The Cardiovascular Protection Of Angiotensin ? Type 1 Receptor Blocking On Postmenopausal Hypertension With Left Ventricular Hypertrophy

Background: Due to the obvious changes in the levels of renin angiotensin system(RAS)and sex hormones in postmenopausal women with hypertension,the rate and degree of hypertension mediated organ damages(HMOD)in these patients are much greater than those in men.Left ventricular mass index(LVMI)plays an important role in predicting the risk of cardiovascular events in men and women,and the relative risk of left ventricular hypertrophy(LVH)in women is greater than that in men.Therefore,reversing LVH is considered one of the important goals for the treatment of patients with hypertension.Objective: The angiotensin II(Ang II)type 1 receptor(AT1R)was relatively adequately blocked by calcium channel blocker(CCB)combined with a larger dose of valsartan.To investigate its effect on improving cardiac and vascular function in postmenopausal hypertensive patients with LVH..Methods: This study is a prospective,open parallel controlled study with a follow-up period of 18 months.It can be calculated according to the sample size calculation formula.103 patients with hypertension and LVH were enrolled.The patients were from the Cardiovascular Outpatient and Inpatient of Lanzhou University second Hospital.Natural postmenopausal hypertensive women with LVH between 45 and 65 who meet the inclusion criteria and were divided into two groups according to whether the blood pressure met the standard.(1)Group A: In accordance with the principle of achieving the standard of blood pressure and 4-week follow-up,the maximum dose of valsartan for this group of patients was gradually adjusted to be no more than 320mg/d on the premise of patient tolerance,that means 5mg of amlodipine besylate + a larger dose of valsartan were taken daily.(2)Group B: Patients took amlodipine besylate 5mg + valsartan 80 mg daily as standard dose group.After 18 months of treatment and follow-up,chemiluminescence was used to detect the serum sexual hormone levels before and after treatment,including luteinizing hormone(LH),follicle stimulating hormone(FSH),progesterone(PRGE),estrogen(E2),testosterone(T),lactation respectively Hormones(PRL),and sex hormone binding globulin(SHBG)was detected by enzyme-linked immunosorbent assay.The levels of various components of RAS were measured by enzyme-linked immunosorbent assay,such as angiotensin II(Ang II),angiotensin(1-7)(Ang(1-7)),angiotensin(1-9)(Ang(1-9)),angiotensin converting enzyme(ACE)and angiotensin converting enzyme 2(ACE2).Enzyme-linked immunosorbent assay was also used to measure myocardial fibrosis and oxidative stress-related indicators,consist of type I collagen(Col I),type III collagen(Col III),8-hydroxydeoxyguanosine(8-OHd G),superoxide dismutase(SOD),glutathione(GSH)and a-smooth muscle actin(a-SMA).The aortic pulse analyzer and blood pressure pulse measurement device were used to evaluate the vascular function of patients.The indicators included pulse pressure(PP),mean arterial pressure(MAP),central contraction Pressure(CSBP),central diastolic pressure(CDBP),heart rate(HR),arterial pressure(AP),reflected wave gain index(AIx),reflected HR index adjusted at 75 beats per minute(AIx @ 75HR)and carotid-femoral pulse wave velocity(cf-PWV).At the same time,ambulatory blood pressure monitoring(ABPM)was used to evaluate the characteristic of blood pressure,the indicators contained24-hour systolic blood pressure(24h-SBP)and 24-hour diastolic blood pressure(24h-DBP)average value,load value and coefficient of variation,daytime systolic blood pressure(Day-SBP)and daytime Diastolic blood pressure(Day-DBP)average value,load value and coefficient of variation,night-time systolic blood pressure(Night-SBP)and night Diastolic blood pressure(Night-DBP)average value,load value and coefficient of variation,and dynamic arteriosclerosis index(AASI).Statistical analysis was performed using SPSS 23.0 statistical software.Results: Patients in group A were given amlodipine besylate 5 mg+valsartan198.57±57.06 mg daily,while patients in group B were given amlodipine besylate 5mg+valsartan 80 mg daily.(1)There were no significant differences in basic clinical characteristics between the two groups when they were enrolled(P > 0.05).