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Keywords:

  • Calcium channel blockers;
  • N-type Ca2+ channels;
  • Cilnidipine;
  • Hypertension;
  • Sympathetic nerve activity

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Relationship Between Sympathetic Nerve Activity and Ca2+ Channel Subtypes
  5. Classification of Ca2+ Channel Blockers
  6. The Fourth-Generation Ca2+ Channel Blocker: Cilnidipine
  7. Conclusion
  8. Conflict of Interest
  9. References

Cilnidipine is a unique Ca2+ channel blocker with an inhibitory action on the sympathetic N-type Ca2+ channels, which is used for patients with hypertension in Japan. Cilnidipine has been clarified to exert antisympathetic actions in various examinations from cell to human levels, in contrast to classical Ca2+ channel blockers. Furthermore, renoprotective and neuroprotective effects as well as cardioprotective action of cilnidipine have been demonstrated in clinical practice or animal examinations. After the introduction of nifedipine as an antihypertensive drug, many Ca2+ channel blockers with long-lasting action for blood pressure have been developed to minimize sympathetic reflex during antihypertensive therapy, which have been divided into three groups; namely, first, second, and third generation based on their pharmacokinetic profiles. Since cilnidipine directly inhibits the sympathetic neurotransmitter release by N-type Ca2+ channel-blocking property, the drug can be expected as fourth generation, providing an effective strategy for the treatment of cardiovascular diseases.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Relationship Between Sympathetic Nerve Activity and Ca2+ Channel Subtypes
  5. Classification of Ca2+ Channel Blockers
  6. The Fourth-Generation Ca2+ Channel Blocker: Cilnidipine
  7. Conclusion
  8. Conflict of Interest
  9. References

L-type Ca2+ channel blockers are widely used for the treatment of hypertension. The first-generation drug, nifedipine, was clinically introduced in the 1960s; however, the drug activated sympathetic tone due to its rapid onset of vasodilator action [1]. The second generation partly allowed the reduction of sympathetic reflex by designing slow-release formulations of the first-generation drugs or by newly developing slow-acting drugs [2]. Later, amlodipine was introduced as the third generation, which exhibits longer half-life in plasma than the second-generation agents [3]. However, such pharmacokinetic and pharmacodynamic improvements do not always evade the sympathetic reflex induced by the hypotensive action of L-type Ca2+ channel blockers [4].

Cilnidipine is a unique Ca2+ channel blocker used for hypertensive patients in Japan, which inhibits sympathetic N-type Ca2+ channels in addition to vascular L-type Ca2+ channels [5–7]. Interestingly, cilnidipine shows antisympathetic profiles in both in vivo and in vitro examinations, which is also observed in clinical practice [6, 8–11]. Therefore, the inhibition of N-type Ca2+ channels may provide a new strategy for the treatment of cardiovascular diseases. This article reviews the current understanding of the pharmacological profile and clinical utility of cilnidipine as a unique antihypertensive drug.

The Relationship Between Sympathetic Nerve Activity and Ca2+ Channel Subtypes

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Relationship Between Sympathetic Nerve Activity and Ca2+ Channel Subtypes
  5. Classification of Ca2+ Channel Blockers
  6. The Fourth-Generation Ca2+ Channel Blocker: Cilnidipine
  7. Conclusion
  8. Conflict of Interest
  9. References

Classification of Ca2+ Channels

Ca2+ channels are classified into at least six subtypes; namely, L-, N-, P-, Q-, R-, and T-type, based on electrophysiological and pharmacological evidence [12–14]. The T-type Ca2+ channels are known as low-voltage-activated (LVA) Ca2+ channels that activate and deactivate slowly, but inactivate rapidly [15–17]. The other five types of Ca2+ channels are all high-voltage-activated (HVA) Ca2+ channels, which depolarize at approximately −40 mV [13]. In excitatory cells, such as smooth muscle cells, cardiac muscle cells, and neurons, HVA Ca2+ channels regulate a variety of cellular functions including muscle contraction, neuronal electrical activity, and release of neurotransmitters and hormones [18, 19]. Molecular biological techniques have shown that Ca2+ channels are composed of α1, α2-δ, β, and γ subunits using L-type Ca2+ channels from skeletal muscles [20]. In particular, the αl subunit forms the Ca2+ transmission pore, which fulfills the most important function. Furthermore, ten α1 subunits have been cloned and classified into three subfamilies: Cav1.x; Cav2.x; and Cav3.x, based on their gene sequence similarity [21].

