Comparative effects of selective T- and L-type calcium channel blockers inthe remnant kidney model

We have previously reported that the dihydropyridine L-type calcium channel blockers (CCBs) have an adverse impact on glomerulosclerosis (GS) in the r emnant kidney model despite significant blood pressure (BP) reduction, beca use of the concurrent deleterious effects on renal autoregulation. The effe cts of the CCB mibefradil, which is approximate to 10-fold more selective f or T- than L-type channels, were compared with the L-type selective amlodip ine. One week after 5/6 ablation, rats were left untreated or received mibe fradil or amlodipine. Systolic BP was monitored by continuous radiotelemetr y. At 7 weeks, proteinuria and percent GS were quantitated. Average BP was significantly and comparably reduced after mibefradil (141 +/-3 mm Hg) and amlodipine (143 +/-5 mm Hg) compared with untreated rats (188 +/-5 mm Hg). Despite the reduction in BP, proteinuria and percent GS in the mibefradil- or amlodipine-treated groups were not significantly different from those in the untreated rats. Excellent correlations were observed between BP and GS in each group (r=0.74 to 0.85, P<0.02). However, the slope of the relation ship between GS and BP (increase in percent GS/mm Hg increase in average BP ) was made significantly steeper by bath mibefradil (2.7+0.6) and amlodipin e (1.9+0.6) as compared with untreated rats (0.7<plus/minus>0.2; P<0.01). T hus, at any given BP elevation, greater GS was seen in mibefradil- and amlo dipine-treated rats as compared with untreated rats. Additional studies per formed at 3 weeks after renal ablation showed that the ability to autoregul ate renal blood flow, already impaired in untreated rats, was essentially a bolished by both mibefradil and amlodipine, thus providing an explanation f or the shift in the slope of the relationship between BP and GS. These data indicate that CCBs with selectivity for either the T- or L-type calcium ch annel fail to protect against GS despite significant BP reductions because of the similar adverse effects on renal autoregulation and BP transmission.