Hemodynamic and hormonal changes to dual renin-angiotensin system inhibition in experimental hypertension.
Hemodynamic and hormonal changes to dual renin-angiotensin system inhibition in experimental hypertension.
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DOI：
10.1161/hypertensionaha.112.201889
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发表时间：
2013-02
期刊：
影响因子：
--
通讯作者：
Ferrario CM
中科院分区：
文献类型：
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作者：
Moniwa N;Varagic J;Ahmad S;VonCannon JL;Simington SW;Wang H;Groban L;Brosnihan KB;Nagata S;Kato J;Kitamura K;Gomez RA;Lopez ML;Ferrario CM
我们检测了缬沙坦、阿利吉仑或两种药物联合应用对同种mRen 2型Lewis高血压大鼠循环、心脏和肾脏的肾素-血管紧张素系统（RAS）的降压作用。通过渗透微型泵，50 mg/kg/天; n=10），或缬沙坦（30 mg/kg/天）与阿利吉仑（50 mg/kg/天; n=10）组合。在治疗前和治疗两周期间通过遥测测量动脉压和心率;收集躯干血、心脏、尿液和肾脏用于测量RAS组分。缬沙坦、阿利吉仑单药治疗可降低动脉压和左心室重量/胫骨长度比，联合治疗可进一步降低动脉压和左心室重量/胫骨长度比。缬沙坦可降低尿蛋白排泄，联合用药可进一步降低尿蛋白排泄。缬沙坦诱导的血浆血管紧张素II的增加被阿利吉仑逆转，并被联合用药部分抑制。阿利吉仑引起的血浆Ang-（1-7）水平下降在联合用药组恢复。联合治疗可增加肾脏Ang-（1-12），而加入阿利吉仑可逆转缬沙坦介导的尿肌酐增加。联合治疗的抗高血压和抗蛋白尿作用与肾实质疾病的显著恶化和肾小管周围纤维化增加相关。数据显示，尽管血压、心室质量和蛋白尿的替代终点有所改善，但血管紧张素II受体和肾素活性的双重阻断伴随着肾实质疾病的恶化，反映了由于血管紧张素II引起的肾小管肾小球反馈丧失所致的肾稳态应激反应。
We examined the antihypertensive effects of valsartan, aliskiren or both drugs combined on circulating, cardiac and renal components of the renin-angiotensin system (RAS) in congenic mRen2.Lewis hypertensive rats assigned to: vehicle (n=9), valsartan (via drinking water, 30 mg/kg/day; n=10), aliskiren (s.c. by osmotic mini-pumps, 50 mg/kg/day; n=10), or valsartan (30 mg/kg/day) combined with aliskiren (50 mg/kg/day; n=10). Arterial pressure and heart rate were measured by telemetry before and during two weeks of treatment; trunk blood, heart, urine and kidneys were collected for measures of RAS components. Arterial pressure and left ventricular weight/tibia length ratio were reduced by monotherapy of valsartan, aliskiren and further reduced by the combination therapy. Urinary protein excretion was reduced by valsartan and further reduced by the combination. The increases in plasma Ang II induced by valsartan were reversed by the treatment of aliskiren and partially suppressed by the combination. The decreases in plasma Ang-(1–7) induced by aliskiren recovered in the combination group. Kidney Ang-(1–12) was increased by the combination therapy while the increases in urinary creatinine mediated by valsartan were reversed by addition of aliskiren. The antihypertensive and antiproteinuric actions of the combined therapy were associated with marked worsening of renal parenchymal disease and increased peritubular fibrosis. The data show that despite improvements in the surrogate endpoints of blood pressure, ventricular mass and proteinuria, dual blockade of Ang II receptors and renin activity is accompanied by worsening of renal parenchymal disease reflecting a renal homeostatic stress response due to loss of tubuloglomerular feedback by Ang II.