In the cardiovascular system, L-type Ca2+ channels are predominantly expressed in the heart and vessels, which regulate cardiac contractility, sinus nodal function, and vascular tone. Thus, the channel has been recognized as a pharmacological target for the treatment of cardiovascular disease. N-type Ca2+ channels are localized at the nerve endings in the sympathetic and central nervous systems, which regulate the release of neurotransmitters [22–24]. T-type Ca2+ channels may be associated with the gradual depolarization phase of the sinus nodal action potential [25], which appears only in smaller animals [26,27].

N-Type Ca2+ Channels and Sympathetic Nerve Activity

In 1988, Hirning et al. [22] first demonstrated that N-type Ca2+ channels predominantly regulate norepinephrine release from the superior cervical ganglia neurons using a selective N-type Ca2+ channel blocker ω-conotoxin GVIA. This finding was further supported by subsequent experiments using isolated rat arterial preparations [28,29]. In a clinical study, systemic administration of ω-conotoxin MVIIA (SNX-111) has been shown to induce sympatholytic action [30]. Using a patch clamp method, N-type Ca2+ channels are shown to contribute about 85% of all Ca2+ currents in the sympathetic neurons [6].

Association Between Hypertension and Sympathetic Nerve Activity

Hypertension is a multifactorial and multifaceted disease in which elevated blood pressure is only one sign of multiple underlying physiological abnormalities [31–33]. Sympathetic nerve activity is one of the major culprits implicated in the onset of hypertension. Julius [34] reported that the occurrence of a hyperkinetic state, that is, one in which both cardiac output and heart rate are elevated, was five times more frequently observed in patients with borderline hypertension than in the normotensive population. In a study of borderline hypertensive patients, microneurography revealed that muscle sympathetic nerve activity was significantly elevated compared with that in normotensive individuals [35]. Goldstein [36] summarized statistics from previous studies on mean norepinephrine levels in hypertensive and normotensive individuals, and showed that this parameter was higher in the former versus latter group. In another study, the muscle sympathetic nerve activity showed a progressive and significant increase from normotensive to severe essential hypertensive states [37]. On the other hand, addition of the central-acting antihypertensive moxonidine to eprosartan therapy reduces muscle sympathetic nerve activity in patients with chronic renal failure [38].

Clinically, an important goal of antihypertensive therapy is to prevent the occurrence of cardiovascular complications. It has been suggested that increased sympathetic activity is the common link among many of the “nonpressure-related” coronary risk factors in hypertension. Some reports have shown that complications of hypertension, including those related to heart, brain, and kidney, developed or worsened as a result of hyperactivity of sympathetic nerves [39–42]. Cohn et al. [39] showed that plasma norepinephrine concentration, a sensitive marker of sympathetic nerve activity, is a significant prognostic marker of mortality in congestive heart failure patients. Moreover, it has been shown that epinephrine enhances procoagulant platelet activation, and this effect is pronounced in hypertensive individuals, who are therefore at increased risk of coronary thrombosis [40]. Patients with essential hypertension complicated by microalbuminuria responded to moxonidine therapy with significant reductions in urinary albumin excretion and markers of arterial endothelial cell function, such as plasma thrombomodulin and tissue plasminogen activator inhibitor-1 [42]. Furthermore, Campese et al. [43–45] reported that in rats with chronic renal failure, renal afferent denervation prevents development of hypertension and progression of renal disease, and on the other hand, it is reported that a renal injury caused by phenol injection increases blood pressure and both central and peripheral sympathetic nerve activity. As shown in Figure 1, hypertension is considered to be closely related to increased sympathetic nerve activity. More importantly, activation of sympathetic nervous system often triggers hypertensive complications including ischemic heart disease, strokes, heart failure, and renal failure (Figure 2), which shows the importance of controlling sympathetic nerve activity in clinical practice. Notably, N-type Ca2+ channels have been known to be associated with release of glutamate in the case of cerebral infarction [46].

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Figure 1. Schema of relation of N-type Ca2+ channels to hypertension.

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Figure 2. Schema of relation of N-type Ca2+ channels to major complications of hypertension.

