Comparative effects of selective T- and L-type calcium channel blockers in the 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 remnant kidney model despite significant blood pressure (BP) reduction, because of the concurrent deleterious effects on renal autoregulation. The effects of the CCB mibefradil, which is approximately 10-fold more selective for T- than L-type channels, were compared with the L-type selective amlodipine. One week after 5/6 ablation, rats were left untreated or received mibefradil or amlodipine. Systolic BP was monitored by continuous radiotelemetry. 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 relationship between GS and BP (increase in percent GS/mm Hg increase in average BP) was made significantly steeper by both mibefradil (2.7+0.6) and amlodipine (1.9+0.6) as compared with untreated rats (0.7+/-0.2; P<0.01). Thus, at any given BP elevation, greater GS was seen in mibefradil- and amlodipine-treated rats as compared with untreated rats. Additional studies performed at 3 weeks after renal ablation showed that the ability to autoregulate renal blood flow, already impaired in untreated rats, was essentially abolished by both mibefradil and amlodipine, thus providing an explanation for 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 channel fail to protect against GS despite significant BP reductions because of the similar adverse effects on renal autoregulation and BP transmission.
Griffin
K A
KA
Departments of Medicine, Loyola University Medical Center and Hines Veterans Administration Hospital, Maywood, IL 60153, USA.
Picken
M
M
Bakris
G L
GL
Bidani
A K
AK
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000378:metabolism*; D004095:Dihydropyridines / Q000494:pharmacology; D006706:Homeostasis; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020748:Mibefradil / Q000494:pharmacology*; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D004095:Dihydropyridines; D020748:Mibefradil; C038806:1,4-dihydropyridine