REVIEW

T-Type Ca Channel Blockade as a Determinant ofKidney Protection
Koichi Hayashi, Koichiro Homma, Shu Wakino, Hirobumi Tokuyama,
Naoki Sugano, Takao Saruta and Hiroshi Itoh

Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan(Received for publication on December 15, 2009)(Accepted for publication on February 18, 2010)

Voltage-dependent Ca channels are classified into several subtypes based on the isoform of
their α1 subunits. Traditional Ca channels blockers (CCBs), including nifedipine and amlodipine, act predominantly on L-type Ca channels, whereas novel CCBs such as efonidipine, benidipine and azelnidipine inhibit both L-type and T-type Ca channels. Furthermore, cilnidipine
blocks L-type and N-type Ca channels. These CCBs exert divergent actions on renal microvessels. L-type CCBs preferentially dilate afferent arterioles, whereas both L-/T-type and L-/
N-type CCBs potently dilate afferent and efferent arterioles. The distinct actions of CCBs on
the renal microcirculation are reflected by changes in glomerular capillary pressure and subsequent renal injury: L-type CCBs favor an increase in glomerular capillary pressure, whereas
L-/T-type and L-/N-type CCBs alleviate glomerular hypertension. The renal protective actionof L-/T-type CCBs is also mediated by non-hemodynamic mechanisms, i.e., inhibition of the inflammatory process and inhibition of Rho kinase and aldosterone secretion. Finally, a growing
body of evidence indicates that T-type CCBs offer more beneficial action on proteinuria and renal survival rate than L-type CCBs in patients with chronic kidney disease (CKD). Similarly, in
CKD patients treated with renin-angiotensin blockers, add-on therapy with N-type CCBs is
more potent in reducing proteinuria than that with L-type CCBs, although no difference isfound in the subgroup with diabetic nephropathy. Thus, the strategy for hypertension treatment with CCBs has entered a new era: treatment selection depends not only on blood pressure control but also on the subtypes of CCBs. (Keio J Med 59 (3) : 84－95, September 2010)

Keywords: renal microcirculation, voltage-dependent Ca channels, efonidipine, T-type calcium channels, chronic kidney disease

Introduction

nal blood flow1 -3 by dilating afferent arterioles preferentially,4 - 8 whereby glomerular hypertension and subsequent renal injury are expected to ensue unless systemic
blood pressure is sufficiently controlled.9 -12
Voltage-dependent Ca channels are widely distributed
throughout the body and play a critical role in the maintenance of vascular tone. Ca channels are classified into
several subtypes, including L-type, T-type, N-type, P/Qtype and R-type Ca channels based on their electrophysiological properties;1 3 among these subtypes, the L-type
Ca channel has been most extensively investigated for
elucidation of its function. The blockade of L-type Ca
channels dilates the systemic vasculature and substan-Calcium channel blockers (CCBs), which target voltage-dependent Ca channels, are widely used in the fieldof hypertension therapy and rank second in the pharmaceutical market for hypertension treatment. Indeed,
CCBs are believed to have less serious adverse effects
than other antihypertensive drugs and are recognized asreliable drugs in terms of lowering blood pressure. A
growing body of evidence, however, points to a problem
associated with kidney function. Conventional CCBs, including nifedipine, diltiazem and amlodipine, elicit
marked increases in the glomerular filtration rate and re-

Reprint requests to: Koichi Hayashi, MD, PhD, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku,
Tokyo 160-8582, Japan, E-mail: khayashi@sc.itc.keio.ac.jp84Keio J Med 2010; 59 (3): 84－95

85

Fig. 1 Classification of voltage-dependent Ca channels.
CCB; calcium channel blocker.

