Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : October 18, 2014
Accepted : November 1, 2014
Published online : December 31, 2014

Original article

Angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE)inhibitors, and statins as anti-glycation agents
Lanny Parengkuan 1), Masayuki Yagi 1), Moniruzzaman Mohammad 1),
Shin-ichi Asahi 2), Yoshikazu Yonei 1)
1) Anti-Aging Medical Research Center and Glycation Stress Research Center, Graduate School of Life and Medical Sciences,
Doshisha University, Kyoto, Japan
2) Hibiya Park Clinic, Minato-ku, Tokyo

Abstract

Background: Angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, and statins are widelyused for the treatment of cardiovascular and diabetic complications. Recently, advanced glycation end products (AGEs) havebeen shown to play a role in promoting and accelerating these diseases. ARBs and ACE inhibitors decrease the formationof AGEs via radical scavenging and transition metal chelation both in-vitro and in animal models. Statins may decrease theformation of AGEs and slow the aging process through several potential mechanisms.
Objective: The purpose of this study was to evaluate the inhibitory activity of ARBs, ACE inhibitors, and statins against humanserum albumin ( HSA) glycation.
Methods: Test samples were prepared in dimethyl sulfoxide. An HSA glycation model was generated by incubating HSA andtest samples with and without glucose at 60 °C for 40 h. The fluorescence (excitation, 370 nm; detection, 440 nm) of each sample
was measured using a Spectra Max paradigm multimode detection platform.
Results: Among the tested statins, only fluvastatin, Lochol (fluvastatin), and Lipovas (simvastatin) displayed weak antiglycation activity, with pure fluvastatin (IC 50 = 1.84 mg/nL) having the highest inhibitory activity. Among ARBs, only
valsartan and olmesartan exhibited weak anti-glycation activity, with valsartan showing stronger activity (IC 50 = 2.28 mg/mL).
These effects were weaker than aminoguanidine (IC 50 = 0.063 mg/mL). In contrast, none of the examined ACE inhibitors had
detectable anti-glycation activity.
Conclusion: A part of ARBs and statins seems to possess anti-glycation activity, however it is weak compared to aminoguanidine.

KEY WORDS: aging, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, glycation, statins

Introduction

Aging is a complex process for which many theories havebeen proposed. For example, in the glycation theory of aging,toxic byproducts, particularly advanced glycation end products(AGEs), generated during energy production cause cellular
damage and lead to reduced longevity. AGEs are proteins
and lipids that are formed through the non-enzymatic reaction
between proteins and reducing sugars, such as fructose
and glucose. Inhibition of AGEs formation and therapeuticintervention to reduce AGEs may slow the aging process andtreating age-related diseases.
Aminoguanidine is a widely used AGEs inhibitor thatwas first discovered in 1986 1, 2 ) as a nucleophilic hydrazine
derivative that binds irreversibly to reactive intermediatesof early glycated products, particularly 3-deoxyglucosone.
Contact Address:Professor Yoshikazu Yonei
Anti-Aging Medical Research Center, Graduate School of Life andMedical Sciences, Doshisha University
1-3, Tataramiyakodani, Kyotanabe-shi, Kyoto, 610-0321 Japan
Phone/Fax: +81-774-65-6394 Email: yyonei@mail.doshisha.ac.jp
Co-authors; Parengkuan L, lannyparengkuan@ymail.com,
Yagi M, myagi@doshisha.ac.jp, Asahi S, asahi777@gmail.com.

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Although aminoguanidine prevents AGEs formation and
AGE-induced protein cross-linking 3 ) , this compound has toxic
effects, thus limiting its therapeutic potential. The adverse toxic
effects associated with aminoguanidine include drug-induced
systemic lupus erythematosus, abnormal liver function, flulike syndromes, and vasculitis 4 ). Aminoguanidine can also
damage DNA through hydroxyl- and hydrogen peroxideformation in the presence of Fe + 3 5 ) . Side effects related tothe trapping of pyridoxal leading to a vitamin B6 deficiency
have also been reported 6). Due to the numerous potential toxic
effects of aminoguanidine, other drugs with demonstrated
AGEs inhibitory efficacy in the clinical setting are needed.
Here, we evaluated the AGEs inhibitory activity ofseveral well-tolerated anti-hypertensive drugs and statins

Glycative Stress Research 2014; 1 (4): 90-95(c) Society for Glycation Stress ResearchGlycative Stress Researchagainst human serum albumin (HSA) to assess their potential
as anti-glycation agents.