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Inhibitory Effects of Ca2+ Channel Blockers on N-Type Ca2+ Channels

Uneyama et al. demonstrated that submicromolecular concentrations of cilnidipine effectively suppressed N-type Ca2+ channel currents in isolated sympathetic neurons [6]. They further compared the inhibitory effect of various dihydropyridines on cardiac L-type Ca2+ channels in isolated ventricular myocytes with that on N-type Ca2+ channels in superior cervical ganglion neurons obtained from Wistar rats (Figure 3) [47]. In that study, all dihydropyridines, except cilnidipine, showed a small inhibitory effect at a concentration of 1 μM. Furthermore, it was noted that the selectivity for L-type/N-type of Ca2+ channels differed markedly among the compounds tested, where nifedipine showed high selectivity for L-type Ca2+ channels and cilnidipine blocked both L- and N-type of Ca2+ channels. The N-type channel blocking action of cilnidipine has also been confirmed in IMR-32 human neuroblastoma cells [7].

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Figure 3. Ratio of IC50 value of each dihydropyridine for cardiac L-type Ca2+ current (ICa,L) and sympathetic N-type Ca2+ current (ICa,N). IC50 value of each dihydropyridine for ICa,L and ICa,N were calculated by least-squares fitting and plotted. Each point represents mean of four to six different experiments. (Reproduced with permission from Uneyama H [47]. Copyright © 1999, Elsevier. All right reserved.)

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Classification of Ca2+ Channel Blockers

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Relationship Between Sympathetic Nerve Activity and Ca2+ Channel Subtypes
  5. Classification of Ca2+ Channel Blockers
  6. The Fourth-Generation Ca2+ Channel Blocker: Cilnidipine
  7. Conclusion
  8. Conflict of Interest
  9. References

Brief History

As with many other classes of drugs, such as antibiotics and antidepressants, many Ca2+ channel blockers have been developed by pharmaceutical companies to cover the shortcomings of older drugs. To better understand the similarity and differences of Ca2+ channel blockers regarding pharmacological property and therapeutic utility, the drugs have been categorized according to selectivity for the voltage-dependent Ca2+ channels in vascular smooth muscle against those in cardiac tissue [48–50], chemical class, binding affinity to receptors in Ca2+ channels [51], chemical structure, or lipophilicities [52]. In 1996, a useful classification was proposed to divide Ca2+ channel blockers into three groups–first, second, and third generation, which were fundamentally based on the effects on Ca2+ channel receptor-binding properties, tissue selectivity, and pharmacokinetic profile [53]. Recently, the classification has been refined based on influence on sympathetic function, since Ca2+ channel blockers have a history that pharmaceutical companies developed these drugs to minimize sympathetic reflex during antihypertensive therapy [54].

Classification of Ca2+ Channel Blockers According to Effects on Sympathetic Function

Table 1 summarizes the classification of Ca2+ channel blockers according to their effects on sympathetic function. In this table, experimental data on norepinephrine release in vitro and plasma norepinephrine levels in vivo are listed, which show pharmacological effects on the sympathetic nerves. On the other hand, clinical data are shown regarding plasma/urinary norepinephrine, 123I-metaiodobenzylguanidine (MIBG), muscle sympathetic nerve activity, low frequency/high frequency ratio (LF/HF ratio) and heart rate, which help us better understand their clinical effects on sympathetic nerve activity.

Table 1.  Classification of dihydropyridines according to effects on sympathetic functions
GenerationData from animal studiesData from clinical studies
NE releasePlasma NE levelPlasma NE levelMIBGMSNALF/HF ratioHeart rate
  1. NE, norepinephrine; MIBG, 123I-metaiodobenzylguanidipine; WR, washout rate; H/M, heart to mediastinum; MSNA, muscle sympathetic nerve activity; LF/HF, low-frequency/high-frequency.

  2. aIncreased in younger patients / no change in elder patients.

  3. bIncludes urine norepinephrine excretion.

  4. – No published data found.

INifedipineNo change[55,56]Increased[57,58]Increased[59,66] Increased[60,66]Increased[61]Increased[59,60,61, 62,66]
Nifedipine (Slow release)  Increased[66,67] Increaseda[64,66]Increased[68,69]Increased[65,68,69]
     No change[64]  No changea[63,64]No change[65,72]No change[66,72]
 
IIBenidipine Increased[57]   No change[72]Increased[74,75]
   No change[58]      Decreased[71]No change[62,72,73]
Efonidipine   WR decreased[76]  No change[77]
       H/M increased       
 
