| Background and objectivesHypertension is one of the most important risk factors for cardiovascular disease.Resistant hypertension(RH)is a troublesome issue in the treatment of hypertension,which often leads to more serious target organ damage and cardiovascular events.It is important to control the blood pressure(BP)in the treatment.There are a variety of factors which can affect BP target attainment.By exploring the risk factors of BP target attainment and the association between daily sodium intake and the BP control in RH,this study provided evidence for clinical treatment in resistant hypertension.The vasoconstriction and vasodilatation of peripheral resistance vessels play an important role in the formation and development of hypertension.Previous studies of isolated vessels showed that high sodium intake had an effect on the structure and function of resistance vessels,but there was a great difference between the isolated blood vessels and the living environment,and it did not reflect the vascular function of the hypertension individuals.We investigated the effect of sodium intake on the vasoconstriction and vasodilatation function of mesenteric small artery(MSA)in Dahl/SS rats,and related protein expression level.MethodsClinical research:We consecutively recruited 147 RH patients(47.6%male,age 54.1 4±16.15 years)who received at least three antihypertensive drugs(Anti-HD)including diuretics.24-hour urinary sodium excretion(24h-UNa)was tested to estimate the daily sodium intake.Home BP monitoring(HBPM)consisted of 4 measurements daily(before medicine in the morning,10 a.m.,4 p.m.,before sleeping at night).Office BP was recorded between 8 a.m.to 10 a.m.before taking medicine.Ambulatory BP monitoring(ABPM)was obtained for each patient.Multiple logistic regression analysis was performed,the variables including age>65 years,sex,education,obesity,alcohol consumption.current smoking,family history of hypertension,low eGFR,albuminuria and 24h-UNa.The high,medium,and low 24h-UNa were defined as>200mmol/24h,100-200mmol/24h,and<100mmol/24h,respectively.After long-term follow-up,multivariate logistic analysis was performed to analyze the risk factors of target organ damage in RH,including left ventricular hypertrophy,albuminuria,microalbuminuria and decreased eGFR.The BP control was analyzed in the end of follow-up.Animal experiments:80 8-week male Dahl/SS rats were randomized into 10 groups and administrated with normal sodium for 6 weeks(0.6%NaCl,NS-6 group),lower sodium for 6 weeks(0.3%NaCl,LS-6 group),high sodium for 6 weeks(8%NaCl,HS-6 group)diet,high sodium plus benazepril for 6 weeks treatment(10mg/kg/d,HB-6 group),normal sodium for 12 weeks(NS-12 group),lower sodium for 12 weeks(LS-12 group),high sodium for 12 weeks(HS-12 group),high sodium plus benazepril for 12 weeks(HB-12 group),high sodium for 6 weeks and lower sodium for another 6 weeks(HLS-12 group)and HLS-12 plus benazepril for 12 weeks treatment(HLB-12 group),respectively.Full-field laser perfusion imaging(LPI)and moorFLPI software were used to record blood flow and noradrenaline(NA,10?g/kg)-induced vasoconstriction or acethlcholine(ACh,10?g/kg)-induced vasodilatation in mesenteric small vessel(MSV).The diameter of MSA was recorded in situ and in vivo before and after NA or ACh injection by a high-speed camera with a microscope.After detecting the function of vessels,MSA was performed hematoxylin-eosin(HE)staining,Masson staining and immunohistochemistry analysis(eNOS,ACE,AT1R and AT2R protein).ResultsClinical research:1.In the multivariate logistic regression models,high and medium 24h-UNa were negatively associated with achieving targets of office BP(p<0.001 and p=0.010).2.In the multivariate logistic regression models,high 24h-UNa(p<0.001),medium 24h-UNa(p=0.013),alcohol consumption(p=0.019)and low eGFR(p=0.013)were negatively associated with achieving targets of morning home BP.High 24h-UNa(p=0.002),albuminuria(p=0.014)and hyperlipidemia(p=0.001)were negatively associated with achieving targets of 10 a.m.home BP.High 24h-UNa(p=0.001),family history(p=0.007)were negatively associated with achieving targets of 4 p.m.home BP,male was positive correlation with achieving targets of 4 p.m.home BP(p=0.015).High 24h-UNa(p=0.003),medium 24h-UNa(p=0.031),educational level lower than bachelor(p=0.034),current smoking(p=0.013),hyperlipidemia(p=0.032)and albuminuria(p=0.013)were negatively associated with achieving targets of night home BP.3.In the multivariate logistic regression models,male was positively associated with achieving targets of all day(p=0.002)and daytime(p=0.004)mean BP in ABPM.4.In the multivariate logistic regression models,current smoking(p=0.035),high and medium 24h-UNa(p=0.039)were positively associated with left ventricular hypertrophy.Current smoking(p=0.018),high and medium 24h-UNa(p=0.008)were positively associated with albuminuria.Current smoking(p=0.006),high and medium 24h-UNa(p=0.035)were positively associated with elevated urinary albumin-to-creatinine ratio(>30mg/g).The RH patients with diabetes mellitus were positively associated with microalbuminuria(p=0.017)and decreased eGFR(p=0.024).5.After 17.4±7.3 months follow-up,with the outpatient treatment and salt restriction education,the 24h-UNa was significantly lower than that in the recruitment(p<0.001),the achieving targets of office BP was increased from 30.89%to 47.06%(p=0.006),the achieving targets of home BP was increased from 38.24%to 50.74%(p=0.044).Animal experiments:1.After a 12-week dietary intervention,NA-induced MSV blood perfusion was significantly