Mibefradil prevents L-NAME-exacerbated nephrosclerosis in spontaneously hypertensive rats.
OBJECTIVE
To determine the potential renal protective effects of a novel calcium channel blocker mibefradil in chronic renal failure.


METHODS
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 antihypertensive effect All animals receiving mibefradil co-treatment 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.
Qiu
C
C
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Bruneval
P
P
Roeckel
A
A
Heudes
D
D
Duong Van Huyen
J P
JP
Roux
S
S
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D004336:Drug Antagonism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology; D020748:Mibefradil / Q000494:pharmacology* / Q000627:therapeutic use; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity*; D009400:Nephrosclerosis / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR
D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D020748:Mibefradil; D009569:Nitric Oxide; D019331:NG-Nitroarginine Methyl Ester