Ka. Griffin et al., Class differences in the effects of calcium channel blockers in the rat remnant kidney model, KIDNEY INT, 55(5), 1999, pp. 1849-1860
Background. Controversy persists as to the existence of class differences b
etween calcium channel blockers (CCBs) in their ability to provide renoprot
ection and as to potential mechanisms involved.
Methods. Rats with 5/6 renal ablation were left untreated or received dilti
azem, verapamil, or felodipine after the first week, and the relationship b
etween continuous radiotelemetrically measured blood pressure (BP) and glom
erulosclerosis (GS) was assessed at seven weeks. Additionally, the effects
of these CCBs on renal autoregulation and hypertrophy were examined at thre
e weeks after renal ablation.
Results. Although an excellent linear correlation was observed between the
average BP levels and GS in all groups (r = 0.75 to 0.84, P < 0.01), signif
icant protection was not achieved with any of the CCBs, but for different r
easons. The antihypertensive effects of diltiazem were not sustained beyond
the second week. Verapamil significantly reduced the average BP (144 +/- 4
mm Hg vs. 181 +/- 8 in untreated rats) but shifted the slope of the relati
onship between BP and GS (increase in percentage GS/mm Hg increase in avera
ge systolic BP) to the left (Ic intercept 121 vs. 144 mm Hg for untreated r
ats, P < 0.01) so that GS was not reduced. Felodipine also significantly re
duced the average BP (144 +/- 3 mm Hg) and shifted the slope to the left (x
intercept 123 mm Hg), but additionally made the slope steeper (2.3 +/- 0.5
vs. 0.82 +/- 0.2 in untreated rats). Because of these differing effects on
the relationship between BP and GS, the rank order of GS for any given BP
elevation was as follows: felodipine > verapamil > diltiazem = untreated. F
elodipine, but not verapamil or diltiazem, caused additional impairment of
the already impaired renal autoregulation in untreated rats, thereby explai
ning its adverse effects on GS. By contrast, the adverse effects of verapam
il on GS were attributable to the greater amplitude of BP fluctuations that
was observed in the verapamil-treated rats such that for any given average
BP, these rats were exposed to greater peak pressures as compared with the
other groups. None of the CCBs had a significant effect on glomerular hype
rtrophy.
Conclusions. These class differences between CCBs in their relative impact
on systemic BP profiles, renal autoregulation, and glomerular pressure tran
smission may have clinically significant implications and may account for t
he variable glomeruloprotection that has been observed with these agents in
both experimental models and in humans.