Class differences in the effects of calcium channel blockers in the rat remnant kidney model

Abstract

Background: Controversy persists as to the existence of class differences between calcium channel blockers (CCBs) in their ability to provide renoprotection and as to potential mechanisms involved.

Methods: Rats with 5/6 renal ablation were left untreated or received diltiazem, verapamil, or felodipine after the first week, and the relationship between continuous radiotelemetrically measured blood pressure (BP) and glomerulosclerosis (GS) was assessed at seven weeks. Additionally, the effects of these CCBs on renal autoregulation and hypertrophy were examined at three 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), significant protection was not achieved with any of the CCBs, but for different reasons. 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 relationship between BP and GS (increase in percentage GS/mm Hg increase in average systolic BP) to the left (x intercept 121 vs. 144 mm Hg for untreated rats, P < 0.01) so that GS was not reduced. Felodipine also significantly reduced 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. Felodipine, but not verapamil or diltiazem, caused additional impairment of the already impaired renal autoregulation in untreated rats, thereby explaining its adverse effects on GS. By contrast, the adverse effects of verapamil 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 hypertrophy.

Conclusions: These class differences between CCBs in their relative impact on systemic BP profiles, renal autoregulation, and glomerular pressure transmission may have clinically significant implications and may account for the variable glomeruloprotection that has been observed with these agents in both experimental models and in humans.