IIIAmlodipineNo change[55]Increased[57,58]Increased[84,85]WR decreased[10]Increased[80,81]Increased[83]Increased[80,81,88,91]
     No changeb[10,83,88]H/M no change No change[63]No change[69,82]No change[10,69,80,85, 87,89,104]
Azelnidipine  No change[86]   No change[86,87]
     Decreasedb[88]      Decreased[88,89,90,91]
 
IVCilnidipineDecreased[55,56, 95,96]No change[57,58]No change[10,59]WR decreased[10,99,100] No change[68,101]Increased[59]
     Decreasedb[98,99]H/M increased   Decreased[102]No change[10,68,98,100,101,104]
             Decreased[99,103]
The First Generation

As shown in Figure 3, nifedipine hardly affects N-type Ca2+ channels of the rat isolated superior cervical ganglion cells, whose IC50 is >100 μM [47]. In fact, nifedipine has no effects on catecholamine release from isolated rabbit aorta evoked by electrical stimulation of perivascular nerves [55], and similar results have been reported in nerve growth factor (NGF)-treated rat pheochromocytoma PC12 cells [56]. Furthermore, in spontaneously hypertensive rats (SHR), antihypertensive doses of nifedipine markedly increase heart rate and plasma norepinephrine concentrations via sympathetic reflex (Figure 4) [57, 58]. In clinical studies, nifedipine has been shown to increase plasma norepinephrine levels, LF/HF ratio, and heart rate [59–62]. However, these effects are partly alleviated by slow-release formulations [63–69].

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Figure 4. Comparison of change in the blood pressure, heart rate and plasma norepinephrine level after oral administration of Ca2+ channel blockers to spontaneously hypertensive rats. SBP, systolic blood pressure (n = 11); HR, heart rate (n = 11); NE, norepinephrine (n = 6). *p < 0.05, **p < 0.01, compared with corresponding pre-drug control (at 0 hour) value. Values are expressed as mean ± SEM. (Reproduced with permission from Hosono M [57]. Copyright © 1995, Jpn Pharmacol Ther. All rights reserved.)

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The Second Generation

Most dihydropyridines, such as benidipine, efonidipine, manidipine, or nitrendipine are categorized as second generation, and they induce vasodilator action more slowly than the first-generation nifedipine. This kinetic profile is explained by slow association and/or dissociation rates of drugs for L-type Ca2+ channels [70]. The IC50s of the second-generation Ca2+ blockers for N-type Ca2+ channels are around 10 μM [47] (Figure 3). As shown in Figure 4, benidipine lowers blood pressure more slowly than nifedipine, and the extent of reflex tachycardia by benidipine is about half of that by nifedipine [57]. Clinical studies have demonstrated that benidipine either has no effects on heart rate or LF/HF ratio [62,71–73] or increased the heart rate [74,75]. Efonidipine is known as a dual L- and T-type Ca2+ channel blocker, which is clinically available in Japan. The drug shows little effect on heart rate, increased heart to mediastinum (H/M) ratio, and decreased washout rate [76,77]. There is no report that efonidipine has an antisympathetic action or N-type Ca2+ channel-blocking property.

The Third Generation

Amlodipine and azelnidipine are classified as third-generation Ca2+ blockers. Amlodipine has a unique pharmacokinetic profile, that is, longer t1/2 (36 h) than second-generation agents, leading to a slower induction of vasodilator action [78]. Thus, activation of sympathetic tone may be minimized during antihypertensive therapy with amlodipine. As shown in Figure 3, the inhibitory effect of amlodipine on N-type Ca2+ channels is similar to that of the second-generation agents in rat isolated superior cervical ganglion cells [47]. Azelnidipine is the newest Ca2+ channel blocker in Japan, which showed noninferiority against amlodipine in phase III clinical trials. Azelnidipine minimally affected N- and T-type Ca2+ channels in PC-12 cells [79]. In isolated aortic preparation of rabbits, amlodipine has no effects on catecholamine release evoked by electrical stimulation of perivascular nerves [55]. As shown in Figure 4, an antihypertensive dose of amlodipine increases heart rate together with elevation of plasma norepinephrine concentrations via sympathetic reflex. Several clinical studies have demonstrated that amlodipine increased or hardly affected the parameters listed in Table 1[8085]. In contrast, recent clinical studies have shown that azelnidipine reduced or hardly affected heart rate or urinary norepinephrine excretion, which was not observed with amlodipine [8691]. Direct effects of azelnidipine on the sinus nodal function or the central nervous system may be associated with its negative chronotropic action [92–94].

