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 Table of Contents  
BRIEF REVIEW
Year : 2017  |  Volume : 6  |  Issue : 1  |  Page : 24-26

Hypertension management: Old drug revisited - Cilnidipine


Professor and Head, Department of Cardiology, Vivekananda Institute of Medical Sciences, Kolkata, West Bengal, India

Date of Web Publication26-Dec-2016

Correspondence Address:
Soumitra Kumar
58/1, Ballygunge Circular Road, Flat - 52B, Kolkata - 700 019, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2250-3528.196653

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  Abstract 

Cilnidipine is a promising fourth-generation calcium channel blocker which along with inhibition of the L-type Ca 2+ channels in vascular smooth muscle cells, also inhibits the N-type Ca 2+ channels in sympathetic neurons. As a result, in addition to hypotensive action secondary to vascular relaxation, it also demonstrates significant sympatholytic action, whereby it attenuates platelet activation (and consequent arterial thrombosis), tachycardia, oxidative stress, and also inhibits activation of renin-angiotensin system in blood vessels. By virtue of the latter effect, they relieve constriction of postglomerular vessels and thereby ameliorate glomerular hypertension and render renoprotective effect. Besides these, cilnidipine also improves insulin resistance, nitric oxide production, and protects against retinal neuronal injury. Thus, it is expected to be a very useful addition in the current armamentarium for the treatment of hypertension.

Keywords: N-type Ca 2+ channel, renoprotection, sympatholytic action


How to cite this article:
Kumar S. Hypertension management: Old drug revisited - Cilnidipine. J Clin Prev Cardiol 2017;6:24-6

How to cite this URL:
Kumar S. Hypertension management: Old drug revisited - Cilnidipine. J Clin Prev Cardiol [serial online] 2017 [cited 2018 Dec 13];6:24-6. Available from: http://www.jcpconline.org/text.asp?2017/6/1/24/196653


  Introduction Top


Among antihypertensive drugs, calcium channel blockers (CCBs) are potent vasodilators. The voltage-gated calcium channel consists of 4 subunits: α1, α2, β, and g. An α1 subunit is the key component of calcium channels and constitutes pore structure for ion conduction. Ten different α1 subunits have been described, and each of them is characterized by a specific distribution and ion conductance pattern. These distinct subunits characterize the channel properties of L-, N-, P-, Q-, and R-type calcium channels. [1],[2]

Of these channels, L-type calcium channels are the main targets of CCBs. However, some CCBs possess the ability to block other calcium channels. Cilnidipine is a recently developed CCB which possesses both L- and N-type calcium channels blocking activity [Table 1]. Cilnidipine has inhibitory action on sympathetic system by virtue of the fact that N-type channels are distributed along the nerve and in the brain. Selectivity of L-type/N-type Ca 2+ channels differs markedly among CCBs in a study on Wistar rats, whereas nifedipine showed high selectivity for L-type Ca 2+ channels and cilnidipine blocked both L- and N-type of Ca 2+ channels. [3]
Table 1: Summary of pharmacological actions of cilnidipine


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Sympatholytic activities of cilnidipine are observed in both in vitro and in vitro. In a study on 2920 hypertensive patients, co-prescription of cilnidipine and angiotensin receptor blocker resulted in a significant reduction of heart rate, more so in those with baseline heart rate of ≥75 beats/min. [4] Furthermore, cilnidipine has been demonstrated to be effective in situations such as morning surge of hypertension and white coat hypertension which are linked to sympathetic overactivity [Figure 1]. [5]
Figure 1: N-type Ca2+ channel activation leading to major complications of hypertension

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A close and graded relation exists between blood pressure and end-stage renal disease. Looking from a different viewpoint, chronic renal failure and albuminuria are also independent risk factors for cardiovascular disease and strokes. Thus, the treatment of hypertension targeted at preventing progression of renal disease is also likely to reduce the risk of cardiovascular events. [6]

