Baroreflex plays an important role in maintaining relatively stable arterial blood pressure.Nucleus tractus solitaries(NTS)is the first level relay station of baroreflex and a key part of the brainstem that controls cardiovascular reflex function.The peripheral and central ACE2--Ang1-7--Mas axis can protect the heart and lower blood pressure by antagonizing the ACE--Ang II--AT1 axis.Chronic intermittent hypobaric hypoxia(CIHH)can significantly reduce the blood pressure of renal vascular hypertension by modifying the baroreceptor reflex.The purpose of this study was to investigate the regulatory effect of CIHH on baroreceptor reflex in young spontaneously hypertensive rats and the mechanism of Ang1-7 in NTS by using functional study,electrophysiology,immunofluorescence and molecular biology.Methods:The 3-week-old spontaneously hypertensive rats(SHR)and normotensive control rats(WKY)were randomly divided into 4 groups: WKY group,WKY + CIHH group,SHR group and SHR + CIHH group.WKY + CIHH group and SHR + CIHH group received hypobaric hypoxia treatment(5 hours per day)at a simulated altitude of 4000 meters for 35 days.The feeding environment and conditions of WKY group and SHR group were same with those of WKY and SHR groups except that they were not treated with CIHH.Arterial blood pressure and weight were measured regularly every week,blood pressure(BP),heart rate(HR),and renal symathetic nerve activity(RSNA)were recorded in anesthetized rats.Changes in RSNA and HR were observed when blood pressure was changed by intravenous injection of phenylephrine(PE)and sodium nitrate(SNP).The function curve of baroreceptive reflex was obtained,and the differences among the groups were compared.The changes of baroreflex in each group were observed by microinjection of Ang1-7 and Mas receptor blocker A779 into the NTS.Using enzyme-linked immunosorbent assay(ELISA)to detect the concentration of Ang1-7 in the serum of rats in each group.The levels of Ang1-7 and Mas receptors in NTS were observed by immunofluorescence and protein expression of ACE2 and Mas receptor in NTS was determined by Western blot.Results:1.There was no significant difference in basal blood pressure among groups before CIHH treatment.As the rats developed,the arterial blood pressure in SHR increased gradually.Systolic blood pressure in SHR group at 6 weeks was significantly higher than that in age-matched WKY group(P <0.05).The systolic blood pressure,diastolic blood pressure and mean arterial pressure in SHR at 7-8 week-age were significantly higher than that in age-matched WKY group(P<0.05,P<0.01).However,the blood pressure of rats in the WKY group did not change significantly with the development of rats(P >0.05).The systolic blood pressure,diastolic blood pressure and mean arterial pressure of SHR rats were significantly reduced after 5 weeks of CIHH treatment(P<0.01),but still higher than that of WKY group.CIHH treatment had no effect on systolic blood pressure,diastolic blood pressure and mean arterial pressure of WKY rats(P>0.05).With the increase of age,the body weight of the rats in each group increased steadily and the heart rate decreased steadily.CIHH had no significant effect on body weight and heart rate(P>0.05).2.ELISA results showed that the serum Ang1-7 level of SHR group was lower than that of WKY group,and was increased by CIHH treatment.Immunofluorescence results showed that compared with WKY group,the levels of Ang1-7 and Mas receptors in NTS of SHR group were significantly reduced(P<0.05).However,the levels of Ang1-7 and Mas receptors in the SHR+CIHH group were increased compared with the SHR group.In addition,CIHH had no effect on the level of serum Ang1-7 and the content of Mas receptors in NTS of WKY rats(P>0.05).3.The relative change value of integrated RSNA was calculated and derived from raw RSNA.Compared with the WKY group,SHR showed decreased inhibition of RSNA and HR with reduced slope,and the curve moved to the upper right.CIHH treatment increases the slopes of the baroreflex curve of RSNA and heart rate and shifts them to the lower left.CIHH had no effect on baroreflex curve in WKY rats.The results showed that the function of baroreflex was impaired in young SHR rats,which could be improved by CIHH treatment.4.Microinjection of Ang1-7 into NTS can improve the baroreflex in young SHR rats,and enhance the sympathetic inhibition and HR inhibition of baroreflex.However,microinjection of Mas receptor blocker A779 into NTS could weaken the facilitation of CIHH on the impaired baroreceptor reflex function and its sympathetic inhibition and HR inhibition to baroreflex.5.Western blot results showed that the expression of ACE2 and Mas receptor in NTS was significantly decreased in SHR compared with that in WKY rats(P<0.05,P<0.01).The expression of ACE2 and Mas receptor in NTS was significantly increased in SHR+CIHH group compared with SHR group(P<0.05).There was no significant difference in the expression of ACE2 and Mas receptor in NTS between WKY and WKY+CIHH rats(P>0.05).Conclusions:CIHH reduces the arterial blood pressure and improve impaired baroreflex function in young SHR by enhancing the function of ACE2-Ang1-7-Mas in NTS. |
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