Study On The Distribution Characteristics Of TCM Syndrome Types In Postmenopausal Hypertensive Patients And The Related Mechanism Of Icariin Intervention

Objective:1.To evaluate the effectiveness and safety of the kidney-tonifying method combined with antihypertensive drugs in the treatment of postmenopausal and perimenopausal hypertension in women.2.To explore the distribution characteristics of TCM syndromes and characteristics of ambulatory blood pressure in postmenopausal hypertensive patients.3.To investigate the regulation effect of icariin on female castrated SHR circulation and myocardial RAS and related mechanisms.Methods:1.Systematic review and meta-analysisComputer search of 7 databases of China Knowledge Network,VIP database,Wanfang Data Knowledge Service Platform,China Biomedical Literature Database,PubMed,Embase,The Cochrane Library.Randomized controlled trials of kidney tonifying therapy combined with western medicine in the treatment of postmenopausal and perimenopausal hypertension were collected.Use Rev Man 5.3 and Stata 14.0 software for Meta analysis,publication bias detection,sensitivity analysis,and subgroup analysisTSA 0.9 software was used for trial sequential analysis(TSA)of the efficacy of blood pressure lowering.2.Cross-sectional studyTaking postmenopausal hypertensive patients as the research object,analyze the general data,the distribution of hypertension grades,the distribution of TCM syndrome types,and the distribution of circadian rhythms;The included patients were divided into two groups:the menopausal period less than 10 years group and the menopausal period greater than or equal to 10 years group,and analyze whether there are differences in ambulatory blood pressure parameters between the two groups;Analyze the correlation between age and ambulatory blood pressure parameters;BPV is expressed by standard deviation and coefficient of variation,and the relationship between each variable and BPV is analyzed using multiple linear regression methods.3.Animal experiment48 9-week-old castrated female castrated SHR were randomly divided into 6 groups,model group(SHR group),estradiol group(SHR+E2 group),ICA low-dose group(SHR+LI group),ICA medium-dose group(SHR+MI group),ICA high-dose group(SHR+HI group),icariin medium-dose+ICI 182780 group(SHR+MI+ICI group).8 9-week-old female castrated WKY only served as a normal control group.SHR+E2 group was given estradiol valerate(0.1mg/kg/day)by gavage,ICA low,medium and high dose group was given ICA 10 mg/kg/day,20 mg/kg/day,40 mg/kg/day by gavage respectively,SHR+MI+ICI group was given ICA20 mg/kg/day,and fulvistran injection 52 mg/kg/month was given subcutaneously.The body weight,blood pressure and heart rate of rats in each group were monitored weekly.Weigh the heart,spleen and kidneys and calculate the organ coefficients;ELISA method was used to detect rat serum Ang?,Ang(1-7),E2 levels;Western-blot method was used to detect rat left ventricular myocardial tissue AT1R,MasR,ACE1,ACE2,GPR30,ERK1/2,p-ERK1/2 Protein expression level.Results:1.Systematic review and meta-analysis on the treatment of postmenopausal and perimenopausal hypertension with the method of invigorating the kidney and antihypertensive drugs(1)The results of the meta-analysis showed that 14 articles were finally included,with a total of 1139 patients.The antihypertensive effect and the curative effect of postmenopausal and perimenopausal hypertension of the kidney-tonifying method combined with antihypertensive drugs in the treatment of menopausal hypertension are better than those of the western medicine group;SBP levels,DBP levels,kupperman scores,and luteinizing hormone levels are lower than those of the western medicine group;estradiol level is higher than the western medicine group.(2)The incidence of adverse reactions:the kidney-tonifying method combined with the antihypertensive drugs group is lower than the western medicine group.(3)Publication bias:Draw a funnel diagram for the antihypertensive effect and perform Egger's method test,suggesting that the included literature has publication bias.(4)Sequential analysis of trials of antihypertensive efficacy:It is suggested that the positive results of Meta-analysis may appear prematurely,and there may be false-positive results.2.Study on the Distribution of TCM Syndrome Types and Ambulatory Blood Pressure in Postmenopausal Hypertensive Patients(1)A total of 214 patients were enrolled in this study,and patients with deficiency of both yin and yang accounted for the highest proportion.(2)Among all included patients,non-spoon type patients accounted for the highest proportion.(3)24hSBP,nSBP,maximum-minimum difference between systolic blood pressure,24hSBPSD,dSBPSD,24hSBPCV,dSBPCV,dDBPCV,nDBPCV in the menopausal period less than 10 years group are higher than those in the menopausal period greater than or equal to 10 years group.