Glomerular filtration is primarily regulated by afferent and efferent arterial tone. Since the sympathetic nerves are distributed in afferent and efferent arteries, cilnidipine has been shown to dilate both afferent and efferent arteries and reduces glomerular capillary pressure, afferent and efferent arteriolar resistances, and urinary albumin excretion. [7] Clinical studies have confirmed renoprotective efficacy of cilnidipine. Cilnidipine appeared to be comparable to benazepril in terms of urinary albumin excretion and this was achieved without affecting serum creatinine. [8] Combination of cilnidipine and valsartan was shown to decrease the albumin/creatinine ratio more markedly than valsartan alone. [9] More recent, multicenter, open-labeled, randomized trial of cilnidipine versus amlodipine randomized trial for evaluation in renal disease (CARTER) has shown that cilnidipine is superior to amlodipine in preventing the progression of proteinuria in patients with hypertension and chronic renal disease when coupled with a renin-angiotensin system inhibitor. [10] Excess reactive oxygen species play an important role in pathogenesis of variety of renal diseases such as glomerulonephritis and tubule-interstitial nephritis. In deoxycorticosterone acetate-salt rat models, cilnidipine was found to significantly inhibit the increase in nicotinamide adenine dinucleotide phosphate oxidase-derived superoxide production, whereas amlodipine had no effect. [11] Superior antiproteinuric effect of cilnidipine in the CARTER study can in part be explained by its superior antioxidant activity. Cilnidipine also protects the podocytes and antiproteinuric effect in spontaneously hypertensive rat/ND mcr-cp rat model of spontaneous hypertension through reduction of angiotensin II level and spontaneous diminution in oxidative stress. [12]

Angiotensin II receptor blockers can lead to an increase in plasma renin activity and plasma angiotensin II levels. These are effectively suppressed by cilnidipine but not amlodipine. [13] Thus, in effect, cilnidipine is expected to constitute a synergistic combination with angiotensin II receptor blockers.

In an animal experiment, amlodipine, cilnidipine, and candesartan were administered to dogs for 4 weeks. The QT interval and monophasic action potential duration were shortened only in the cilnidipine groups; however, such effects were not demonstrated in the amlodipine or candesartan group. [14] Plasma angiotensin II and aldosterone concentrations were reported to be decreased in the cilnidipine group and elevated in the amlodipine group. Long QT interval has been reported in various cardiovascular diseases associated with hypertrophy and also in end-stage renal disease. Long-term treatment of L/N type Ca 2+ channels may provide a novel strategy to prevent sudden cardiac death related to QT prolongation.

Ca 2+ influx, probably through N-type Ca 2+ channels, is involved in the process of pancreatic insulin secretion from β-cells and glucagon secretion from alpha cells in the islets of Langerhans. In a study on fructose-fed rats, insulin sensitivity was significantly lower than in controls and insulin resistance was shown to improve significantly after cilnidipine treatment. [15] Thus, N-type Ca 2+ channels have an important role to play in glucose homeostasis.


  Conclusion Top


Cilnidipine is a promising 4 th generation dual L/N type Ca 2+ channel blocking agent. The blockade of N-type Ca 2+ channels results in neurohormonal regulation (sympathetic nervous system and renin-angiotensin-aldosterone system) in the cardiovascular system. This results in favorable effects in the prevention of number of complications of hypertension, the most notable being prevention of progression of proteinuria and renal disease. Thus, it is expected to be a very useful addition in the current armamentarium for the treatment of hypertension.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Ertel EA, Campbell KP, Harpold MM, Hofmann F, Mori Y, Perez-Reyes E, et al. Nomenclature of voltage-gated calcium channels. Neuron 2000;25:533-5.  Back to cited text no. 1
    
2.
Miljanich GP, Ramachandran J. Antagonists of neuronal calcium channels: Structure, function, and therapeutic implications. Annu Rev Pharmacol Toxicol 1995;35:707-34.  Back to cited text no. 2
    
