Schmerbach K, Kalk P, Wengenmayer C, Lucht K, Unger T, Hocher B, Thoene-Reineke C
Center for Cardiovascular Research (CCR)/Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Germany.
Clin Lab. 2012;58(7-8):625-33.
The ONTARGET trial revealed an association of ACEI/ARB combination treatment (telmisartan and ramipril) with adverse renal outcome versus respective monotherapy; preclinical evidence regarding renal outcome in ACEI/ARB combination treatment is scarce.
Spontaneously hypertensive stroke prone rats (SHR-SP) rats on a salt-rich diet were randomly allocated to 4 groups: SHR (untreated, n = 24), SHR + telmisartan (SHR-T, 2.39 +/- 0.69 mg/kg bw; n = 27), SHR + ramipril (SHR-R, 6.28 +/- 3.48 mg/kg bw; n = 27) and combination treatment (SHR-TR, 0.51 +/- 0.14 mg/kg bw; same dose for telmisartan and ramipril; n = 26). Study duration was 12 weeks, blood pressure was assessed weekly and doses were adjusted to maintain equal blood pressure. Finally, blood and urine samples were obtained and kidneys were harvested for histological studies.
Blood pressure in untreated rats rose to a maximum of 239 mmHg, whereas in all treatment groups it remained stable between 140 and 150 mmHg. Mortality was 50% in the untreated group, whereas all treatment groups survived completely. Renal function--as indicated by plasma urea and cystatin c--was significantly worse in SHR-TR animals compared to all other groups. With plasma creatinine a similar trend was observed. All treatment options significantly decreased albuminuria. Renal glomerulosclerosis was decreased by monotherapy, whereas combination therapy failed to have a significant effect. Interstitial fibrosis was decreased to a similar extent by all treatment options.
ACEI/ARB combination treatment failed to render significant additional benefits on renal outcome in hypertensive rats when compared to monotherapy. Instead our data indicate that dual RAAS blockade might have an adverse effect on kidney function and histology when compared to monotherapy in salt-loaded SHR-SP.
ONTARGET试验显示，与各自的单一疗法相比，ACEI/ARB联合治疗（替米沙坦和雷米普利）与不良肾脏结局相关；关于ACEI/ARB联合治疗肾脏结局的临床前证据很少。
将高盐饮食的自发性高血压脑卒中倾向大鼠（SHR-SP）随机分为4组：SHR（未治疗，n = 24）、SHR + 替米沙坦（SHR-T，2.39 ± 0.69 mg/kg体重；n = 27）、SHR + 雷米普利（SHR-R，6.28 ± 3.48 mg/kg体重；n = 27）和联合治疗组（SHR-TR，0.51 ± 0.14 mg/kg体重；替米沙坦和雷米普利剂量相同；n = 26）。研究持续时间为12周，每周评估血压，并调整剂量以维持血压相等。最后，采集血液和尿液样本，并摘取肾脏进行组织学研究。
未治疗大鼠的血压最高升至239 mmHg，而所有治疗组的血压在140至150 mmHg之间保持稳定。未治疗组的死亡率为50%，而所有治疗组均完全存活。与所有其他组相比，SHR-TR组动物的肾功能（以血浆尿素和胱抑素c表示）明显更差。血浆肌酐也观察到类似趋势。所有治疗方案均显著降低蛋白尿。单一疗法可减轻肾小球硬化，而联合疗法未能产生显著效果。所有治疗方案均使间质纤维化减轻至相似程度。
与单一疗法相比，ACEI/ARB联合治疗未能为高血压大鼠的肾脏结局带来显著的额外益处。相反，我们的数据表明，与盐负荷SHR-SP的单一疗法相比，双重RAAS阻断可能对肾功能和组织学产生不利影响。
