Benidipine, a long-acting calcium-channel blocker, prevents the progression to end-stage renal failure in a rat mesangioproliferative glomerulonephritis.

Abstract

BACKGROUND:

Although the renoprotective effect of calcium-channel blockers (CCBs) has been examined in several models of hypertensive nephropathy, it remains unclear. It also remains to be clarified whether CCBs prevent the progression to end-stage renal failure in chronic progressive glomerulonephritis (GN). A new rat model of progressive mesangioproliferative GN was used to study the effect of benidipine hydrochloride, a long-acting dihydropyridine CCB, on the clinical features and morphological lesions.

METHODS:

This animal model of progressive GN was induced by a single intravenous injection of anti-Thy-1 monoclonal antibody (MoAb 1-22-3) two weeks after unilateral nephrectomy. After 10 weeks of treatment with benidipine (1, 3, and 5 mg/kg body weight, p.o.) or hydralazine (5 mg/kg body weight, p.o.), systolic blood pressure (SBP), urinary protein excretion, creatinine clearance, glomerulosclerosis index, tubulointerstitial lesion index, glomerular cross-sectional area, and glomerular expression of transforming growth factor-beta (TGF-beta) and alpha-smooth muscle actin (alpha-SMA) were measured.

RESULTS:

Untreated rats developed hypertension, massive proteinuria, renal dysfunction, severe glomerular and tubulointerstitial injury, higher glomerular size, and marked glomerular staining for TGF-beta and alpha-SMA, while uninephrectomized control rats did not. Each dose of benidipine and hydralazine equally reduced SBP to uninephrectomized control levels. Three and five mg/kg/day of benidipine increased creatinine clearance, ameliorated glomerular and tubulointerstitial injury, and reduced glomerular staining for TGF-beta and alpha-SMA, but 1 mg/kg/day of benidipine and hydralazine failed. Only a dose of 5 mg/kg/day of benidipine reduced glomerular size, although it did not reduce the size to control levels.

CONCLUSION:

These results indicate that in a rat model of progressive mesangioproliferative GN, benidipine prevents the progression to end-stage renal failure in a dose-dependent manner. This renoprotective action is associated with the suppression of glomerular expression of TGF-beta and alpha-SMA.

• Authors: T Nakamura, J E Obata, M Onitsuka, Y Shimada, Y Yoshida, H Kawachi, F Shimizu
• Journal: Nephron (Nephron) Vol. 86 Issue 3 Pg. 315-26 (Nov 2000) ISSN: 1660-8151 [Print] Switzerland
• PMID: 11096289 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2000 S. Karger AG, Basel

Chemical References

• Actins
• Calcium Channel Blockers
• Dihydropyridines
• Transforming Growth Factor beta
• Vasodilator Agents
• Hydralazine
• benidipine
• Creatinine

Topics

• Actins (analysis)
• Animals
• Blood Pressure
• Body Weight
• Calcium Channel Blockers (pharmacology)
• Creatinine (metabolism)
• Dihydropyridines (pharmacology)
• Disease Models, Animal
• Disease Progression
• Fluorescent Antibody Technique
• Glomerulonephritis, Membranoproliferative (drug therapy, pathology)
• Hydralazine (pharmacology)
• Kidney Failure, Chronic (drug therapy, pathology, prevention & control)
• Kidney Glomerulus (chemistry, pathology)
• Male
• Nephrectomy
• Proteinuria (drug therapy, pathology)
• Rats
• Rats, Wistar
• Transforming Growth Factor beta (analysis)
• Vasodilator Agents (pharmacology)