The N- and L-Type Calcium Channel Blocker Cilnidipine Suppresses Renal Injury in Dahl Rats Fed a High-Sucrose Diet, an Experimental Model of Metabolic Syndrome

Konda, Tomoyuki; Enomoto, Azusa; Matsushita, Junko; Takahara, Akira; Moriyama, Toshiki

doi:10.1159/000085713

Cited by 48 publications

(50 citation statements)

References 82 publications

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“…A recent study reported that cilnidipine attenuated interstitial fibrosis, ectodermal dysplasia-1-positive cell infiltration and albuminuria in Dahl salt-sensitive rats fed a high-sucrose diet, which mimics metabolic syndrome, whereas amlodipine had no effect on these parameters. 33 This study extended these findings to show that cilnidipine significantly attenuated renal elevation of collagen I/IV and TGF-b mRNA levels and normalized creatinine clearance, as well as serum creatinine and blood urea nitrogen in the DOCA-salt hypertensive rats. Thus, our results, taken together with the previous reports, strongly support the idea that the L/N-type calcium channel blocker cilnidipine would exhibit beneficial effects against renal injury related to hypertension.…”

Section: Discussionsupporting

confidence: 56%

L/N-type calcium channel blocker cilnidipine ameliorates proteinuria and inhibits the renal renin–angiotensin–aldosterone system in deoxycorticosterone acetate-salt hypertensive rats

et al. 2011

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Cilnidipine, an N/L-type calcium channel blocker, has been reported to inhibit sympathetic nerve activity and has a greater renoprotective effect than L-type calcium channel blockers. To investigate the hypothesis that cilnidipine might ameliorate advanced hypertensive nephropathy and inhibit the renal renin-angiotensin-aldosterone system, cilnidipine (1 mg per kg per day) or amlodipine (1 mg per kg per day) was administered to uninephrectomized deoxycorticosterone (DOCA)-salt hypertensive rats (DOCA-salt) for 4 weeks by gavage. Although the blood pressure in the DOCA-salt group was higher than that of control, neither cilnidipine nor amlodipine had any effect on the increase in blood pressure in the DOCA-salt group. The DOCA (40 mg per kg per week, subcutaneously (s.c.)) and salt (1% NaCl in drinking water) treatment significantly aggravated the levels of urinary protein excretion and creatinine clearance and increased glomerulosclerosis and collagen deposition in the tubulointerstitial area of the kidney. These effects were attenuated by cilnidipine treatment. Reverse transcription-polymerase chain reaction analysis revealed that the renal expression of mRNA for collagen I/IV and transforming growth factor-b was enhanced in the DOCA-salt group and that the overexpression of these molecules was suppressed by cilnidipine. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived superoxide production in the kidney and urinary norepinephrine excretion, which were enhanced in the DOCA-salt group, were suppressed by cilnidipine. Cilnidipine also decreased the activity and expression of angiotensin-converting enzyme (ACE) and the aldosterone concentration in the renal homogenate. Although neither cilnidipine nor amlodipine had any effect on the increased blood pressure in the DOCA-salt group, these renal changes were not induced by treatment with amlodipine. In conclusion, cilnidipine inhibited renal dysfunction, sympathetic nerve activity and renal renin-angiotensin-aldosterone system in the DOCA-salt group.

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Section: Discussionsupporting

confidence: 56%

L/N-type calcium channel blocker cilnidipine ameliorates proteinuria and inhibits the renal renin–angiotensin–aldosterone system in deoxycorticosterone acetate-salt hypertensive rats

et al. 2011

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“…Amlodipine has been shown to increase renal blood flow without causing increase in GFR, and is expected to improve long-term prognosis. Cilnidipine has already demonstrated renoprotective effect in hypertensive animal models [18]. and similar effect was reported in human hypertensive non-CKD subjects [19,20].…”

Section: Fig (1)supporting

confidence: 69%

Change of Glomerular Hemodynamics in Patients with Advanced Chronic Kidney Disease after Cilnidipine Therapy

