CONTROL OF HYPERTENSION BY VERAPAMIL ENHANCES RENAL DAMAGE IN A RAT REMNANT KIDNEY MODEL

The effect of calcium channel blockers on the progression of renal failure is controversial. In contrast with earlier studies, we recently reported that moderately large doses of verapamil significantly accelerated chronic renal failure in the rat remnant kidney model [1]. Studies reporting beneficial effects of verapamil were characterised by a much lower dose of verapamil and by the start of treatment immediately after renal ablation, which potentially interfered with the initial phase of remnant kidney hypertrophy. We therefore studied the effects of a high, fully antihypertensive oral dose of verapamil (100-150 mg/kg/per day; group Vera high) and a low, haemodynamically almost ineffective dose (10-15 mg/kg per day; group Vera low), on the progression of chronic renal failure in female Wistar rats with 5/6 nephrectomy. The treatment was started no earlier than 5 weeks after renal ablation, and matched groups of 20 animals were followed for 16 weeks thereafter. High-dose verapamil reduced systolic blood pressure to median values of 130-140 mmHg throughout the experimental period, whereas blood pressure in Vera low animals remained elevated at median values of 165-172 mmHg similar to non-treated rats with 172-185 mmHg median systolic blood pressure. Despite control of hypertension, proteinuria increased more rapidly and to more elevated values in the Vera high animals (5.98 +/- 0.91 mg/mu-mol creatinine before death/sacrifice) than in the Vera low and control groups (3.08 +/- 0.91 and 3.60 +/- 0.71 mg/mu-mol creatinine, respectively, P < 0.05 vs Vera high), and significantly more animals died during the observation period in the Vera high compared to the control group (6 of 20 vs 1 of 20, P < 0.05). Kidney remnants were larger in the Vera high group, mainly due to tubulointerstitial changes with filling of dilated tubular lumina with proteinaceous casts. Mean glomerular diameter did not differ between groups, and the percentage of glomeruli with segmental or global glomerulosclerosis was not significantly increased in the Vera high group. It is concluded that chronic high-dose verapamil therapy in the 5/6 nephrectomy model, albeit effective in controlling hypertension, is deleterious to renal function when remnant hypertrophy has previously been allowed to occur. A low, haemodynamically barely effective, dose of verapamil fails to alter the course of renal failure in this setting.