Control of Hypertension by Yerapamil Enhances Renal Damage in a Rat Remnant Kidney Model

Abstract

Abstract. 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/jumol creatinine before death/sacrifice) than in the Vera low and control groups (3.08 ± 0.91 and 3.60 ± 0.71 mg//imol creatinine, respectively, P < 0.05 vs Vera high), and signifiCorrespondence and offprint requests to: Professor F. P. Brunner, Kantonsspital Basel, 4031 Basel, Switzerland. cantly more animals died during the observation period in the Vera high compared to the control group (6 of 20 vs lof 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.

Antihypertensive treatment of patients with proteinuric renal diseases: Risks or benefits of calcium channel blockers?

“…Brunner et al studied the effects of different dosages of verapamil in the rat remnant kidney model, and found that an intermediate dose resulted in minor effects on blood pressure, more proteinuria and more glomerulosclerosis. The higher dose, which lowered blood pressure more effectively, did not significantly increase proteinuria nor glomerulosclerosis [46,47]. Dworkin used both nifedipine and amlodipine in the uninephrectomized DOCA-salt rat model and in the uninephrectomized spontaneously hypertensive rat (SHR) rat [27,28,53].…”

“…One factor that may explain the differences in outcome of the various studies is the interval between the induction of injury and the start of the treatment. In most studies in Table 1 (the protective studies) treatment was started immediately after induction of the injury, whereas in the negative studies the start of treatment was often delayed [46,47,51,52]. The importance of the timing of the start of treatment is highlighted by the studies of Dworkin.…”

Calcium Channel Blockers Inhibit Proliferation and Matrix Production in Rat Mesangial Cells: Possible Mechanism of Suppression of AP-1 and CREB Activities

“…While initial experiments showed that CCBs did not improve renal survival in rats with subtotal nephrectomy [3, 4], it has been reported recently that both CCBs and ACE inhibitiors attenuate glomerular injury in subtotally nephrectomized rats [5]as well as in uninephrectomized spontaneously hypertensive rats [6]. CCBs have been shown to attenuate a deterioration in renal function and to reduce proteinuria in patients with nondiabetic renal insufficiency [7]and in those with diabetic nephropathy [8].…”