The Fourth Generation

Cilnidipine inhibits N-type Ca2+ channels more potently than other Ca2+ channel blockers, as shown in Figure 3. Several in vitro studies have demonstrated that cilnidipine attenuates norepinephrine release from sympathetic nerve endings [55,95]. Furthermore, such effects have been observed in vivo experiments using anesthetized rats [9] and dogs (Figure 5) [96,97]. Thus, cilnidipine may hardly activate sympathetic function during antihypertensive therapy, as shown in Figure 4. An antisympathetic dose of cilnidipine has been shown to have no effect on vagal nerve stimulation-induced bradycardia, which may be explained by the fact that N-type Ca2+ channels more predominantly regulate neurotransmission of norepinephrine than that of acetylcholine [8] (Figure 6).

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Figure 5. Effects of cilnidipine on renal nerve stimulation (RNS)-induced increase in norepinephrine (NE) secretion rate in anesthetized dogs (n = 5). Cilnidipine was intrarenal arterially infused at a rate of 0.3 μg/kg/min. Values are expressed as means ± SEM. *p < 0.05, compared with the corresponding control values. (Reproduced with permission from Takahara A [96]. Copyright ©1997, Jpn J Pharmacol. All rights reserved.)

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Figure 6. Effects of cilnidipine on neurally mediated chronotropic response in anesthetized dogs. (A) Inhibitory effects on sympathetic tachycardia induced by bilateral carotid arterial occlusion. (B) No effects on vagal nerve stimulation-induced bradycardia. Values are expressed as mean ± SEM. *p < 0.05, **p < 0.01, compared with corresponding pre-drug control value. (Reproduced with permission from Konda T [8]. Copyright © 2001, Elsevier. All rights reserved.)

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Most clinical studies have demonstrated that cilnidipine decreased or hardly affected plasma norepinephrine level, LF/HF ratio, or heart rate [59,68,98–102]. Furthermore, the MIBG cardiac imaging study showed that increased H/M ratio in combination with decreased washout rate was observed after treatment with cilnidipine [10] (Figure 7). In a study conducted in 2920 hypertensive patients, treatment with cilnidipine and angiotensin receptor blocker showed significant reductions in heart rate, particularly in those with a higher baseline heart rate ≥75 beats/min, whereas there were few adverse reactions associated with central nervous functions [103]. Hoshide et al. [104] demonstrated that the reductions in heart rate were significantly greater in the cilnidipine group than the amlodipine group in a 24-h ambulatory blood pressure monitoring study with hypertensive patients. Since the antisympathetic effects of cilnidipine are essentially contrastive to those of the first-, second-, and third-generation agents, the L/N-type Ca2+ channel blocker cilnidipine can be categorized as a new generation according to its effects on sympathetic function [54].

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Figure 7. Comparison of heart to mediastinum (H/M) ratio MIBG uptake and washout rate before and 3 months after drug treatment in hypertensive patients treated with amlodipine (n = 24) and cilnidipine (n = 23). Values are expressed as mean ± SD. (Reproduced with permission from Sakata K [10]. Copyright © 1999, Lippincott Williams & Wilkins. All rights reserved.)

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The Fourth-Generation Ca2+ Channel Blocker: Cilnidipine

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Relationship Between Sympathetic Nerve Activity and Ca2+ Channel Subtypes
  5. Classification of Ca2+ Channel Blockers
  6. The Fourth-Generation Ca2+ Channel Blocker: Cilnidipine
  7. Conclusion
  8. Conflict of Interest
  9. References

As described above, cilnidipine inhibits N-type Ca2+ channels in addition to L-type Ca2+ channels as shown in Figure 8. The extent of the antisympathetic effect of cilnidipine via its N-type Ca2+ channel-blocking property was analyzed in the halothane-anesthetized canine model, in which a dose whereby cilnidipine decreased mean blood pressure by 14 mmHg showed 37% suppression of sympathetic tachycardia induced by a vasodilator acetylcholine (Figure 9) [54]. The sympathetic tachycardia induced by the vasodilator has been confirmed to show >90% inhibition by propranolol. Thus, the pharmacological profile of cilnidipine as an antihypertensive drug may be equivalent to a combination of a pure L-type Ca2+ channel blocker plus small dose of α- and ß-adrenergic receptor antagonist.

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Figure 8. Diagrammatic representation of L/N-dual action of cilnidipine.

