Olmesartan reduces angiotensin II without affecting ACE activity in kidneys of mRen2.Lewis rats

Abstract

We investigated the possibility that the antihypertensive actions of the angiotensin II (Ang II) receptor blocker –olmesartan medoxomil– may in part be associated with a functional inhibition of angiotensin converting enzyme (ACE) activity due to increased Ang‐(1–7) production in the absence of changes in plasma Ang II (Ichikawa, 2001; Agata, 2006). Experiments were performed in 10 – 11 week old mRen2.Lewis congenic hypertensive rats administered either a saline vehicle (VEH, n=7) or olmesartan (OLM: 0.5 mg/kg/day for 6 weeks; n=7) by subcutaneous implantation of osmotic minipumps. Plasma and kidney tissue Ang peptides and serum and kidney ACE activity were measured at the completion of the experiments. VEH OLM SAP (mm Hg) 208 ± 3 99 ± 3* Kidney cortex Ang peptides (fmol/mg) Ang I 7.6 ± 0.9 16.7±2.2* Ang II 15.9±1.6 6.3±0.6* Ang‐(1–7) 10.3±1.6 7.71±1.5 ACE activity (nmol/mg/min) 1.9±0.7 2.4±0.9 Plasma/Serum Ang peptides (fmol/ml) Ang I 92±6 565 ± 77* Ang II 31±5 254 ± 43* Ang‐(1–7) 27±4 60 ± 5* ACE activity (nmol/ml/min) 69±5 77 ± 1 SAP= Systolic Arterial Pressure; p<0.05 Our results support the concept that the reduction in Ang II kidney content may contribute to the protective effects of olmesartan on renal structure and function. We also provide evidence for independent regulation of Ang II between plasma and kidney tissue in response to AT1 blockade. The absence of changes in ACE activity suggests no measurable effect of olmesartan on ACE activity. This work is supported by an unrestricted grant from Daiichi Sankyo, Inc.