tially reduces blood pressure. In the renal microvasculature, however, the vasodilator response to L-type CCBs
is observed only in preglomerular microvessels (e.g., afferent arterioles), whereas efferent arterioles are refractory to the dilator action of these agents.4- 8 The renal
microvascular response thus supports speculation thatglomerular hypertension may develop following the administration of these agents.
In contrast, T-type Ca channels have been identified as
an important molecular target in various organs, andthey function as a part of physiological and/or pathophysiological activities. 1 4 In the cardiac sinus node,T-type Ca channels participate in the generation of thepacemaker potential.1 5 In the kidney, several Ca channel
subtypes are reported to be present, including L-type,T-type, N-type and P/Q-type Ca channels.1 6, 1 7 Recently,
much interest has been focused on the role of T-type Ca
channels in the kidney. It has been demonstrated that theblockade of T-type Ca channels exerts a beneficial action
on kidney function in chronic kidney disease (CKD), including reduction in proteinuria1 8-2 2 and improvement
in kidney survival.2 3 Collectively, the role of Ca channels may differ depending on the subtype expression
within the kidney, and the specific blockade of Ca channel subtypes would be anticipated to exert a salutary action on the renal microvasculature.
In this article, we review the role of Ca channel subtypes in renal physiology. Furthermore, the effects of theblockade of these Ca channels on CKD are also surveyed.
1. Ca Channel Subtypes
Voltage-dependent Ca channels are classified into L-,
P/Q-, N-, R- and T-type subtypes based on their pharmacological and electrophysiological properties; they are
made up of heteromeric multisubunits, including α1, α2,β, δ and γ (skeletal muscle).1 3 Among these, the α1 subunit possesses the main characteristics of the Ca channel,
such as the ion-conducting pore, ion selectivity and voltage sensitivity, and is encoded by the CACNA1 genefamily, which consists of 10 genes (Fig. 1). In the kidney, a number of Ca channels with various α1 subunits,
including Ca V2.1 (α1A), CaV1.2 (α1C), Ca V1.3 (α1D),
CaV3.1 (α1G) and CaV3.2 (α1H), are expressed and function as L-type (CaV1.2, CaV1.3), T-type (CaV3.1, CaV3.2)
and P/Q-type (CaV2.1) Ca channels;1 3 precise or organized electrophysiological analyses, however, have notbeen conducted because the kidney contains divergent
cell populations. Furthermore, the kidney is suppliedwith numerous nerve endings that possess N-type (α1B)
Ca channels. Interestingly, P- (Ca V2.1a) and Q-type(CaV2.1b) Ca channel subunits are splice variants of asingle gene (i.e., CACNA1A) and are expressed in theafferent arteriole.1 6 Although splice variants have been
demonstrated in neuronal and cardiac cells2 4 as well asHayashi K, et al: T-type Ca Channels and Kidney86

in vascular smooth muscle cells from atherosclerotic tissues,2 5 whether these variants affect the renal function
remains undetermined.
2. Characterization of Renal Microvessels
Afferent and efferent arterioles exist adjoining theglomerulus; they adjust their vascular tone in response tovarious vasoactive stimuli. The fact that glomerular filtration exhibits divergent changes depending on the vasoactive stimuli applied implies that the responsivenessof afferent and efferent arterioles to these stimuli differs.
For example, atrial natriuretic peptide causes afferent arteriolar dilation and efferent arteriolar constriction.2 6, 2 7
Furthermore, elevated renal perfusion pressure2 8, endothelin2 9 and high K levels3 0 elicit predominant constriction of the afferent arteriole.
It has been demonstrated that voltage-dependent Ca
channels functionally prevail in the afferent arteriole.4, 7, 3 0- 3 3 High K-induced membrane depolarization
selectively constricts the afferent arteriole, whereas theefferent arteriole is relatively insensitive to such depolarization.3 0, 3 2 Furthermore, Ca channel agonists (e.g., Bay
K-8644), which directly activate voltage-dependent Ca
channels, cause preferential afferent arteriolar constriction.3 3 Carmines, et al.3 2 directly assessed the intracellular Ca concentration ([Ca2+]i) of isolated rabbit glomeruli
with attached afferent and efferent arterioles. They demonstrated that high K-induced depolarization elevated[Ca2+]i in afferent but not in efferent arterioles. They also
demonstrated that the inhibition of voltage-dependent Ca
channels by nifedipine completely prevented the high
K-induced rise in [Ca2+]i.
When administered in vivo, CCBs, including nifedipine,4, 3 4 nicardipine3 5 and verapamil,4, 7 cause a greater
increase in glomerular filtration rate than that in renal
plasma flow, resulting in an elevated filtration fraction.
These observations suggest predominant action on theafferent arteriole. However, in the in vivo setting, systemic blood pressure is decreased, which may confoundthe effect of CCBs on renal arterioles. To eliminate thepressure-induced changes in vascular tone, Loutzenhiser,
et al.5, 3 6-3 8 used the isolated perfused rat normal kidneymodel. This model provides constant renal perfusionpressure, whereby the myogenic tone of renal microvessels is unaltered. In a series of the experiments, Loutzenhiser, et al. found that under angiotensin II- or norepinephrine-induced vasoconstrictor tone, CCBs including
nifedipine, nisoldipine, diltiazem and amlodipine caused
greater increases in glomerular filtration rate than thosein renal plasma flow, resulting in exaggerated increases
in filtration fraction. 5, 3 6- 3 8 Thus, these observations
again support the finding that CCBs act predominantly
on the renal preglomerular vessels.
Recent advances in laboratory techniques have facilitated more detailed direct observation of the renal micro-

