A new-generation N/L-type calcium channel blocker leads to less activation of the renin–angiotensin system compared with conventional L type calcium channel blocker

Konoshita, Tadashi; Makino, Yasukazu; Kimura, Tomoko; Fujii, Miki; Wakahara, Shigeyuki; Arakawa, Kazuhisa; Inoki, Isao; Nakamura, Hiroyuki; Miyamori, Isamu

doi:10.1097/hjh.0b013e32833d01dd

Cited by 40 publications

(37 citation statements)

References 29 publications

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“…It has been reported that cilnidipine suppresses RAS hyperactivity through its sympatholytic action (12). When compared with amlodipine, cilnidipine leads to weaker activation of the RAS in human patients (14), and the renotropic action of cilnidipine has been implicated in the reduction of RAS activity (13), suggesting that reduction of renal fibrosis, EMT, and macrophage infiltration by cilnidipine is via suppression of RAS activity in UUO kidneys. However, this is unlikely, as we could not find significant differences in expression levels of angiotensinconverting enzyme, angiotensinogen, and renin among the untreated, cilnidipine-treated, and amlodipine-treated UUO kidneys (unpublished observation).…”

Section: Discussionmentioning

confidence: 99%

Involvement of N-type Ca²⁺channels in the fibrotic process of the kidney in rats

Mishima

Maeshima

Miya

et al. 2013

American Journal of Physiology-Renal Physiology

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type Ca 2ϩ channels are densely distributed in sympathetic nerves that innervate renal tubules. However, the role of N-type Ca 2ϩ channels in renal fibrosis remains unknown. To address this issue, we examined the difference between the effects of amlodipine (an L-type Ca 2ϩ channel blocker) and cilnidipine (a dual L/N-type Ca 2ϩ channel blocker) on fibrotic changes using a rat unilateral ureteral obstruction (UUO) model. The expression of both L-type and N-type Ca 2ϩ channels was significantly upregulated in UUO kidneys compared with that in contralateral kidneys. There were no significant differences in mean blood pressure among the rats tested. Both amlodipine and cilnidipine significantly attenuated fibrotic changes in UUO kidneys. The antifibrotic effect of cilnidipine was more potent than that of amlodipine. Amlodipine as well as cilnidipine reduced type III collagen deposition, ␣-smooth muscle actin (␣-SMA) expression, and interstitial cell proliferation. In addition, cilnidipine significantly reduced deposition of type I collagen and macrophage infiltration in UUO kidneys. With the use of in vivo bromodeoxyuridine labeling, label-retaining cells (LRCs) were identified as a population of tubular cells that participate in epithelial-mesenchymal transition after UUO. Some LRCs migrated into the interstitium, expressed ␣-SMA and vimentin, and produced several extracellular matrixes in UUO kidneys. The number of interstitial LRCs was significantly decreased by cilnidipine but not amlodipine. These data suggest that N-type Ca 2ϩ channels contribute to multiple steps of renal fibrosis, and its blockade may thus be a useful therapeutic approach for prevention of renal fibrosis.N-type calcium channel; renal fibrosis; unilateral ureteral obstruction; epithelial-mesenchymal transition THE RENAL SYMPATHETIC NERVES innervate the tubules, the vessels, and the juxtaglomerular granular cells of the kidney (5). Renal sympathetic nerve activation reduces urinary sodium and water excretion by increasing renal tubular water and sodium reabsorption throughout the nephron. It also decreases renal blood flow and glomerular filtration rate by constricting the renal vasculature and activates the renin-angiotensin system (RAS) by stimulating renin release from juxtaglomerular granular cells. Conversely, angiotensin II stimulates sympathetic nerve activity through central mechanisms and by facilitating adrenergic neurotransmission at the sympathetic nerve terminal, thus suggesting significant interactions between renal sympathetic nerves and the RAS in the control of renal function (4). N-type Ca 2ϩ channels are densely distributed in the sympathetic nervous system and play a predominant role in neurotransmitter release from the nerve endings of sympathetic neurons (8). In patients with chronic renal diseases, increased sympathetic nerve activity and plasma renin activity are observed (10), thus suggesting that sympathetic nerve activity via N-type Ca 2ϩ channels is involved in renal injury. Renal fibrosis is the common end point o...