3.
Uneyama H, Uchida H, Konda T, Yoshimoto R, Akaike N. Selectivity of dihydropyridines for cardiac L-type and sympathetic N-type Ca2+channels. Eur J Pharmacol 1999;373:93-100.  Back to cited text no. 3
    
4.
Nagahama S, Norimatsu T, Maki T, Yasuda M, Tanaka S. The effect of combination therapy with an L/N-Type Ca(2+) channel blocker, cilnidipine, and an angiotensin II receptor blocker on the blood pressure and heart rate in Japanese hypertensive patients: An observational study conducted in Japan. Hypertens Res 2007;30:815-22.  Back to cited text no. 4
    
5.
Yamagishi T. Beneficial effect of cilnidipine on morning hypertension and white-coat effect in patients with essential hypertension. Hypertens Res 2006;29:339-44.  Back to cited text no. 5
    
6.
Manjunath G, Tighiouart H, Ibrahim H, MacLeod B, Salem DN, Griffith JL, et al. Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol 2003;41:47-55.  Back to cited text no. 6
    
7.
Konno Y, Kimura K. Vasodilatory effect of cilnidipine, an L-type and N-type calcium channel blocker, on rat kidney glomerular arterioles. Int Heart J 2008;49:723-32.  Back to cited text no. 7
    
8.
Rose GW, Kanno Y, Ikebukuro H, Kaneko M, Kaneko K, Kanno T, et al. Cilnidipine is as effective as benazepril for control of blood pressure and proteinuria in hypertensive patients with benign nephrosclerosis. Hypertens Res 2001;24:377-83.  Back to cited text no. 8
    
9.
Katayama K, Nomura S, Ishikawa H, Murata T, Koyabu S, Nakano T. Comparison between valsartan and valsartan plus cilnidipine in type II diabetics with normo- and microalbuminuria. Kidney Int 2006;70:151-6.  Back to cited text no. 9
    
10.
Fujita T, Ando K, Nishimura H, Ideura T, Yasuda G, Isshiki M, et al. Antiproteinuric effect of the calcium channel blocker cilnidipine added to renin-angiotensin inhibition in hypertensive patients with chronic renal disease. Kidney Int 2007;72:1543-9.  Back to cited text no. 10
    
11.
Toba H, Yoshida M, Tojo C, Nakano A, Oshima Y, Kojima Y, et al. L/N-type calcium channel blocker cilnidipine ameliorates proteinuria and inhibits the renal renin-angiotensin-aldosterone system in deoxycorticosterone acetate-salt hypertensive rats. Hypertens Res 2011;34:521-9.  Back to cited text no. 11
    
12.
Fan L, Yang Q, Xiao XQ, Grove KL, Huang Y, Chen ZW, et al. Dual actions of cilnidipine in human internal thoracic artery: Inhibition of calcium channels and enhancement of endothelial nitric oxide synthase. J Thorac Cardiovasc Surg 2011;141:1063-9.  Back to cited text no. 12
    
13.
Aritomi S, Niinuma K, Ogawa T, Konda T, Nitta K. Effects of an N-type calcium antagonist on angiotensin II-renin feedback. Am J Nephrol 2011;33:168-75.  Back to cited text no. 13
    
14.
Takahara A, Nakamura Y, Wagatsuma H, Aritomi S, Nakayama A, Satoh Y, et al. Long-term blockade of L/N-type Ca (2+) channels by cilnidipine ameliorates repolarization abnormality of the canine hypertrophied heart. Br J Pharmacol 2009;158:1366-74.  Back to cited text no. 14
    
15.
Takeda S, Ueshiba H, Hattori Y, Irie M. Cilnidipine, the N- And L-type calcium channel antagonist, reduced on 24-h urinary catecholamines and C-peptide in hypertensive non-insulin-dependent diabetes mellitus. Diabetes Res Clin Pract 1999;44:197-205.  Back to cited text no. 15
    


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