circulation.2 7- 3 0, 3 9- 4 5 Casellas and Navar4 3 developed
an in vitro technique that allows direct visualization of
the juxtamedullary nephron circulation. In their experiments, both verapamil and diltiazem potently inhibitedafferent arteriolar vasoconstriction, whereas efferent arterioles were relatively refractory to the vasodilator action of these agents.46 Similarly, Ito, et al.41, 42 developed
the isolated renal cortical microvessel model and foundthat nifedipine predominantly dilated the afferent arteriole.4 7 Loutzenhiser and Epstein developed a model ofthe isolated perfused hydronephrotic kidney that facilitated direct observation of the renal microvasculature
under defined in vitro conditions.2 7-3 0 Using this model,
we demonstrated that both dihydropyridine-class (e.g.,
nifedipine, nicardipine and amlodipine) and benzothiazepine-class (e.g., diltiazem) CCBs reversed the angiotensin II-induced constriction of the afferent arteriole,whereas the efferent arteriole was refractory to the vasodilator action of these antagonists.4 8, 4 9 Furthermore, using intravital pencil-lens CCD camera videomicroscopy,
we observed that nifedipine caused predominant dilationof the afferent arteriole in the canine kidney (Fig. 2A).5 0
Of note, we also have shown that nifedipine elevates thefiltration fraction (i.e., glomerular filtration rate/renal
plasma flow) in dogs5 0 (Fig. 2B). Since this parameter
nearly parallels the glomerular capillary pressure, ourfindings suggest a potential risk for the development ofglomerular hypertension as a result of nifedipine administration.
The preferential afferent arteriolar action of CCBs suggests the predominant distribution of L-type Ca channels
in this vessel (Fig. 3). Indeed, Hansen, et al. 1 7 havedemonstrated that mRNA encoding CaV1.2 (α1C) L-type
Ca channel subunits is expressed in afferent arterioles
from rabbit cortical preglomerular arterioles. In contrast,
this subunit was not found in cortical efferent arterioles,
although it was present in juxtamedullary efferent arterioles. Similarly, Ono, et al. [personal communication]
have recently demonstrated that CaV1.2 is prevalent in
the rat afferent arteriole, whereas the efferent arteriole
lacks this subunit. These observations thus endorse thefunctional evidence indicating preferential activity ofL-type Ca channels in the afferent, but not in the efferent, arteriole.
In summary, it is reasonable to conclude that voltagedependent Ca channels predominate in the afferent arteriole; in contrast, these channels are sparse or functionally silent in the efferent arteriole.
3. Role of T-type and N-type Ca Channels
in Renal Microvessels
Unlike the conventional types of CCBs, novel CCBs
developed in Japan (e.g., manidipine and efonidipine)
are reported to dilate both afferent and efferent arterioles.8, 1 0 Using microdissected renal arterioles, Arima, etKeio J Med 2010; 59 (3): 84－95