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Section: Discussionmentioning

confidence: 99%

Involvement of N-type Ca²⁺channels in the fibrotic process of the kidney in rats

Mishima

Maeshima

Miya

et al. 2013

American Journal of Physiology-Renal Physiology

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“…This phenomenon of less activation of the RAS by cilnidipine compared to amlodipine was already shown in animals and human subjects [30][31][32] explained by N-type calcium channel's regulation of norepinephrine release [33] and N-type calcium channel suppression and reduction of norepinephrine secretion rate by cilnidipine [34,35]. On the other hand, PAC at cilnidipine and efonidipine was significantly lower than that at amlodipine.…”

Section: Discussionmentioning

confidence: 53%

A crossover comparison of urinary albumin excretion as a new surrogate marker for cardiovascular disease among 4 types of calcium channel blockers

Konoshita

Makino

Kimura

et al. 2013

International Journal of Cardiology

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40.6 (18.7-94.7). By all agents, significant augmentations were observed in PRA, angiotensin I and angiotensin II (AngII). AngII at cilnidipine was significantly lower than that at amlodipine. PAC at cilnidipine and efonidipine was significantly lower than that at amlodipine. Nifedipine CR significantly reduced ANP concentration. Conclusions: It is revealed that only nifedipine CR and cilnidipine could reduce albuminuria statistically. Thus, it is suggested that the 2 CCBs might be favorable for organ protection in hypertensives.

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“…Whereas cilnidipine is as efficacious as amlodipine, the former clearly offers some advantages-lack of SNS activation, fewer adverse effects, and less ankle edema. [15][16][17] These clinical effects are likely to improve patient compliance and tolerability. Unlike other DHP CCBs, cilnidipine reduces proteinuria in patients with diabetes or chronic kidney disease (CKD).…”

Section: Discussionmentioning

confidence: 99%

Hypertension Therapeutics Update: A Brief Clinical Summary on Azilsartan, Cilnidipine and Nebivolol

Sharma¹

2015

Hypertension Journal

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Uncontrolled hypertension is the major risk factor for cardio vascular disease. The economic burden of disease is enor mous in developed as well as in developing countries. The epidemiological studies have explained many etiological factors associated with chronic untreated hypertension, which varies according to geography and ethnicity.In last five decades, many classes and types of antihyper tensive drugs have been developed. This pharma cological review provides an update on new molecules belonging to three pharmacological classes of antihypertensives-angiotensin receptor blocker (azilsartan), calcium channel blocker (cilnidipine) and beta blocker (nebivolol) and their clinical implications.

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A new-generation N/L-type calcium channel blocker leads to less activation of the renin–angiotensin system compared with conventional L type calcium channel blocker

Abstract: It is suggested that cilnidipine leads to less activation of the RAS compared with amlodipine for the first time in human clinical patients and therefore cilnidipine might be expected to be superior in organ protection in addition to the antialbuminuric effect.

Cited by 40 publications

References 29 publications

Involvement of N-type Ca²⁺channels in the fibrotic process of the kidney in rats

Involvement of N-type Ca²⁺channels in the fibrotic process of the kidney in rats

A crossover comparison of urinary albumin excretion as a new surrogate marker for cardiovascular disease among 4 types of calcium channel blockers

Hypertension Therapeutics Update: A Brief Clinical Summary on Azilsartan, Cilnidipine and Nebivolol

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A new-generation N/L-type calcium channel blocker leads to less activation of the renin–angiotensin system compared with conventional L type calcium channel blocker

Abstract: It is suggested that cilnidipine leads to less activation of the RAS compared with amlodipine for the first time in human clinical patients and therefore cilnidipine might be expected to be superior in organ protection in addition to the antialbuminuric effect.

Cited by 40 publications

References 29 publications

Involvement of N-type Ca2+channels in the fibrotic process of the kidney in rats

Involvement of N-type Ca2+channels in the fibrotic process of the kidney in rats

A crossover comparison of urinary albumin excretion as a new surrogate marker for cardiovascular disease among 4 types of calcium channel blockers

Hypertension Therapeutics Update: A Brief Clinical Summary on Azilsartan, Cilnidipine and Nebivolol

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Involvement of N-type Ca²⁺channels in the fibrotic process of the kidney in rats

Involvement of N-type Ca²⁺channels in the fibrotic process of the kidney in rats