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Mibefradil prevents L-NAME-exacerbated nephrosclerosis in spontaneously hypertensive rats

Qiu, Changbin1; Bruneval, Patrick2; Roeckel, Andree1; Heudes, Didier2; Van Huyen, Jean-Paul Duong2; Roux, Sebastien1,3

Original Articles
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Objective To determine the potential renal protective effects of a novel calcium channel blocker mibefradil in chronic renal failure.

Method We compared the long-term effects of mibefradil with an angiotensin-converting enzyme inhibitor cilazapril on blood pressure, proteinuria, renal function and histological alterations in N-nitro-L-arginine methylester (L-NAME)-treated spontaneously hypertensive rats (SHR). Three groups of SHR were studied for 45 days: group 1 (n = 14), treated with L-NAME only (50 mg/l in the drinking water); group 2 (n = 15) L-NAME plus co-treatment with mibefradil (30 mg/kg per day); group 3 (n = 15), L-NAME plus co-treatment with cilazapril (10 mg/kg per day).

Results Both mibefradil and cilazapril attenuated the increased systolic blood pressure, and prevented the development of proteinuria and the decreased creatinine clearance (Ccr) seen at day 42 in the group treated with L-NAME alone. Notably, mibefradil had similar effects to cilazapril on proteinuria and Ccr, despite a reduced anti-hypertensive effect. All animals receiving mibefradil cotreatment remained alive throughout the experiment, whereas the mortality rate was 43% in SHR treated with L-NAME alone. Both mibefradil and cilazapril completely prevented renal structural damage as assessed by scoring glomerular, tubulo-interstitial and vascular lesions.

Conclusions Our data show that mibefradil prevented the development of hypertension and proteinuria, renal functional impairment and nephrosclerosis, and also improved animal survival. The renal protective effects of mibefradil were at least equivalent to those of an ACE inhibitor in this animal model of chronic renal failure.

1Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland

2INSERM U430, Hôpital Broussais, Paris, France.

3Correspondence and requests for reprints to Dr Sebastien Roux, Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, CH-4070 Basel, Switzerland. Tel: +41 61 688 5235; fax: +41 61 688 2438; email: sebastien.roux@roche.com

Received 26 February 1999 Revised 2 June 1999 Accepted 7 July 1999

© 1999 Lippincott Williams & Wilkins, Inc.