Methods

In-vitro models of glycation using glucose and HSA wereused to test the inhibitory activity of anti-hypertensive drugs
and statins against AGEs formation 7 ) .
The tested compounds included 12 statins: atorvastatin,
simvastatin, pitavastatin, pravastatin, fluvastatin, lovastatin(Wako Pure Chemical Industries, Chuo-ku, Osaka, Japan),
Lipitor/atorvastatin (Astellas, Itabashi-ku, Tokyo, Japan),
Lipovas/simvastatin ( MSD, Chiyoda-ku, Tokyo, Japan),Livalo/pitavastatin (Kowa, Chuo-ku, Tokyo, Japan), Mevalotin/
pravastatin (Daiichi Sankyo, Chuo-ku, Tokyo, Japan), Lochol/
fluvastatin (Novartis, Minato-ku, Tokyo, Japan), and Crestor/
rosuvastatin (Astra Zeneca, Kita-ku, Osaka, Japan); 11
angiotensin II receptor blockers (ARBs): valsartan, telmisartan(Tokyo Chemical Industry, Kita-ku, Tokyo, Japan), candesartan( Sigma-Aldrich, St. Louis, MO, USA), losartan ( LKTLaboratories, Inc., St. Paul, MN, USA), Nu-lotan/losartan(MSD); Diovan/valsartan (Novartis), Blopress/candesartan(Takeda Pharmaceutical, Chuo-ku, Osaka, Japan), Micardis/
telmisartan (Astellas); Olmetec/olmesartan (Daiichi Sankyo),
Avapro/irbesartan (Dainippon Sumitomo, Chuo-ku, Osaka,
Japan), and Irbetan/irbesartan (Shionogi, Chuo-ku, Osaka,
Japan); 10 angiotensin converting enzyme (ACE) inhibitors:
Coversyl/perindopril (Kyowa-Hako Kirin Servier, Chiyodaku, Tokyo, Japan), Adecut/delapril ( Takeda Pharmaceutical),Captoril /captopril ( Daiichi Sankyo), Renivace / enalapril(MSD), Longes/lisinopril (Shionogi), Zestril/lisinopril (Astra
Zeneca), Cibacen/benazepril (Novartis), Tanatril/imidapril(Mitsubishi Tanabe Pharma Corp., Chuo-ku, Osaka, Japan),
Preran/trandolapril (Sanofi Aventis, Shinjuku-ku, Tokyo,
Japan), and Odric/trandolapril (Nippon Shinyaku, Minamiku, Kyoto, Japan). Test compounds were dissolved in dimethyl
sulfoxide (DMSO; Wako Pure Chemical Industries) prior touse.
The HSA model was used to assay the AGEs inhibitory
activity of the test compounds as previously reported 7 ) . For
the assay, 100 µL of each test sample (anti-hypertensive drugs,
statins, or DMSO [control]) was added to 900 µL of glucose(+) or glucose (-) HSA solution, and the resulting reaction
mixtures were incubated at 60 °C for 40 h. The glucose (+)
reaction solution contained 0.1 M phosphate buffer (pH 7.4),
40 mg/mL HSA (Sigma Chemical Ltd., Perth, WA, USA),
2.0 M glucose, and distilled water at a 5:2:1:1 volume ratio.
The glucose (-) reaction solution contained 0.1 M phosphatebuffer (pH 7.4), 40 mg/mL HSA, and distilled water at a 5:2:2
volume ratio.
After the 40-h incubation, sample solution (200 µL),
distilled water (200 µL), and 5 µg/mL quinine sulfate (200µL) were dispensed into a well of black microplate, and thefluorescence (excitation, 370 nm; detection, 440 nm) was
measured using the Spectra Max paradigm multimode detection
platform (Molecular Devices, Sunnyvale, CA, USA) 7 , 8 ) .
The AGEs inhibitory activity of each sample wascalculated using the following formula:
Inhibitory activity against AGEs fluorescence, (%) =(1 – Glu (+) sample – Glu (-) sample) / (Glu (+) control –Glu (-) control) × 100(Glu means glucose in this formula)

The 50% inhibitory concentration ( IC 50) against AGEs
fluorescence, was calculated from a regression curve of theinhibitory activity for three concentrations of each sample (n =3). The activity of each extract was compared with the activityof aminoguanidine 8 ) .