attenuated in HS-12 group than that in NS-12(p=0.0367),HLS-12(p=0.0334)and HLB-12 group(p=0.0459).NA-induced maximum decline of MSV blood perfusion was significantly enhanced in HS-12 group than that in NS-12 group(p=0.0016),the maximum decline was significantly attenuated in HLB-12 group than that in HS-12(p=0.0403)and HB-12 group(p=0.0447).2.ACh-induced MSV blood perfusion was significantly attenuated in HS-12 group than that in NS-12(p=0.0302),HB-12(p=0.0288),HLS-12(p=0.0035)and HLB-12 group(p=0.0005),there was no difference between HB-12,HLS-12 and HLB-12 group.ACh-induced maximum blood perfusion increase was significantly higher in LS-12 group than that in NS-12 group(p=0.0131),the maximum increase was significantly higher in HLB-12 group than that in HS-12 group(p=0.0025).Comparing the 12-week intervention group with the 6-week intervention group,ACh-induced maximum blood perfusion increase was significantly higher in LS-12 group than that in LS-6 group(p=0.0279).3.After the 12-week dietary intervention,NA-induced maximum vasoconstriction of MSA was significantly higher in HS-12 group than that in NS-12(p<0.0001),HLS-12(p=0.0257)and HLB-12 group(p=0.0013).NA-induced maximum vasoconstriction was significantly lower in HLB-12 group than that in HB-12 group(p=0.0143).The duration of NA-induced vasoconstriction was shorter in LS-12 group than that in NS-12 group(p=0.0007),it was significantly longer in HS-12 group than that in NS-12(p=0.0010),HB-12(p=0.0191),HLS-12(p=0.0066)and HLB-12 group(p=0.0009).The time of NA-induced maximum vasoconstriction was significantly prolong in HB-12 group than that in HLS-12(p=0.0127)and HLB-12(p=0.0060)group.Comparing the 12-week group with the 6-week intervention group,the duration of NA-induced vasoconstriction was significantly longer in HS-12 group than that in HS-6 group(p=0.0031),and it was sighnificantly longer in HB-12 group than that in HB-6 group(p=0.0019).4.ACh-induced maximum vasodilatation of MSA was significantly higher in LS-12 group than that in NS-12 group(p<0.0001),it was significantly lower in HS-12 group than that in NS-12(p<0.0001),HB-12(p=0.0389),HLS-12(p<0.0001)and HLS-12 group(p<0.0001).ACh-induced maximum vasodilatation of MSA was significantly higher in HLS-12(p=0.0025)and HLB-12 group(p=0.0033)than that in NS-12 group,it was significantly higher in HLS-12(p=0.0390)and HLB-12 group(p=0.0045)than that in HB-12 group.The duration of vasodilatation was significantly shorter in HS-12 group than that in NS-12(p=0.0237),HB-12(p=0.0119)and HLB group(p=0.0128).The start time of ACh-induced vasodilatation was significantly prolong in LS-12 group than that in LS-6 group(p=0.0442).5.The ratio of MSA media thickness to lumen diameter of HS-12 group was significantly higher than that in NS-12(p=0.0005),HB-12(p=0.0408)and HLS-12 group(p=0.0003).The collagen volume fraction was significantly elevated in HS-12 group than that in NS-12(p<0.0001),HB-12(p=0.0004)and HLB-12 group(p<0.0001).6.The results of immunohistochemistry showed that the eNOS expression in the MSA was significantly lower in HS-12 group than that in NS-12(p=0.0042),HLS-12(p=0.0308)and HLB-12 group(p=0.0276).The ACE expression in MSA was significantly higher in HS-12 group than that in NS-12(p<0.0001),HB-12(p=0.0007)and HLS-12 group(p<0.0001).The AT1R expression was significantly lower in HLS-12 group than that in HS-12(p=0.0041)and HLB-12 group(p=0.0064).The AT2R expression was significantly higher in HLS-12 group than that in HS-12 group(p=0.0079).ConclusionsClinical research:1.High sodium intake is a negative predictor for office and home BP target attainment,which is probably due to high-sodium related hyperresponsiveness of arteries to catecholamine.Our findings emphasize the importance of sodium restriction in the treatment of RH.2.High sodium intake is a positive predictor for target organ damage in RH,and diabetes mellitus could aggravate target organ damage.Reducing sodium intake can improve office and home BP control in RH.Animal experiments:1.High sodium intake enhanced the vasoconstrictive function and attenuated the vasodilatative function of MSA in vivo,which could not be significantly ameliorated by benazepril.The results addressed the important role of high sodium intake in the hyperresponsiveness of small artery to catecholamine and impairment of endothelium-independent vasodilatation function in hypertension.2.Change from high to low sodium diet improved the vasoconstrictive and vasodilatative function of mesenteric small vessels in Dahl/SS rats.Our results emphasized the significant role of sodium restriction in overcoming the hyperresponsiveness of small artery to catecholamine and ameliorating endothelium-independent vasodilatation function in hypertension.3.High sodium diet induced mesenteric small artery remodeling in Dahl/SS rats,which maybe ameliorated by benazepril,but that can not reverse by changing to low salt intake.4.High sodium diet could up-regulate ACE and AT1R but down-regulate eNOS expression in MSA of Dahl/SS rats.Low sodium diet could up-regulate eNOS and AT2R expression,and down-regulate ACE and AT1R.The activation of renin-angiotensin system in MSA maybe play an important role in change of NA-induced vasoconstriction and ACh-induced vasodilatation.With the findings of the clinical research and animal experiment,we demonstrated that high sodium intake played important role in the RH,which might be associated with the change of vasoconstriction and vasodilatation in the resistance vessel. |
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