Satomura¹,

Fujita²,

Fuke³

et al. 2009

TOCCHEMJ

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Cilnidipine, a dual calcium channel antagonist, is assumed to regulate hypertension via N-and L-type calcium channel. The N-type calcium channel is associated with sympathetic nerve activation. This effect may improve the glomerular hemodynamics in the injured nephron, and may mitigate the progression of renal injury. To clarify the effect of cilnidipine in instances of already existing decreased renal blood flow, we examined the alteration of renal hemodynamics before and after cilnidipine therapy in patients with advanced chronic kidney disease (CKD). Cilnidipine was administrated daily to 17 CKD patients with hypertension for 12 months. Another 16 patients were similarly administered amlodipine during this study, a long-acting L-type calcium channel antagonist has also been shown to be renoprotective. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and protein excretion in 24-hour accumulated urine were measured at the start and end of the study. The parameters of renal hemodynamics were calculated by Gomez's estimation equation. Systolic blood pressure decreased to 80 % of the level at the beginning of the study, and ERPF increased to 127 % of the level at baseline. Glomerular capillary pressure on single nephron was reduced to 90 %, although total GFR decreased within the non-statistical change. Especially, renal vascular resistance ratio (RA/RE) on single nephron improved to 120 %. Cilnidipine improves ERPF and glomerular hypertension without worsening total renal function. N-and L-type calcium channel antagonist is effective and safe for patients with advanced CKD as a result of improvement of glomerular capillary resistance.

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“…Our results are in agreement with those of previous studies, showing that cilnidipine had greater antiproteinuric effects than amlodipine when used in combination therapy. 5,8 The Cilnidipine vs. Amlodipine Randomized Trial for Evaluation in Renal Disease study showed that cilnidipine was more beneficial than amlodipine in hypertensive patients. 7 Besides RAS inhibition, strict control of BP is considered important for preventing the progression of kidney disease.…”

Section: Discussionmentioning

confidence: 99%

“…3,6 Furthermore, cilnidipine was shown to be more beneficial than amlodipine in combined treatment for hypertensive patients with kidney disease and significant proteinuria who were receiving treatment with a renin-angiotensin system (RAS) inhibitor. 7 The beneficial effect of cilnidipine might be attributable to the inhibition of renal sympathetic nerve activity 8 and reduction of glomerular hypertension (because of the vasodilation of efferent arterioles), which are consequences of the N-type calcium channel blockade. However, the precise mechanism underlying the renoprotective effect of cilnidipine remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Renoprotective and antioxidant effects of cilnidipine in hypertensive patients

Soeki

Kitani²,

Kusunose

et al. 2012

Hypertens Res

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Cilnidipine, an L/N-type calcium channel blocker (CCB), has been reported to have more beneficial effects on proteinuria progression in hypertensive patients than amlodipine, an L-type CCB. The N-type calcium channel blockade that inhibits renal sympathetic nerve activity might reduce glomerular hypertension by facilitating vasodilation of the efferent arterioles. However, the precise mechanism of the renoprotective effect of cilnidipine remains unknown. Because cilnidipine exerted significantly higher antioxidant activity than amlodipine in cultured human mesangial cells, we hypothesized that cilnidipine might exert a renoprotective effect by suppressing oxidative stress. A total of 35 hypertensive patients receiving a renin-angiotensin system inhibitor were randomly assigned to a cilnidipine (n ¼ 18; 10 mg per day cilnidipine titrated to 20 mg per day) or amlodipine (n ¼ 17; 5 mg per day amlodipine titrated to 10 mg per day) group; the target blood pressure (BP) was set at 130/85 mmHg. After 6 months of treatment, systolic and diastolic BPs were significantly reduced in both of the groups, without any significant difference between the groups. The urinary albumin, 8-hydroxy-2 0 -deoxyguanosine (OHdG) and liver-type fatty-acid-binding protein (L-FABP) to creatinine ratios significantly decreased in the cilnidipine group (Po0.05) compared with those in the amlodipine group. The reductions in urinary albumin, 8-OHdG and L-FABP were not correlated with the change in systolic BP. In conclusion, cilnidipine, but not amlodipine, ameliorated urinary albumin excretion and decreased urinary 8-OHdG and L-FABP in the hypertensive patients. Cilnidipine probably exerts a greater renoprotective effect through its antioxidative properties.

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The N- and L-Type Calcium Channel Blocker Cilnidipine Suppresses Renal Injury in Dahl Rats Fed a High-Sucrose Diet, an Experimental Model of Metabolic Syndrome

Cited by 48 publications

References 82 publications

L/N-type calcium channel blocker cilnidipine ameliorates proteinuria and inhibits the renal renin–angiotensin–aldosterone system in deoxycorticosterone acetate-salt hypertensive rats

L/N-type calcium channel blocker cilnidipine ameliorates proteinuria and inhibits the renal renin–angiotensin–aldosterone system in deoxycorticosterone acetate-salt hypertensive rats

Change of Glomerular Hemodynamics in Patients with Advanced Chronic Kidney Disease after Cilnidipine Therapy

Renoprotective and antioxidant effects of cilnidipine in hypertensive patients

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