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Figure 9. Effects of cilnidipine (n = 4) and nifedipine (n = 4) on the positive chronotropic and inotropic responses to sympathetic reflex in anesthetized dogs. HR, heart rate; LVdP/dtmax, maximum upstroke velocity of left ventricular pressure. Data are presented as mean ± SEM. *p < 0.05, **p < 0.01, compared with corresponding pre-drug control value. (Reproduced with permission from Takahara A [54]. Copyright © 2007, Elsevier. All rights reserved.)

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Cardiovascular Action

Since the first generation of Ca2+ channel blockers were known to suppress cardiac functions, such as contractility, sinoatrial automaticity, and atrioventricular conduction at vasodilator doses [105], pharmaceutical companies have developed new Ca2+ channel blockers with vascular selective action in addition to slow kinetics as a new generation. The blood-perfused canine heart preparation is an excellent model to quantitatively determine cardiovascular selectivity of Ca2+ channel blockers, and many Ca2+ channel blockers were analyzed using this model [105]. Cilnidipine has been demonstrated to have about 10 times more potent coronary vasodilator action and higher vascular selectivity than nicardipine [106,107].

As shown in Figure 4, cilnidipine has a slow onset and long-lasting antihypertensive action in SHR. In clinical studies, the antihypertensive effect of cilnidipine has been demonstrated in hypertensive patients [103,108], and also in patients with severe hypertension [109]. Similar effects on blood pressure between cilnidipine and amlodipine have been revealed by 24-h ambulatory blood pressure monitoring in patients [104]. Furthermore, cilnidipine has been clinically demonstrated to be effective for morning hypertension and white-coat hypertension, which is closely associated with sympathetic nerve activation [11,110,111]. The cardioprotective action of cilnidipine has been analyzed in a rabbit model of myocardial infarction, in which cilnidipine decreased the myocardial interstitial norepinephrine levels during ischemia and reperfusion periods, leading to reduction of the myocardial infarct size and incidence of ventricular premature beats [112]. Furthermore, in vivo experimental data have suggested that cilnidipine shows antianginal effects in the experimental model of vasopressin-induced angina and improvement of the ventricular repolarization abnormality in the canine model of long QT syndrome [113,114]. On the other hand, the CANDLE trial [115] and other clinical studies have demonstrated that cilnidipine improves left ventricular function [116,117], and produces a greater decrease in left ventricular mass than quinapril [110].

Cerebrovascular Action

The brain is known to have an autoregulatory capacity that allows cerebral blood vessels to maintain constant cerebral blood flow by dilating or contracting in response to abrupt changes in blood pressure [118]. Watanabe et al. [119] demonstrated that the cerebral blood flow was maintained regardless of whether blood pressure was decreased by cilnidipine. Furthermore, cilnidipine had the activity to shift downwards the lower limit of autoregulation for cerebral blood flow according to the results of the estimation of the lower limit of autoregulation for cerebral blood flow by exsanguination. In a previous study, using neuronal cells acutely isolated from the rat brain, cilnidipine has been shown to suppress L- and N-type Ca2+ channel currents, whereas nilvadipine inhibits only L-type Ca2+ channels [120]. Interestingly, an antihypertensive and antisympathetic dose of cilnidipine reduced the size of cerebral infarction in the rat focal brain ischemia model in contrast to nilvadipine [121], which is in accordance with previous study using a peptidic N-type Ca2+ channel blocker ω-conotoxin MVIIA [46]. Thus, the results may support that N-type Ca2+ channel activation includes pathophysiological process of brain ischemia. A clinical study of cold pressor test has shown that cilnidipine decreased plasma level of ß-thromboglobulin, a marker of platelet activation [122], which may prevent arterial thrombosis formation associated with increased sympathetic tone.

Renal Action

Glomerular hypertension is closely associated with the progression of kidney diseases. Thus, it is important to keep glomerular pressure lower by dilation of both afferent and efferent arteries in hypertensive patients. Since sensitivity of Ca2+ channel blockers to afferent and efferent arteries varies, as reviewed by Hayashi et al. [123], Ca2+ channel blockers should be appropriately selected for hypertensive patients with chronic kidney disease. On the other hand, N-type Ca2+ channel activity may be partly associated with control of the glomerular pressure, since the sympathetic nerves are distributed to the afferent and efferent arteries [124]. Using the hydronephrotic kidney model of anesthetized rats, cilnidipine has been demonstrated to dilate both afferent and efferent arteries [125]. Since cilnidipine elicits predominant action on the afferent arteriole in the in vitro isolated perfused hydronephrotic kidney [123], the inhibition of N-type Ca2+ channels, leading to suppression of norepinephrine release in the kidney [96], would dilate both arterioles. In renal injury animal models, cilnidipine reduces glomerular capillary pressure, afferent and efferent arteriolar resistances, urinary albumin excretion, and glomerular volume as well as plasma norepinephrine levels [126–128].