87

Fig. 2 Effects of various Ca channel blockers on in vivo renal microvessels and renal hemodynamics in dogs.
(A) CCBs with preferential blockade of L-type Ca channels (nifedipine) cause predominant afferent arteriolar action, whereas
CCBs with blocking activity toward L-/T-type Ca channels (efonidipine and mibefradil) dilate both afferent and efferent arterioles.
Cilnidipine, an L-/N-type Ca channel blocker, dilates both microvessels, although the response is greater in the afferent arteriole (from
Honda M, et al.5 0). (B) The changes in filtration fraction, a marker for glomerular pressure, vary depending on the CCB used (from
Honda M, et al.5 0). #, p=0.05 vs. baseline; *, p<0.05 vs. baseline; **, p<0.01 vs. baseline; §, p<0.05 vs. nifedipine; †, p<0.05 vs.
afferent arterioles.

al.4 7 reported that manidipine caused efferent as well asafferent arteriolar dilation. Furthermore, Takabatake, etal.5 1 reported that in a rat micropuncture study, efonidipine reduced pre- and postglomerular capillary resistance.
Finally, we demonstrated that several CCBs, including
manidipine, nilvadipine, benidipine and efonidipine,cause substantial dilation of efferent arterioles in the isolated perfused rat hydronephrotic kidney.4 8, 5 2, 5 3 Since
traditional CCBs act on L-type voltage-dependent Ca
channels, and these channels are predominant in the afferent arteriole,3 0, 5 3 the effects on the efferent arterioleby these CCBs are most likely attributed to additional
actions of these CCBs, not due to the class effects ofthese agents.
Recently, a pharmacological study has demonstrated
that efonidipine possesses blocking activity toward
T-type, as well as L-type, voltage-dependent Ca channels.54 T-type Ca channels are distributed substantially inseveral parts of the microvasculature, including mesenteric and cremaster arterioles, and the blockade of thesechannels by selective T-type CCBs, e.g., mibefradil, inhibits the vasoconstriction of these arterioles. In the renal microvasculature, Hansen, et al.1 7 demonstrated thatT-type Ca channels are prevalent in juxtamedullary efferent arterioles, as well as in afferent arterioles of superficial and juxtamedullary nephrons. Furthermore, using
in situ hybridization, Ono, et al. recently identified theCaV3.1 subunit (an α1 subunit of T-type Ca channels) insuperficial efferent as well as in afferent arterioles [personal communication]. Similarly, using the micropuncture technique, Nakamura, et al.5 5 found that mibefradildecreased both afferent and efferent arteriolar resistancein kidneys from spontaneously hypertensive rat (SHR)
kidneys. Recently, Ozawa, et al.5 6 directly visualized efferent arteriolar dilation by some CCBs that possess
blocking activity toward T-type Ca channels. Both mibefradil and nickel chloride potently reverse the angiotensin II-induced constriction of efferent arterioles in theisolated perfused hydronephrotic rat kidney model. Furthermore, the intravital pencil-type CCD camera tech-

Hayashi K, et al: T-type Ca Channels and Kidney

88

Fig. 3 Schematic illustrating the localization of Ca channels in the kidney.

nique revealed that efonidipine and mibefradil provoke
efferent as well as afferent arteriolar dilation in dog kidneys in vivo5 0 (Fig. 2A). Collectively, these novel findings strongly suggest a critical role for T-type Ca channels in mediating the efferent arteriolar tone.
N-type Ca channels are present at sympathetic nerve
terminals that are distributed along afferent and efferent
arterioles. It has been reported that cilnidipine, an
N-type CCB, reduced both afferent and efferent arteriolar resistance in a renal micropuncture study of nitro-Larginine methylester-treated SHR5 7 and dilated both arterioles in the in vivo hydronephrotic kidney.5 8 Similarly,
using an intravital CCD camera, we found that cilnidipine causes substantial vasodilation of efferent, as well asafferent, arterioles in the canine kidney in vivo (Fig. 2A).
This class of CCB is characterized by a unique pharmacological action, i.e., inhibitory action on norepinephrine
secretion5 9, 6 0 and neurally stimulated renal vasoconstriction.6 1 It is noteworthy that, in the in vitro isolated perfused hydronephrotic kidney, cilnidipine elicits predominant action in the afferent arteriole. 6 2 It was inferred,
therefore, that the integrity of the sympathetic nerve isrequired for the full activity of N-type CCBs.
The vasodilator action of T-type and N-type CCBs on
renal microvessels favors reduced glomerular capillarypressure. Indeed, we have shown that both T-type (efonidipine and mibefradil) and N-type CCBs (cilnidipine) reduce or tend to decrease the filtration fraction, an observation contrasting the effects of nifedipine (Fig. 2B).50
4. Role of CCBs in the Progression of Renal Injury
The glomerular hemodynamic effects of L-type CCBs
suggest that these CCBs fail to correct glomerular hypertension in certain experimental conditions. The overall

