Calcium-Channel Blockers as Antidementia Drugs

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Circulation Journal Vol.80, November 2016
Circulation Journal
Official Journal of the Japanese Circulation Society
http://www.j-circ.or.jp
Article p 2336
In this issue of the Journal, Hwang et al report their large 
population-based cohort study using the database of the 
Korean National Health Insurance Service to focus on dementia, 
and they show that CCB users had a significantly reduced risk 
of dementia (adjusted hazard ratio for total dementia 0.81, for 
Alzheimer disease 0.80, and for vascular dementia 0.81).7 
Overall, the risk reduction ratio was around 20% in CCB 
users. In a basic experiment, Kishi and Sunagawa demon-
strated that combination therapy with atorvastatin and a CCB, 
amlodipine, inhibited sympathetic nervous system activation 
and improved cognitive function in hypertensive rats via an 
antioxidant effect in the rostral ventrolateral medulla, indepen-
dent of the BP-lowering effect.8 Tsukuda et al also reported a 
preventive effect of a non-hypotensive dose of nifedipine on 
cognitive decline in diabetic mice, with a decrease in superox-
ide anion production in the brain and an increase in cerebral 
blood flow.9 Moreover, CCBs such as amlodipine are reported 
to have vascular protective effects via an increase in endothe-
lial nitric oxide.10 Katusic and Austin clearly showed a neuro-
vascular protective function of endothelial nitric oxide.11 
Therefore, a CCB-induced vascular protective effect is one of 
the possible mechanisms of preventing the incidence of 
ascular risk factors such as hypertension, obesity and 
diabetes have been focused on as potentially modifi-
able risk factors for Alzheimer disease, as well as 
vascular dementia,1 because dementia is considered to be 
induced via disruption of neurovascular coupling, with vascu-
lar disorder as one possible mechanism.2 One vascular risk 
factor, mid-life high blood pressure (BP), is associated with 
poor cognitive performance, compared with late-life high BP.3 
Launer et al demonstrated in the Honolulu Heart Program/
Honolulu Asia Aging Study the possibility that lowering mid-
life systolic BP using antihypertensive drugs may reduce late-
life dementia.4 Therefore, antihypertensive drugs are expected 
to be effective as antidementia drugs (Figure). Among the 
antihypertensive drugs, calcium-channel blockers (CCBs) and 
renin-angiotensin system (RAS) blockers, such as angioten-
sin-converting enzyme inhibitors (ACEIs) and angiotensin 
type 1 receptor blockers (ARBs), showed benefit in preventing 
cognitive decline in several randomized, double-blind pla-
cebo-controlled trials. For example, in the SYSTolic hyperten-
sion in EURope (SYST-EUR) trial, treatment with a CCB, 
nitrendipine, demonstrated prevention of dementia,5 and in the 
Perindopril pROtection aGainst REcurrent Stroke (PROGRESS) 
study, an ACEI, perindopril,6 showed a preventive effect on 
cognitive decline.
V
The opinions expressed in this article are not necessarily those of the editors or of the Japanese Circulation Society.
Received September 21, 2016; accepted September 27, 2016; released online October 5, 2016
Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Toon, Japan
Mailing address: Masaki Mogi, MD, PhD, Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, 
Graduate School of Medicine, Shitsukawa, Toon 791-0295, Japan. E-mail: mmogi@m.ehime-u.ac.jp
ISSN-1346-9843 doi: 10.1253/circj.CJ-16-0980
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp
Calcium-Channel Blockers as Antidementia Drugs
Masaki Mogi, MD, PhD; Masatsugu Horiuchi, MD, PhD
Figure. Effect of antihypertensive 
drugs on dementia and possible rela-
tionship between hypertension (HT) 
and vascular degeneration.
EDITORIAL
Circulation Journal Vol.80, November 2016
2292 MOGI M et al.
Dziewas R, et al. High-normal blood pressure is associated with poor 
cognitive performance. Hypertension 2008; 51: 663 – 668.
 4. Launer LJ, Hughes T, Yu B, Masaki K, Petrovitch H, Ross GW, et 
al. Lowering midlife levels of systolic blood pressure as a public 
health strategy to reduce late-life dementia: Perspective from the 
Honolulu Heart Program/Honolulu Asia Aging Study. Hypertension 
2010; 55: 1352 – 1359.