Results

The results of the HSA assay for each test compound arepresented in Table 1. In the statin group, only fluvastatin,
Lochol/fluvastatin, and Lipovas/simvastatin showed antiglycation activity, with pure fluvastatin having the highest
inhibition rate. Among ARBs, Diovan/valsartan and Olmetec/
olmesartan displayed anti-glycation activity, with Diovan/
valsartan showing stronger anti-glycation activity. In contrast,
no ACE inhibitor had detectable anti-glycation activity.

Discussion

Our findings show that the ARBs valsartan/Diovan andolmesartan/Olmetec, and the statins fluvastatin and simvastatin/
Lipovas have anti-glycation activity. Notably, none of theexamined ACE inhibitors had detectable anti-glycation activity.
Although the anti-glycation activities of the ARBs and statinsare not as high as that of aminoguanidine ( IC 50 = 0.063 mg/mL) 9 ), these findings suggest that treatment with these drugs
may be effective in preventing AGE-related complications
with a reduced risk of adverse effects in diabetic andcardiovascular patients. However these result may be different
from the in vivo reaction considering the glucose absorbent
mechanism and the possibility of enhance insulin reaction are
different for each compounds.
Anti-hypertensive drugs such as ARBs and ACE inhibitors
decrease the formation of AGEs via radical scavenging andtransition metal chelation 10) both in-vitro and in animal models
of diabetes 11, 12). Furthermore, the results of in-vitro experiments
and preclinical and clinical studies suggest that ACE inhibitors
prevent AGEs formation by promoting expression of thereceptor of AGE (RAGE) 11). Sebekova et al. 13) reported
that treatment with the ACE inhibitor ramipril for 2 months
significantly decreased the fluorescent AGE level in 12 subjects
with nondiabetic nephropathy. It is conceivable that blockadeof the renin-angiotensin system (RAS) with drugs such as ACE
inhibitors may affect AGEs accumulation by either improving
renal function or reducing oxidative stress. Culture experiments
using NRK-49F cells exposed to AGEs demonstrated that
the ACE inhibitor captopril blocks AGE-induced collagenproduction 14). In addition, increased protein expression of
RAGE was also attenuated by ACE inhibition 14).
ARBs have protective effects against kidney damage
and can reduce renal AGEs accumulation and proteinuria
in diabetic rodents in vivo 12, 15 -17) to a similar degree to thatof ACE inhibitors 18). For example, in-vivo studies using a
renal ablation model showed that treatment with the ARBs,
losartan, decreased serum AGEs concentrations and improved
renal function independent of changes in the profibrotic
cytokine transforming growth factor-ß 19). Here, in contrast,
we found that losartan, in both its pure and commercially
produced forms, did not display anti-glycation activity. These
apparently contrasting results may be explained by the factthat the previous study found that AGEs were reduced in_ 91 _

Anti-glycative effect of ARBs, ACEIs, and statins

Table 1. Inhibition of formation of fluorescence AGEs by ARBs, ACE inhibitors and statins.
No
1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