effect of L-type CCBs on glomerular hemodynamics isdetermined by the balance between the reduction in afferent arteriolar resistance and the fall in systemic bloodpressure, and the changes in these two factors may varydepending on the experimental settings, the magnitudeof depressor activity, and the types of CCBs used. For
example, verapamil is reported to reduce proteinuria andprotect against renal injury in remnant kidney models.6 3, 6 4 In contrast, there have been several reports suggesting deleterious effects of dihydropyridine-class
CCBs in renal diseases.9-1 2, 6 5-6 7 Wenzel, et al.6 6 demonstrated that nitrendipine actually increased proteinuria
and glomerulosclerosis in a two-kidney, one-clip modelof hypertension.
In contrast, CCBs that act on both L-type and T-type
Ca channels and dilate afferent and efferent arterioles
may alleviate glomerular hypertension and could exert
salutary actions on the progression of renal injury. Shudo, et al. 1 8, 6 8, 6 9 reported that efonidipine acutely decreased proteinuria in spontaneously hypertensive rats,
whereas systemic blood pressure was only partially reduced. Additionally, mibefradil potently prevents the development of renal injury in SHR5 5 and DOCA hypertensive rats. 2 0 Likewise, cilnidipine, an L-type andN-type CCB, has been reported to suppress the elevationin blood pressure and blunt the progression of renal injury in Dahl salt-sensitive rats7 0 and to ameliorate glomerular injury and proteinuria in Dahl rats fed on a high-sucrose diet.71
Our previous studies demonstrated that 8-week-treatment with CCBs including nifedipine and efonidipine
showed contrasting effects for these antagonists.5 2 Despite the same reduction in systemic blood pressure,efonidipine markedly prevented an increase in proteinuria, whereas nifedipine did not prevent an increase inKeio J Med 2010; 59 (3): 84－95

proteinuria in subtotally nephrectomized SHR, a modelof CKD with hypertension.72 Furthermore, the histopathological changes and serum creatinine levels were alsoameliorated by efonidipine but not by nifedipine. Of
note, efonidipine reduces proteinuria to the same level asenalapril, and both drugs cause afferent and efferent arteriolar dilation. Thus, the renal protective effect ofefonidipine may be attributed, at least in part, to the glomerular hemodynamic action of this agent, since efonidipine is anticipated to reduce glomerular capillary pressure in the same way that enalapril does.
5. Mechanisms for T-type CCB-induced
Renal Protection
In addition to hemodynamic factors, multiple mechanisms appear to contribute to the ability of T-type CCBs
to protect the kidney. It has been reported that CCBs
suppress mesangial cell proliferation by inhibiting activator protein-1 (AP-1)7 3 and that CCBs modulate genetranscriptions involved in proinflammatory changes (interleukin 1β and granulocyte/monocyte colony stimulating factors).7 4 Efonidipine, a T-type Ca antagonist, hasbeen shown to suppress the phorbol myristate acetate(PMA)-induced activation of nuclear factor kappa B(NF-κB) in cultured human mesangial cells.7 5 Furthermore, CCBs could act as free radical scavengers.76
Rossier, et al. 7 7 found that aldosterone release provoked by angiotensin II and KCl was inhibited by mibefradil but not by nicardipine, suggesting an important
contribution of T-type Ca channels to aldosterone release. Similarly, Somekawa, et al.7 8 recently demonstrated that efonidipine downregulates the expression of aldosterone synthetase, CYP11B2, in rat adrenal cells. Indeed, plasma aldosterone levels are reported to be lower
in patients with hypertension7 9 or chronic glomerulonephritis treated with efonidipine rather than with amlodipine.8 0 Since aldosterone is reported to promote renal injury,8 1 the blockade of aldosterone release would be anticipated to exert salutary action on the progression ofrenal injury.
We have recently shown that Rho kinase activation
participates in the progression of renal injury in subtotal
nephrectomized rats, a model of chronic renal failure.8 2
Conversely, the inhibition of Rho kinase should therefore confer benefit in the treatment of renal disease8 3-8 5in addition to its hypotensive action.8 6 Of interest, ourrecent study demonstrated that T-type CCBs prevent renal Rho kinase activation induced by subtotal nephrectomy and alleviate the progression of kidney disease (Fig.
4).8 7 Furthermore, the expression of T-type Ca channels
is upregulated in kidneys from rats with chronic kidneydisease. 8 7 Since Rho kinase is known to elicit the inflammatory process as well as the enhancement of vascular tone,8 8 the blockade of T-type Ca channels is expected to act as a tool for the prevention of CKD.

