Comparison of L-type and mixed L- and T-type calcium channel blockers on kidney injury caused by deoxycorticosterone-salt hypertension in rats

The efficiency of calcium channel blockers (CCBs) in the treatment of chron ic renal disease (CRD) is controversial. In this study, we investigated whe ther combined T- and L-type CCBs, using mibefradil (30 mg/kg/d), provided s uperior protection versus traditional L-type voltage-gated CCBs, using amlo dipine (10 mg/kg/d), in the deoxycorticosterone acetate (DOCA)-salt model o f high glomerular blood pressure (P-GC) and rapidly developing kidney damag e. After 4 to 5 weeks of DOCA-salt, amlodipine did not reduce proteinuria ( protein, 341 +/- 90 versus 482 +/- 54 mg/24 h; P = not significant) or degr ee of glomerular damage (20% +/- 4% versus 28% +/- 6% damaged glomeruli; P = not significant) compared with untreated rats. Conversely, mibefradil red uced proteinuria and glomerular damage versus untreated DOCA-salt rats (pro tein, 244 +/- 75 mg/24 h; P < 0.02; damaged glomeruli, 11% +/- 3%; P < 0.05 ). Both CCBs had similar antihypertensive actions, returning blood pressure to the untreated sham value. Of note, P-GC also was reduced by a similar e xtent (and to the sham value) with both mibefradil (58 +/- 2 mm Hg; P < 0.0 01) and amlodipine (61 +/- 2 mm Hg; P +/- 0.005) versus untreated DOCA-salt rats (70 +/- 1 mm Hg). This study shows that combined T- and L-type CCBs p rovide superior protection against CRD in the DOCA-salt model compared with L-type CCBs alone. However, this protection was not hemodynamic because si milar systemic and glomerular antihypertensive responses occurred with both mibefradil and amlodipine. Although mibefradil was withdrawn from the mark et because of adverse drug interactions not associated with CCBs, other mix ed channel blockers may provide an alternative or adjunctive therapy to ang iotensin-converting enzyme inhibition in CRD. (C) 2001 by the National Kidn ey Foundation, Inc.