(4)24hSBP,dSBP,nSBP,MMD,24hSBPSD,dSBPSD,nSBPSD,dSBPCV,dDBPCV are positively correlated with age;24hDBP,SBP-BPF,dDBP,nDBP,Hr are negatively correlated with age.(5)The related factors of 24hSBPSD are:MMD,MAP,daytime blood pressure load;the related factors of 24hDBPSD are:24hDBP,BP-BPF,MMD,hypertension grade 3,BUN;the related factors of 24hSBPCV are:24hSBP,24hDBP,MMD,daytime blood pressure load;The related factors of 24hDBPCV are:MMD,MAP,SBP-BPF,DBP-BPF,BUN.3.Icariin exerts blood pressure protection by regulating renin-angiotensin system on female ovariectomized spontaneously hypertensive rats(1)Mean arterial pressure(MAP):The MAP of the SHR group was higher than that of the WKY group;compared with the SHR group,the MAP of the SHR+E2 group,SHR+LI group,SHR+MI group,and SHR+HI group decreased(P<0.05);compared with the SHR+MI group,the MAP increased in the SHR+MI+ICI group(P<0.05).(2)Heart rate:Compared with the SHR group,the heart rate of the SHR+LI group,SHR+MI group and SHR+HI group decreased(P<0.05 or P<0.01).(3)Organ coefficient:?Cardiac coefficient:Compared with the WKY group,the heart coefficients of the 6 groups of SHR rats increased(P<0.01);compared with the SHR+MI group,the heart coefficients of the SHR+MI+ICI group increased(P<0.05).?Left renal coefficient:Compared with the WKY group,the left renal coefficient of the SHR group increased(P<0.01);compared with the SHR group,the left renal coefficient of the SHR+E2 group decreased(P<0.05).?Right kidney coefficient:Compared with the WKY group,the right kidney coefficient of the SHR group increased(P<0.01);compared with the SHR group,the left kidney coefficient of the SHR+E2 group,SHR+LI group,SHR+MI group,SHR+HI group Decrease(P<0.05 or P<0.01).?Spleen coefficient:Compared with the WKY group,the spleen coefficient of the SHR group was increased(P<0.01);compared with the SHR+MI group,the spleen coefficient of the SHR+MI+ICI group was increased(P<0.05).(4)ACE1-Ang?-AT1R axis:?ACE1 protein:Compared with the WKY group,the ACE1 protein expression in the SHR group was increased(P<0.01);compared with the SHR group,the ACE1 protein expression in the SHR+MI group and SHR+HI group was decreased(P<0.05).?Ang II content:Compared with the WKY group,the Ang ? content in the SHR group was significantly increased(P<0.01);compared with the SHR group,the Ang II content in the SHR+E2 group,SHR+MI group,and SHR+HI group was significantly decreased(P<0.05 or P<0.01).?AGT1R protein:Compared with the SHR group,the expression of AGT1R protein in the SHR+MI group increased(P<0.05).(5)ACE2-Ang(1-7)-MasR axis:?ACE2 protein:Compared with the WKY group,the expression of ACE2 protein in the SHR group was increased(P<0.05).?Ang(1-7)content:Compared with the WKY group,the Ang(1-7)content in the SHR group was significantly increased(P<0.01);compared with the SHR+E2 group,the Ang(1-7)content in the SHR+LI group was significantly higher Increased(P<0.01);Compared with the SHR+MI group,the Ang(1-7)level in the SHR+MI+ICI group was significantly reduced(P<0.01).?MAS 1 protein:Compared with the WKY group,the expression of MAS 1 protein in the SHR group was reduced(P<0.05 or P<0.01).(6)E2 and its receptor GPR30:?E2 content:Compared with the SHR group,the E2 content of the SHR+E2 group,SHR+LI group,SHR+MI group,and SHR+HI group has a rising trend(P>0.05).?GPR30 protein:Compared with the WKY group,the expression of GPR30 protein in the SHR group had a rising trend(P>0.05).(7)ERK1/2 pathway:?p-ERK1/2 protein:Compared with WKY group,the expression of p-ERK1/2 protein in SHR group increased(P>0.05);the expression of p-ERK1/2 protein in SHR+HI group decreased(P<0.05).?p-ERK1/2/ERK1/2:Compared with the WKY group,p-ERK1/2/ERK1/2 in the SHR group has a rising trend(P>0.05);compared with the SHR group,the SHR+E2 group and the SHR+HI group p-ERK1/2/ERK1/2 had a decreasing trend(P>0.05);compared with the SHR+MI group,p-ERK1/2/ERK1/2 in the SHR+MI+ICI group increased significantly(P<0.01).Conclusion:1.For postmenopausal and perimenopausal hypertension in women,the kidney-tonifying method combined with antihypertensive drugs can reduce the patients'systolic and diastolic blood pressure levels,improve menopausal symptoms,and improve the level of sex hormones.The effect is better than that of the western medicine group.2.Deficiency of Yin and Yang is the most common TCM syndrome in postmenopausal hypertensive patients,and the BPV of patients with longer menopause years is higher than that of patients with short menopause years.3.ICA can lower the blood pressure and heart rate of SHR.The above-mentioned effects are related to the regulation of circulation and myocardial tissue RAS.ICA can inhibit the ACE1-Ang?-AT1R axis and has a tendency to increase the ACE2-Ang(1-7)-MasR axis.At the same time,this effect is related to the inhibition of the ERK1/2 pathway.