Selectivity of dihydropyridines for cardiac L-type and sympathetic N-type Ca2+ channels

Uneyama, Hisayuki; Uchida, Hirohisa; Konda, Tomoyuki; Yoshimoto, Ryota; Akaike, Norio

doi:10.1016/s0014-2999(99)00237-x

Cited by 44 publications

(35 citation statements)

References 22 publications

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“…Several previous reports demonstrated that cilnidipine and amlodipine had a lowering effect of blood pressure to a similar extent at the dose used in this study (3 mg·kg Ϫ1 ·day Ϫ1 ) in hypertensive rats (12,25,26). Previous pharmacological study also demonstrated that cilnidipine and amlodipine inhibited L-type Ca channel current to a similar extent using a whole cell patch-clamp technique (29). Taken together, we speculate that both Ca 2ϩ channel blockers inhibited L-type Ca channel to a similar extent in this study, although the blood pressurelowering effects of cilnidipine as well as amlodipine could not be observed at this dose.…”

Section: Discussionsupporting

confidence: 73%

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: Discussionsupporting

confidence: 73%

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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“…However, the selectivity of cilnidipine for N-type calcium channels, shown as the ratio of IC50 of CCB for N-type and L-type channels, was about 50 times that of amlodipine (27). In humans, amlodipine-induced blood pressure reduction is known to increase skeletal muscle sympathetic-nerve activity (28).…”

Section: Discussionmentioning

confidence: 99%

Comparison between Cilnidipine and Amlodipine Besilate with Respect to Proteinuria in Hypertensive Patients with Renal Diseases

2004

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Unlike other dihydropyridine calcium channel blockers (CCBs), cilnidipine has been reported to exert an Ntype calcium-channel-blocking activity and to reduce sympathetic hyperactivity. This study compared cilnidipine and amlodipine with respect to their effects on renal function and proteinuria. Twenty-eight proteinuric hypertensive outpatients (13 men and 15 women, aged 62 2 years) who had been maintained on CCBs for more than 3 months were randomly assigned to a group receiving amlodipine besilate (14 patients) or a group receiving cilnidipine (14 patients). CCBs were increased in dosage or other drugs were added until blood pressure decreased below 140/90 mmHg, but no inhibitors of the renin-angiotensin (RA) system were added or changed in dosage. Before and at 6 and 12 months after randomization, the concentrations of urine protein, urine albumin, serum and urine creatinine (Cr), and serum 2-microglobulin were determined.The amlodipine group showed a significant increase in proteinuria, while the increase was suppressed in the cilnidipine group. The rate of increase in proteinuria at 12 months was 87% (95% confidence interval (

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“…Other antihypertensive agents selected for the study were an ARB (valsartan) (19,20) and two Cachannel blockers. One of the Ca-channel blockers was an Ltype Ca-channel blocker (nifedipine CR), which blocks only L-type Ca-channels present in vascular smooth muscle, and the other was an L-and N-type Ca-channel blocker (cilnidipine), which blocks L-type Ca-channels as well as N-type Ca-channels present in sympathetic nerve endings and also has a sympatholytic effect (21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Various Antihypertensive Agents as Evaluated by Indices of Vascular Stiffness in Elderly Hypertensive Patients

Takami¹,

Shigemasa²

2003

Hypertens Res

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lar diseases (1-10). Increased SBP leads to left ventricular hypertrophy, while decreased DBP results in decreased coronary circulation. Left ventricular hypertrophy accelerates the progression of cardiovascular remodeling, decreases left ventricular diastolic function, increases left ventricular end-DBP, and promotes endocardial ischemia. Thus, hypertension in elderly patients is associated with basic conditions of cardiac failure or ischemic heart disease. Therefore, antihypertensive drugs that decrease not only blood pressure (BP) but also arterial stiffness and PP are required for the treatment of such patients. We compared the effects of an angiotensin-receptor blocker (ARB), an angiotensin-converting

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Selectivity of dihydropyridines for cardiac L-type and sympathetic N-type Ca2+ channels

Cited by 44 publications

References 22 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

Comparison between Cilnidipine and Amlodipine Besilate with Respect to Proteinuria in Hypertensive Patients with Renal Diseases

Efficacy of Various Antihypertensive Agents as Evaluated by Indices of Vascular Stiffness in Elderly Hypertensive Patients

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Selectivity of dihydropyridines for cardiac L-type and sympathetic N-type Ca2+ channels

Cited by 44 publications

References 22 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

Comparison between Cilnidipine and Amlodipine Besilate with Respect to Proteinuria in Hypertensive Patients with Renal Diseases

Efficacy of Various Antihypertensive Agents as Evaluated by Indices of Vascular Stiffness in Elderly Hypertensive Patients

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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