奥美沙坦对Dahl盐敏感型高血压大鼠盐敏感性的影响

Effects of olmesartan on the salt sensitivity of Dahl salt-sensitive rats

目的探讨血管紧张素受体拮抗剂(ARB)对Dahl盐敏感型高血压(Dahl S)大鼠盐敏感性的影响及其机制。方法实验1:将15只9周雄性Dahl S大鼠随机分为对照组(n=8)和ARB治疗组(n=7)。通过渗透泵用100nmol/(kg·h)的速度分别给对照组和ARB组泵入2.5%碳酸钠或2.5%碳酸钠的奥美沙坦溶液。用无线遥测传送器,连续观察两组大鼠在基线、正常盐(0.5%NaCl)喂食、高盐(8%NaCl)喂食及恢复到正常盐喂食各1周的24h平均动脉压(MAP)的变化。使用24h尿钠排泄和MAP(Na-MAP)关系曲线的斜率值评估盐敏感性。实验2:将24只10周龄雄性Dahl S大鼠随机分为正常盐喂食组,高盐喂食组,正常盐喂食+ARB组和高盐喂食+ARB组,每组6只。使用的饲料和投药剂量与方法和实验1相同。观察7d后,测定大鼠肾脏内氧化应激水平{肾皮质的烟酰胺腺嘌呤二核苷酸磷酸[NAD(P)H]氧化酶活性和p22phox mRNA水平}和24h尿H2O2排泄量。结果实验1中,对照组的MAP在正常盐喂食1周、高盐喂食1周、恢复正常盐喂食1周时比同期ARB治疗组高[分别(124.0±2.0)比(99.1±1.6)、(138.6±2.7)比(127.2±3.6)、(120.7±2.5)比(92.5±2.0)mm Hg,均P<0.05]。对照组Na-MAP曲线斜率与ARB治疗组差异无统计学意义(P>0.05)。实验2中,与正常盐喂食组相比,高盐组的收缩压、肾皮质NAD(P)H氧化酶活性、肾皮质p22phox mRNA相对含量和24h尿H2O2排泄量较高[分别(149.3±7.9)比(120.8±5.1)mm Hg、(347.7±23.6)比(253.2±11.8)CPM×103/mg pro、(0.70±0.08)比(0.53±0.07)p22phox/GAPDH、(151.0±17.9)比(40.2±6.3)nmol/(L·24h)],血浆血管紧张素Ⅱ(AngⅡ)较低[(26.4±4.0)比(49.8±4.1)pmol/L,均P<0.01]。与高盐组比较,高盐+ARB组的收缩压、肾皮质NAD(P)H氧化酶活性、肾皮质p22phox mRNA相对含量、24h尿H2O2排泄量、肾皮质AngⅡ降低[分别(113.7±6.4)比(149.3±7.9)mm Hg、(277.1±19.0)比(347.7±23.6)CPM×103/mg pro、(0.54±0.08)比(0.70±0.08)、(108.4±11.2)比(151.0±17.9)nmol/(L·24h)、(73.1±7.0)比(162.1±15.4)fmol/g tiss],血浆AngⅡ升高[(61.3±5.7)比(26.4±4.0)pmol/L,均P<0.05]。结论无论正常盐还是高盐喂食,奥美沙坦可以明显降低Dahl S大鼠MAP。奥美沙坦可以有效地抑制高盐喂食引起的Dahl S大鼠肾脏内和全身氧化应激水平的增加,同时并不增加Dahl S大鼠的盐敏感性。

Objective To study the effect of the angiotensin receptor blocker （ARB） on the salt sensitivity of blood pressure in Dahl salt-sensitive （Dahl S） rats. Methods Experiment 1, the mean arterial blood pressure （MAP） of Dahl S rats was monitored by radio telemetry and, after baseline measurements, the rats were treated with either vehicle （n=8） or the ARB olmesartan [100 nmol/（kg · h）, subcutaneously （n=7）]. The rats were fed the 0.5% salt diet during the baseline period and the first 7 d of treatment, the diet was then switched to one containing 8 salt for another 7 d, and the rats were returned to the 0.5% salt diet for the final 7 d. Salt sensitivity was indicated by the slope of the Na-MAP relationship. Experiment 2, Dahl S rats were divided into 4 groups： normal diet （0.5 % salt; NS）, 8 % high salt diet （HS）, and NS or HS plus olmesartan groups. On day 7 after the end of the experiment, renal { renal cortical nicotinamide adenine dinucleotide phosphate [NAD（P） H] oxidase activity and p22^phox mRNA levels and urinary （24 h urine H2O2 excretion） oxidative stress levels were measured. Results In the first experiment, the MAPs in control group which were measured at baseline, 7 days＇ after 0.5%salt diet,7 days＇ after 8% salt diet and 7 days＇ after returned 0.5% salt diet were （124.0±2.0）, （138.6±2.7）, （120.7± 2.5）mm Hg respectively while those in ARB group were （99.14±1.6）, （127.2±3.6）, （92.5±2.0）mm Hg. The slope of the Na-MAP relationship showed no significant difference between control group and ARB group （P 〉0.05 ）. In the second experiment, systolic blood pressure（ SBP）, renal cortical NAD（P） H oxidase activity, renal cortical p22^phox mRNA levels, 24 h urine H2O2 excretion [（149.3±7.9） vs （120.8±5.1）mm Hg, （347.7±23.6} vs （253.2±11.8） CPMX 103/mg pro, 0.70±0.08 vs 0. 53±0. 07, （151.0±17.9） vs （40.2±6.3）nmol/（L · 24 h）, all P〈0.01] were significantly increased, and plasma angiotensin Ⅱ concentration （ 26.4 4± 4.0 ） vs （49.8 ± 4.1 ） pmol/L, P〈0.01] was significantly reduced in the HS group compared with the NS group. SBP, renal cortical NAD（P） H oxidase activity, renal cortical p22^phox mRNA levels, 24 h urine H202 excretion, renal cortical angiotensin Ⅱ concentration [（113.7±6.4） vs （149.3±7.9）mm Hg, （277.1±19.0） vs （347.7±23.6） CPMN 103/mg pro, （0.54±0.08） vs （0.70±0.08）, （108.4±11.2） vs （151.0±17.9）nmol/（L · 24 h）, （73.1±7.0） vs （162.1± 15.4）fmol/g tissue, all P〈0.05） were significantly reduced, and plasma angiotensin Ⅱ concentration [（61.3±5.7） vs （26.4±4.0） pmol/L, P〈0.05] was significantly increased in the HS plus ARB group compared with the HS group. Conclusion We have demonstrated that ARB olmesartan can significantly reduce blood pres- sure, even for the high salt diet, and does not affect salt sensitivity in Dahl S rats. The effects of it could be in part due to renal cortical oxidative stress levels.