In clinical studies, Rose et al. [129] demonstrated that cilnidipine significantly decreased urinary albumin excretion without affecting serum creatinine concentration in hypertensive patients, which is comparable to the angiotensin-converting enzyme inhibitor benazepril. Other studies have shown that the renal protective effect of cilnidipine was greater than pure L-type Ca2+ channel blockers [130,131]. Furthermore, the combination of cilnidipine and valsartan was shown to decrease the albumin/creatine ratio more markedly than valsartan alone [132]. Recently, the multicenter, open-labeled and 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 (Figure 10) [133]. Recently, prevalence of cardiovascular disease and cardiovascular mortality have been suggested to be closely associated with renal function; namely, cardio-renal connection [5,134–136]. Thus, the renal protective effects of cilnidipine may secondarily contribute to cardioprotection.

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Figure 10. Change in urinary protein/creatinine (Cr) ratio during the 12-month treatment period assessed in the Cilnidipine versus Amlodipine Randomized Trial for Evaluation in Renal disease (CARTER). Results are expressed as the mean ± SEM. The urinary protein/Cr ratio was suppressed in the cilnidipine group but not in the amlodipine group. *p < 0.05, cilnidipine versus amlodipine groups. (Reproduced with permission from Fujita T [133]. Copyright © 2007, Nature. All rights reserved.)

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Metabolic Syndrome

Hypertension, insulin resistance, and dyslipidemia are associated with central obesity as factors of the metabolic syndrome, and increased body weight is in turn associated with sympathetic activation. Some reports have shown that elevated muscle sympathetic nerve activity and plasma norepinephrine levels are seen in obesity. Furthermore, central obesity may be one of the factors facilitating the development of hypertension in the long term [137,138]. Therefore, it is obvious that controlling sympathetic activity is important in the metabolic syndrome.

Pancreatic insulin secretion from β-cells and glucagon secretion from α-cells in the islets of Langerhans are Ca2+-dependent processes initiated by Ca2+ influx through N-type Ca2+ channels [139–142]. In a study using N-type Ca2+ channel α1B-subunit-deficient homozygous knockout mice fed normal diet, there was improved glucose tolerance without any change in insulin sensitivity, and also body weight gain reduced in the mice fed a high-fat diet [143]. In another study with fructose-fed rats, insulin sensitivity was significantly lower than in controls, and insulin resistance improved significantly after cilnidipine treatment [144]. These imply that N-type Ca2+ channels play a significant role in glucose homeostasis.

Clinically, it was revealed that cilnidipine significantly reduced 24-h urinary catecholamines in hypertensive patients with type 2 diabetes, and thereby may improve insulin resistance [145]. Also, Ueshiba [146] demonstrated that with cilnidipine treatment in patients with obesity, fasting serum immunoreactive insulin (F-IRI), and insulin resistance index as assessed by homeostasis model assessment (HOMA-R) lowered, and serum dehydroepiandrosterone (DHEA) and serum DHEA-sulfate (DHEA-S) increased.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Relationship Between Sympathetic Nerve Activity and Ca2+ Channel Subtypes
  5. Classification of Ca2+ Channel Blockers
  6. The Fourth-Generation Ca2+ Channel Blocker: Cilnidipine
  7. Conclusion
  8. Conflict of Interest
  9. References

The antisympathetic effects of cilnidipine are essentially contrastive to those of the first-, second-, and third-generation Ca2+ channel blockers. Thus, the L/N-type Ca2+ channel blocker cilnidipine can be categorized as the fourth-generation according to its effects on sympathetic function. The present information will be useful for selection of Ca2+ channel blockers according to the pathophysiological condition of a patient.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. The Relationship Between Sympathetic Nerve Activity and Ca2+ Channel Subtypes
  5. Classification of Ca2+ Channel Blockers
  6. The Fourth-Generation Ca2+ Channel Blocker: Cilnidipine
  7. Conclusion
  8. Conflict of Interest
  9. References
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