(2)ABPM.There was no significant difference in blood pressure average,load,and coefficient of variation between the two groups before and after treatment(P > 0.05),However,after treatment,AASI in group A was significantly lower than that before treatment and that in group B after treatment(P <0.05).(3)The levels of various indicators of RAS,which were comparable in both groups at baseline.After treatment,the ACE2 in the A group was significantly higher than that in the group B(P <0.05).Ang(1-7),Ang(1-9),and ACE2 in the group A were also significantly increased after treatment(P <0.05),while the levels of ACE and Ang II were significantly reduced(P <0.05).(4)The levels of oxidative stress and myocardial fibrosis had no significant difference between the two groups before and after treatment.(5)Changes in sexual hormone levels and SHBG.After treatment,the SHBG level in the group A was higher than that in the group B,and it was significantly higher than that before treatment.(6)Changes in cardiac structure and function,interventricular septum diastolic thickness(IVSDT),the ratio of early diastolic peak flow velocity(E)to early diastolic mitral annular velocity(Em)and the ratio of Em to late diastolic mitral annular velocity(Am)were significantly improved(P <0.05),but the indicators in the group B did not have the same difference.(7)Assessment of vascular function,cf-PWV was significantly reduced in the A group after treatment(P <0.05).Conclusion: CCB combined with a high dose of ARB can improve the cardiac and vascular function of postmenopausal women with hypertension and LVH in a dose-dependent manner to a certain extent.And this effect may be related to the relatively sufficient blocking of AT1 R in postmenopausal hypertensive women and the more significant activation of ACE2-Ang(1-7)-Mas R axis and Ang II-AT2 R axis.Background: Ovariectomy(OVX)is one of the most classic methods of constructing animal menopause models.Bilateral OVX induced estrogen deficiency causes hypertension and cardiac dysfunction,partly due to angiotensin converting enzyme(ACE)over-activation and angiotensin II(Ang II)type 1 receptor(AT1R)significantly increased expression.Our previous clinical research confirmed that relatively adequate block of AT1 R can effectively improve cardiac and vascular damage in postmenopausal hypertensive patients with left ventricular hypertrophy(LVH),but the mechanism is not clear.Objective: OVX spontaneously hypertensive rat(SHR)model was constructed with LVH.By combining calcium channel blocker(CCB)with high-dose angiotensin receptor blocker(ARB)valsartan to block its AT1 R relatively fully,the changes in the components of the renin-angiotensin system(RAS),receptor-active modified protein3(RAMP3)and related g-protein-coupled receptor(GPCRs),and hemodynamics were detected.To investigate the reverse effect of blocking AT1 R on LVH of SHR after OVX and its related mechanism.Methods: This study was an animal experiment.Seventy two female SHRs with12 weeks of age were selected,of which 48 were modeled with OVX,12 were modeled with sham-operated(Sham)models,and 12 SHR with nonsurgical operation. Serum estradiol(E2)levels in the OVX group were measured at 4 weeks after surgery.Vaginal exfoliated cells were examined at 2 weeks after surgery.After confirming that the model was successfully constructed,all SHRs were divided into 6 groups:(1)group 1,amlodipine besylate 10 mg / kg d + valsartan 7.5mg / kg.d,(2)group 2,amlodipine besylate 10 mg / kg kg.d + valsartan 15 mg / kg.d,(3)group 3,given amlodipine besylate 10 mg / kg.d + valsartan 22.5mg / kg.d,(4)group 4,given amlodipine besylate 10 mg / kg.d +valsartan 30 mg / kg.d,(5)Sham group,given amlodipine besylate 10 mg / kg.d + valsartan 30 mg / kg.d,(6)Non-OVX group,given amlodipine besylate 10 mg / kg.d +valsartan at 30 mg / kg.d.In each group of 12 rats,6 of them were treated according to the above-mentioned group for 12 weeks,and the other 6 SHRs were injected RU486 subcutaneously from the 8th week,which was the inhibitor of RAMP3,and the intervention was continued for 4 weeks.Before and after the intervention,enzyme-linked immunosorbent assay was used to measure RAS-related indicators in each group,including ACE,ACE2,Ang II,Ang(1-9),and Ang(1-7).The chemiluminescence method was used to detect the levels of various sexual hormones in the serum,such as luteinizing hormone(LH),follicle stimulating hormone(FSH),progesterone(PRGE),estrogen(E2),testosterone(T)prolactin(PRL),and