89

In summary, T-type Ca channels play an important rolein the development of chronic kidney disease, which action is mediated by multifaceted pathways, including hemodynamic, hormonal and inflammatory factors.
6. Clinical Aspects of the Role of CCBs
The divergent action of L-type and T-type CCBs on renal microcirculation and kidney injury in animal models
may be extrapolated to human CKD. Previous clinical
trials, including ALLHAT (Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial)8 9 and
INSIGHT (Intervention as a Goal in Hypertension Treatment),9 0 showed equivocal effects of L-type CCBs (amlodipine and nifedipine) on the progression of CKD,
compared with ACE inhibitors or diuretics (Table 1). In
contrast, AASK (African American Study of Kidney
Disease and Hypertension)9 1 demonstrated that the amlodipine-treated group manifested an elevation in glomerular filtration rate (GFR) at 3 months but exhibited agreater reduction in GFR than the ACE inhibitor-treatedgroup in African American patients without diabetes
mellitus (non-DM) with CKD. Furthermore, the additionof felodipine to ACE inhibitor therapy conferred no additive benefit in non-DM patients with CKD (REIN-2;
Ramipril Efficacy in Nephropathy trial-2).9 2 Additionally, IDNT (Irbesartan Diabetic Nephropathy Trial), in
which the effect of and irbesartan on the progression of
CKD was evaluated, revealed that amlodipine [an angiotensin receptor blocker (ARB)] potently prevented theprogression of CKD, whereas amlodipine failed to offer
renal protection in type 2 diabetic patients with CKD.9 3
Similarly, the GUARD (Gauging Albuminuria Reduction with Lotrel in Diabetic Patients with Hypertension)
trial showed that the reduction in albuminuria was less inthe amlodipine-treated group than in the diuretics-treatedgroup. 9 4 Head-to-head comparison of amlodipine vs.
valsartan also unveiled an increase in albuminuria inJapanese type 2 DM patients treated with amlodipine(SMART; Shiga Microalbuminuria Reduction Trial).9 5
In concert, these observations suggest reduced or no protective action of the L-type CCB in the progression of
CKD.
One caveat is that the adequate control of blood pressure would be anticipated to alleviate the progression of
CKD. In the sub-analysis of IDNT, the relative risk forthe development of end-stage renal disease was reported
to be lower in patients with systolic blood pressure below 121 mmHg, and the risk in the amlodipine-treatedgroup tended to parallel the levels of systolic blood pressure.9 3 Furthermore, in the NICE Combi (Nifedipine andCandesartan Combination) study, in which the effects ofthe maximal dose of candesartan and combination therapy with candesartan and controlled-release nifedipine on
microalbuminuria were compared, the combination
treatment group manifested significantly reduced albu-

Hayashi K, et al: T-type Ca Channels and Kidney

90

Fig. 4 Effects of efonidipine on Rho kinase activity and renal histology in subtotally nephrectomized spontaneously hypertensive rats
(SHR-Nx).
(A) The phosphorylation level of MYPT1, as a marker for Rho kinase activity, in renal cortex of SHR-Nx. *P<0.05 vs. Sham,##P<0.01 vs. SHR-Nx. (B) Effects of Ca channel blockers on the expression of α-smooth muscle action (SMA) and interstitial fibrosis
in kidneys from SHR-Nx. R(-) indicates an R(-)-enantiomer of efonidipine that selectively blocks T-type Ca channels but has no effecton L-type Ca channels. Data adopted with modification from Sugano N, et al.87

