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Benidipine inhibits both L- and T-type Ca channels, and has been shown to dilate the efferent arterioles as effectively as the afferent arterioles. In this study, we conducted an open-label and randomized trial to compare the effects of benidipine with those of amlodipine on blood pressure (BP), albuminuria and aldosterone concentration in hypertensive patients with mild-to-moderate stage chronic kidney disease (CKD). Patients with BP ≥ 130/80 mm Hg, with estimated glomerular filtration rate (eGFR) of 30-90 ml min(-1) per 1.73 m(2), and with albuminuria>30 mg per g creatinine (Cr), despite treatment with the maximum recommended dose of angiotensin II receptor blockers (ARBs) were randomly assigned to two groups. Patients received either of the following two treatment regimens: 2 mg per day benidipine, which was increased up to a dose of 8 mg per day (n=52), or 2.5 mg per day amlodipine, which was increased up to a dose of 10  mg per day (n=52). After 6 months of treatment, a significant and comparable reduction in the systolic and diastolic BP was observed in both groups. The decrease in the urinary albumin to Cr ratio in the benidipine group was significantly lower than that in the amlodipine group. Although plasma renin activity was not different in the two groups, plasma aldosterone levels were significantly decreased in the benidipine group. Moreover, urinary Na/K ratio was significantly decreased in the benidipine group but remained unchanged in the serum. It may be concluded that benidipine results in a greater reduction of plasma aldosterone and albuminuria than amlodipine, and that these effects are independent of BP reduction.

The present study tested the effects of valsartan, an angiotensin II receptor blocker, on the progression of renal insufficiency in patients with nondiabetic renal diseases. The study subjects were 22 patients with nondiabetic renal diseases whose serum creatinine (Cr) ranged from 1.5 to 3.0 mg/dl. Valsartan (40-80 mg) or placebo was given once daily for 1 year each in a random crossover manner. In both periods, antihypertensive medications were titrated when the blood pressure was not lower than 140/90 mmHg. Blood sampling and urinalysis were performed bimonthly throughout the study periods. The average blood pressure was comparable between the valsartan and the placebo periods (130 +/- 9/86 +/- 6 vs. 131 +/- 8/86 +/- 6 mmHg). Serum Cr significantly increased from 1.9 +/- 0.5 to 2.3 +/- 0.8 mg/dl (p < 0.001) during the placebo period, but the change was insignificant in the valsartan period (2.1 +/- 0.6 to 2.2 +/- 0.9 mg/dl). The slope of decrease in the reciprocal of serum Cr was steeper in the placebo period than in the valsartan period (-0.064 +/- 0.070/year vs. -0.005 +/- 0.050/year, p < 0.01). During the valsartan period, urinary protein excretion was less than that during the placebo period (0.75 +/- 0.73 vs. 1.24 +/- 0.92 g/g Cr, p < 0.001). Serum K was significantly higher in the valsartan period than in the placebo period (4.6 +/- 0.5 vs. 4.4 +/- 0.5 mEq/l, p < 0.05); however, no patients discontinued taking valsartan as a result of hyperkalemia. It is possible that long-term treatment with an angiotensin II receptor blocker, valsartan, is effective at retarding the deterioration of renal function in patients with nondiabetic renal disease by a mechanism independent of blood pressure reduction.

Proteoglycans are an important component of the extracellular matrix, and are thought to play multiple roles not only in kidney remodeling, but also in regulating glomerular permeability, and in modulating the activity of other cytokines and growth factors. The aim of this study was to examine the gene expressions of proteoglycan core proteins in hypertensive rat kidneys, and their modulation by AT1 receptor antagonist. SHRSP/Izm rats and normotensive control WKY/Izm rats on a normal salt diet were treated with or without the AT1 receptor antagonist candesartan cilexetil (1 mg/kg/day) from 10 weeks to 22 weeks. At the end of the treatment period, renal tissue was excised, and gene expressions of the proteoglycan core proteins versican, perlecan, decorin, and biglycan were examined by Northern blot analysis and RT-PCR. Treatment with candesartan cilexetil caused significant decreases in blood pressure and amelioration of proteinuria and renal histological scores in the SHRSP/Izm rats. Compared to WKY/Izm rats, expression of biglycan mRNA showed a small increase in SHRSP/Izm rats which did not attain statistical significance. On the other hand, treatment with candesartan caused significant reductions in biglycan and decorin mRNA in the SHRSP/Izm rats. In contrast, the level of versican mRNA appeared to be increased after candesartan treatment. These results suggest that treatment with AT1 receptor antagonist was associated with diverse changes in renal proteoglycan gene expression in SHRSP/Izm rats. These changes could contribute to the beneficial effects of AT1 receptor antagonist on tissue remodeling and inhibition of disease progression in hypertensive rat kidneys.

Angiotensin converting enzyme inhibitors (ACEI) are known to inhibit the progression of established renal failure. The aim of this study was to compare the efficacy of an ACEI and an AT1 receptor antagonist (AT1R-Ant) in preventing the development of renal disease, at an early stage of hypertensive nephrosclerosis. SHRSP/Izm rats (n = 61) were treated from 10 wk until 22 wk with the ACEI delapril (40 mg/kg/d) or the AT1R-Ant candesartan cilexetil (1 mg/kg/d). Proteinuria, and structural/ultrastructural changes were assessed at 14 and 22 wk. Treatment with either agent resulted in reductions in blood pressure and cardiovascular hypertrophy. Neither proteinuria nor major renal histological changes were evident at 14 wk. At 22 wk, however, proteinuria accompanied by nephrosclerotic changes was seen in the untreated SHRSP/Izm. Treatment with either ACEI or AT1R-Ant resulted in similar reductions in proteinuria (untreated, 32.2 +/- 7.4; delapril-treated, 5.5 +/- 1.2; candesartan-treated, 3.9 +/- 0.3 mg/100 g/d). Prominent sclerosis of small-to-medium sized renal arteries was seen in the untreated SHRSP/Izm at 22 wk, but was similarly attenuated by the ACEI and AT1R-Ant. The glomerular ultrastructure was comparable between the two groups. No significant changes in renal AT1a or AT1b receptor subtype mRNA expression were seen throughout the course of the study. In contrast, a decrease in AT2 receptor mRNA was seen in the drug-treated groups at 14 wk but not at 22 wk. These results suggest that both ACEI and AT1R-Ant have similar efficacy in attenuating the onset of renal injury in early hypertensive nephrosclerosis, and that treatment with either agent is associated with a transient decrease in AT2 receptor mRNA expression.