sex hormone binding globulin(SHBG)was measured by enzyme-linked immunosorbent assay.Enzyme-linked immunosorbent assay was also used for detection of oxidative stress-related indicators,including: 8-hydroxydeoxyguanosine(8-OHd G),superoxide dismutase(SOD),glutathione(GSH),and a-smooth muscle actin(a-SMA).The protein expression levels of RAMP3 and related GPCRs in myocardial tissue were assessed by western blotting.And rat tail systolic blood pressure(SBP),diastolic blood pressure(DBP),mean arterial pressure(MAP)and heart rate(HR)were measured.Retrograde intubation through the right common carotid artery to the left ventricle through a multimedia biosignal recorder to record hemodynamic parameters such as peak left ventricular systolic pressure(LVSP),left ventricular end diastolic pressure(LVEDP),and maximum left ventricular pressure Ascending rate(? d P / dtmax),maximum left ventricular pressure falling rate(?d P/ dtmin),left ventricular isovolumetric diastolic pressure change rate(IRP average d P/ dt),and left ventricular relaxation time constant(Tau).Statistical analysis was performed using SPSS 23.0 statistical software.Results:(1)Rat tail pressure.After 12 weeks of intervention,the SBP of SHR in the OVX group was higher than that in the non-OVX group(P <0.05).However, there was no significant difference in the SHR in the three groups after the high-dose valsartan intervention.The above trends did not change after the intervention(P>0.05).(2)Hemodynamics,after the intervention of CCB combined with large-dose valsartan for 12 weeks,LVSP,? d P / dtmax,?d P / dtmin,IRP Average d P / dt,and Tau increased gradually,and all of them were higher than those at baseline(P <0.05).While,LVEDP decreased gradually(P <0.05).LVEDP,? d P / dtmax,?d P / dtmin,IRP Average d P / dt and Tau of SHR treated by RU486 were significantly different from those who did not use RU486(P <0.05).(3)The level of oxidative stress and the degree of myocardial fibrosis,?-SMA and 8-OHd G in the OVX group and Sham groups before intervention were higher than those in the non-OVX group.GSH and SOD were lower than those in the non-OVX group.After 12 weeks of intervention,?-SMA and 8-OHd G in each group decreased gradually.And the above-mentioned levels of SHR in the three groups of CCB combined with large-dose valsartan were significantly lower than their levels at baseline,while GSH and SOD showed opposite trends(P <0.05).(4)The levels of serum RAS components,the ACE and Ang II of SHR in OVX group at baseline were higher than those in non-OVX group,however,Ang(1-9)and Ang(1-7))was lower than that in the non-OVX group(P <0.05).But ACE2 were similar among groups.After 12 weeks of intervention with valsartan,ACE and Ang II in each group decreased compared to the levels before treatment.Ang(1-9)and Ang(1-7)of SHR which were treated by CCB combined with larger doses of valsartan were higher than before(P <0.05).After the intervention of RU486,the level of Ang II increased significantly(P <0.05).(5)Serum sexual hormone levels,LH and FSH in the OVX group before intervention were higher than those in the non-OVX group.PRGE,E2,T,PRL,SHBG,E2 / T,and E2 / PRL were all lower than those in the non-OVX group(P <0.05).After the intervention,the SHBG increased gradually among the groups,and were all higher than the levels at 0 weeks.At the same time,after RU486 was added to SHR in OVX group with different doses of valsartan,the SHBG was lower than that without RU486(P <0.05).(6)The levels of RAMP3 and related G protein-coupled receptors(GPCRs).The levels of total protein,cell membrane protein and ratios of cell membrane to total protein on RAMP3 and related GPCRs in the non-OVX group were higher than those in the OVX groups before treatment.The ratio of membrane protein to total protein of SHR in OVX groups increased after intervention,and they were also higher than those in the non-OVX group(P <0.05).After the treatment with RU486,the levels of membrane proteins in the OVX group and the non-OVX group were lower,but there was no significant difference between the groups(P> 0.05).Conclusion: CCB combined with relatively sufficient block of AT1 R can improve the diastolic function of SHR combined with LVH after OVX.RAMP3 and the GPCRs which were transported to the membrane by RAMP3 may play an important synergistic role in a dose-dependent manner.