Table 1 Renal protective effects of L-type CCB
CCBControl

ALLHAT89

Amlodipine

Diuretics, ACE inhibitors, β-blockers

Non-DMDM

6 yearseGFR preserved

INSIGHT90

Nifedipine-GITS

Diuretics

Non-DMDM

4 years

Nifedipine-GITS better thandiuretics in maintaining eGFRAASK91

Amlodipine

ACE inhibitors, β-blockers

Non-DM

4 years

Greater reduction in eGFR with
Amlodipine than ACE with
inhibitors

REIN-292

ACE inhibitors + Felodipine

ACE inhibitors

Non-DM

4 years

Renal events did not reduce
despite addition of felodipine

IDNT93

Amlodipine

ARB

DM

5 years

Renal events more frequent with
amlodipine than with ARBGUARD94

ACE inhibitors + Amlodipine

ACE inhibitors + Diuretics

DM

1 years

Reduction in albuminuria lesswith amlodipine than with
diuretics

SMART95

Amlodipine

ValsartanDM

24 weeksAlbuminuria increased with
amlodipine

GITS; gastrointestinal therapeutic system.

Observation
periodResults

Keio J Med 2010; 59 (3): 84－95

91

Table 2 Renal protective effects of L/N- and L/T-type CCB
Study name

CCB

Control

Subjects

Results

Hayashi K, et al.21

Efonidipine (L/T-type)ACE inhibitors

Non-DM

Same proteinuria-reducing effects
CCr well preserved withefonidipine

Ishimitsu T, et al.80

Efonidipine (L/T-type)

Amlodipine (L-type)

Chronicglomerulonephritis

Proteinuria-reducing effect betterwith efonidipine

Nakamura T, et al.97

Azelnidipine (L/T-type)

Amlodipine (L-type)

Mild CKD

Proteinuria-reducing effect betterwith azelnidipine

Ogawa S, et al.98

Azelnidipine (L/T-type)

Nifedipine-CR (L-type)DM

Proteinuria-reducing effect betterwith azelnidipine

Tsuchihashi T, et al.99

Cilnidipine (L/N-type)

Other CCBs

Essential hypertension
Renal hypertension

Proteinuria decreased
No changes in proteinuria

Fujita T, et al.100(Carter study)

ARB + Cilnidipine(L/N-type)

ARB + Amlodipine(L-type)

Non-DM
DM

Proteinuria-reducing effectbetter with cilnidipine
No difference

Abe M, et al.101

ARB + Benidipine(L/T/N-type)

ARB + Amlodipine(L-type)

CKD stage3-5
Non-DM, DM

Proteinuria-reducing effect betterwith benidipine

Omae K, et al.23

L/T-type CCB
Benidipine
Barnidipine
Manidipine
Nilvadipine
Efonidipine

L-type CCB
Nifedipine
Amlodipine
Nicardipine
Nitrendipine

CKD (non-DM)

Better outcome of renal eventswith L/T-type CCB

CCr; creatinine clearance.

minuria with greater reductions in systemic blood pressure.9 6 Accordingly, these observations lend support tothe formulation that strict blood pressure control offers
renal protection that does not depend on the type of antihypertensive agent used.
In contrast, a growing body of clinical evidence has
shown that CCBs with blocking activity toward T-type
Ca channels provide salutary action in protection against
renal injury (Table 2). We previously demonstrated that
efonidipine was as potent as ACE inhibitors in reducing
proteinuria.2 1 Furthermore, efonidipine significantly reduced proteinuria even in a subset of patients in whichmean blood pressures failed to decrease below 100
mmHg. Ishimitsu, et al.8 0 also reported that switchingfrom amlodipine to efonidipine caused a significant decrease in proteinuria in patients with chronic glomerulonephritis. Finally, comparison of azelnidipine (an L/Ttype CCB), Table 3 with amlodipine or nifedipine (Ltype CCBs) showed greater reductions in proteinuria byazelnidipine in patients with CKD9 7 and DM,9 8 respectively.
Cilnidipine is a representative N-type CCB(Table 3)and dilates both afferent and efferent arterioles throughthe inhibition of N-type Ca channels in nerve terminals
innervating renal afferent and efferent arterioles. It has
been reported that cilnidipine exerts antiproteinuric action when administered in patients with essential hypertension.9 9 Recently, Fujita, et al.1 0 0 demonstrated that