 5. Forette F, Seux ML, Staessen JA, Thijs L, Babarskiene MR, Babeanu 
S, et al. The prevention of dementia with antihypertensive treatment: 
New evidence from the Systolic Hypertension in Europe (SYST-
EUR) study. Arch Intern Med 2002; 162: 2046 – 2052.
 6. Tzourio C, Anderson C, Chapman N, Woodward M, Neal B, 
MacMahon S, et al. Effects of blood pressure lowering with perin-
dopril and indapamide therapy on dementia and cognitive decline in 
patients with cerebrovascular disease. Arch Intern Med 2003; 163: 
1069 – 1075.
 7. Hwang D, Kim S, Choi H, Oh IH, Kim BS, Choi HR, et al. Calcium-
channel blockers and dementia risk in older adults: National Health 
Insurance Service – Senior Cohort (2002 – 2013). Circ J 2016; 80: 
2336 – 2342.
 8. Kishi T, Sunagawa K. Combination therapy of atorvastatin and 
amlodipine inhibits sympathetic nervous system activation and 
improves cognitive function in hypertensive rats. Circ J 2012; 76: 
1934 – 1941.
 9. Tsukuda K, Mogi M, Li JM, Iwanami J, Min LJ, Sakata A, et al. 
Diabetes-associated cognitive impairment is improved by a calcium 
channel blocker, nifedipine. Hypertension 2008; 51: 528 – 533.
10. Batova S, DeWever J, Godfraind T, Balligand JL, Dessy C, Feron O. 
The calcium channel blocker amlodipine promotes the unclamping 
of eNOS from caveolin in endothelial cells. Cardiovasc Res 2006; 
71: 478 – 485.
11. Katusic ZS, Austin SA. Neurovascular protective function of endo-
thelial nitric oxide: Recent advances. Circ J 2016; 80: 1499 – 1503.
12. Hsu CY, Huang CC, Chan WL, Huang PH, Chiang CH, Chen TJ, et 
al. Angiotensin-receptor blockers and risk of Alzheimer’s disease in 
hypertension population: A nationwide cohort study. Circ J 2013; 
77: 405 – 410.
13. Katayama T, Hasebe N. Angiotensin-receptor blockers, hypertension 
and Alzheimer disease: The entangled relationship. Circ J 2013; 77: 
315 – 316.
14. Peters R, Booth A, Peters J. A systematic review of calcium channel 
blocker use and cognitive decline/dementia in the elderly. J Hypertens 
2014; 32: 1945 – 1957; discussion 1957 – 1948.
dementia (Figure).
However, this study has limitations. The first is a method-
ological problem. Previously, Hsu et al demonstrated that 
ARB treatment was not significantly associated with a reduc-
tion of risk of Alzheimer disease in Asian patients with essen-
tial hypertension, using a population-based cohort database in 
Taiwan.12 In a commentary, Katayama and Hasebe pointed out 
that a study limitation was the study not being a prospective 
double-blind placebo-controlled study.13 A similar criticism 
can be raised about the present study. The second problem is 
the characteristics of the CCB users. CCBs are widely used 
with other antihypertensive drugs, and many hypertensive 
subjects are treated with a combination of RAS blocker and 
CCB. Therefore, comparison of patients on CCB monotherapy 
and on monotherapy with other hypertensive drugs such as 
RAS blockers is needed. More detailed analysis is necessary 
to determine the direct effect of CCBs on dementia.
On the other hand, Peters et al reported a systematic review 
of CCB use and cognitive decline/dementia in the elderly.14 
They concluded that there is no clear evidence to suggest an 
increased or decreased risk of cognitive decline or dementia in 
elderly CCB users, because of the lack of a robust clinical trial 
with many hypertensive subjects with a long follow-up to 
resolve this issue. The present study shows evidence for a 
preventive effect of CCBs on dementia;however, to elucidate 
their actual effect on dementia will be a challenge.
Disclosures / Source of Funding
None.
References
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Alzheimer’s disease prevalence. Lancet Neurol 2011; 10: 819 – 828.
 2. Mogi M, Horiuchi M. Neurovascular coupling in cognitive impair-
ment associated with diabetes mellitus. Circ J 2011; 75: 1042 – 1048.
 3. Knecht S, Wersching H, Lohmann H, Bruchmann M, Duning T,