add-on therapy with cilnidipine reduces proteinuria morepotently than that with amlodipine in CKD patientstreated with renin-angiotensin blocking agents (CARTER study, Table 2). They suggest that the beneficial action of cilnidipine on proteinuria is mediated by the inhibition of sympathetic nerve activity and the resultant
amelioration of glomerular hypertension. Of note, in a
subset of the DM nephropathy group, they failed toshow a significant decrease in proteinuria with cilnidipine. Since the salutary action of cilnidipine on proteinuria appears to be attributed to the blockade of N-type
Ca channels, it is reasonable to speculate that the failure
to alleviate proteinuria can be ascribed to the impaired
integrity of sympathetic nerve terminals in DM. In contrast, Abe, et al. 1 0 1 recently demonstrated that during
treatment with ARB, benidipine, but not amlodipine, potently reduces proteinuria in DM as well as in non-DM
patients. Based on the pharmacological properties ofbenidipine (i.e., blocking action on L/T/N-type Ca channels), this study underscores a critical role of T-type Ca
channel blockade not only in non-DM but also in DM
patients.
Very recently, Omae, et al.2 3 evaluated the long-term
effects of CCBs with different Ca channel subtype activities on the development of end-stage renal disease in
107 non-DM CKD patients (Table 2). This prospective
study used L-type CCBs (nifedipine, amlodipine, nicardipine and nitrendipine), L/T-type CCBs (benidipine,

Hayashi K, et al: T-type Ca Channels and Kidney

92

Table 3 Characteristics of Ca channel blockers and their chinical significnace
Blocking activity
Drugs

L-typeT-typeN-typeNifedipine

+

–

–

Amlodipine

+

–

?

Efonidipine

+

+

–

Nilvadipine

+

+

–

Azelnidipine

+

+

–

Benidipine

+

+

+

Cilnidipine

+

–

+

Clinical significanceHeart

Contractility ↓Heart rate ↓Heart rate ↓Sympathetic nervous system

Pulse rate ↑Pulse rate ↓Pulse rate ↓Glomerular pressure ↓Glomerular pressure ↓KidneyGlomerular pressure ↑AdrenalAldosterone secretion ↓Data regarding channel blocking activity were adopted with modification from Furukawa T, et al. Eur J Pharmacol 2009;
613: 100–107.

barnidipine, manidipine, nilvadipine and efonidipine,
Table 3) and non-dihydropyridines (diltiazem and verapamil) and found that the use of L-type CCBs was associated with an increase in proteinuria. Furthermore, theuse of L/T-type CCBs was associated with favorable outcomes, as assessed by the changes in eGFR and the renal
survival rate.
In summary, the results obtained from various clinical
trials demonstrate that the effects of CCBs with L-type
Ca channel specific blocking activity on renal outcomesvary depending on several factors, including underlying
renal disease, the blood pressure achieved and the duration of the study. In contrast, CCBs with L/T-type blocking activity consistently offer favorable action on the development of CKD. Although the role of N-type Ca
channel blockade in CKD appears intriguing, its actual
effect may depend on the integrity of the underlying
sympathetic nervous system.
Concluding Remarks
Pharmacological characterization of Ca channel subtypes and their blockers allows understanding of the roleof these channels in the kidney. It is now establishedthat the blockade of T-type or N-type Ca channels exerts
renal protective action by abrogating glomerular hypertension through vasodilator action on both afferent andefferent arterioles. Additionally, T-type CCBs may provide beneficial action through multiple non-hemodynamic mechanisms that act to suppress inflammatory
processes and the renin-angiotensin-aldosterone system.

Such multifaceted action of T-type CCBs serves to protect against renal injury, and their use is anticipated toincrease in the treatment of hypertension with CKD. Although these subclasses of CCB are clinically available
only in Japan and South Korea, a growing body of evidence regarding their efficacy should facilitate thespread of knowledge on these novel types of CCBs.102, 103
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