Group
StatinStatinStatinStatinStatinStatin

ARBs

ARBs

ARBs

ARBs

StatinStatinStatinStatinStatinStatin

ARBs

Chemical compound

Product nameConcentration (mg/ml) Inhibition rate (%)
0.1

Atorvastatin-5.2 ± 3.1

0.1-2.7 ± 5.6

0.001

1.7 ± 4.8

0.001
0.01

Simvastatin

0.001-4.4 ± 8.3-24.0 ± 15.7

0.001

-3.6 ± 1.8

0.01

0.001

0.1

-12.3 ± 2.8

0.01

0.001
0.1

0.01

Lipitor*

Simvastatin

Lipovas*Pitavastatin calcium

Livalo*Pravastatin sodium

Mevalotin*

Fluvastatin sodium

Lochol*rosuvastatin calcium

Crestor*Losartan potassium

Nu-lotan*_ 92 _-5.1 ± 4.8-22.8 ± 7.7

0.1

Atorvastatin-calcium hydrate-23.2 ± 7.2

0.01

0.001

Losartan-8.5 ± 6.3-16.3 ± 6.6

0.01

Candesartan-7.3 ± 7.8

0.001

0.001

Telmisartan

31.5 ± 4.3-19.5 ± 7.4

0.1

Valsartan-12.7 ± 1.7

0.1

0.01

Lovastatin-10.4 ± 2.0

0.1

0.1

Fluvastatin-5.3 ± 7.5-10.5 ± 2.4

0.01

Pravastatin

0.1 ± 6.0

0.1

0.01

Pitavastatin-9.8 ± 5.6

0.01-18.3 ± 6.7-30.1 ± 3.5-23.7 ± 3.2
11.9 ± 3.9
7.6 ± 4.3
4.2 ± 3.8
7.8 ± 6.0
1.7 ± 5.2

0.001

-2.8 ± 6.0

0.01

3.7 ± 6.4

0.1

0.001

6.3 ± 4.7
2.1 ± 6.9

0.1

19.4 ± 3.9

0.001

1.8 ± 6.5

0.01

5.2 ± 4.2

0.1

18.2 ± 1.3

0.001

4.9 ± 3.2

0.01
0.1

0.01

0.001

5.8 ± 3.5
9.5 ± 4.8
7.5 ± 5.6
4.3 ± 5.2

0.1

32.1 ± 4.1

0.001

10.4 ± 5.7

0.01
0.1

0.01

0.001
0.1

0.01

0.001

14.1 ± 4.3
17.3 ± 3.4
15.6 ± 5.2
13.0 ± 5.9
23.5 ± 5.0
20.9 ± 7.1
17.3 ± 8.9

IC 50
None

None

None

None

1.84 ± 0.90

None

None

None

None

None

None

> 10 0None

None

14.07 ± 15.39

None

None

Glycative Stress Research

No
18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

Group
ARBs

ARBs

ARBs

ARBs

ARBs

ARBs

ACE inhibitor

ACE inhibitor

ACE inhibitor

ACE inhibitor

ACE inhibitor

ACE inhibitor

ACE inhibitor

ACE inhibitor

ACE inhibitor

ACE inhibitor

Chemical compound

Product nameValsartan

Diovan*Candesartan cilexetil

Blopress*

Telmisartan

Micardis*

Olmesartan medoxomil

Olmetec*

Irbesartan

Avapro*Irbesartan

Irbetan*Perindopril erbumine

Coversyl*

Delapril hydrochloride

Adecut*Trandolapril

Preran*Trandolapril

Odric*

Captopril

Captoril*

Enalapril maleate

Renivace*

Lisinopril hydrate

Longes*Lisinopril hydrate

Zestril*Benazepril hydrochloride

Cibacen*

Imidapril hydrochloride

Tanatril*Concentration (mg/ml) Inhibition rate (%)
0.1

40.0 ± 1.0

0.001

19.1 ± 5.0

0.01
0.1

0.01

0.001

24.5 ± 3.4
14.7 ± 5.5
3.4 ± 5.4
3.4 ± 5.0

0.1

10.9 ± 4.5

0.001

14.8 ± 5.0

0.01
0.1

0.01

0.001
0.1

10.7 ± 3.0
11.8 ± 4.7-5.7 ± 8.9-7.0 ± 7.8-9.4 ± 7.3

0.01-11.8 ± 8.1

0.1-12.4 ± 1.7

0.001-13.6 ± 16.2

0.01

-6.9 ± 8.1

0.001
0.01
0.1

0.001
0.1

-6.2 ± 10.0

20.5 ± 52.5
-9.3 ± 5.4-5.6 ± 7.0
5.2 ± 0.6

0.01

-8.0 ± 4.8

0.1-3.8 ± 5.9

0.001
0.01

0.001
0.1

0.01

0.001
0.1

0.01

0.001
0.1

0.01

0.001
0.1

0.01

0.001
0.1

0.01

0.001

-6.0 ± 6.3-7.4 ± 3.9-4.8 ± 5.5-6.5 ± 4.6-6.6 ± 5.4-3.4 ± 5.1-3.3 ± 2.5-8.9 ± 2.9-4.3 ± 4.6-3.9 ± 5.3-5.2 ± 5.5-7.0 ± 6.0-1.3 ± 5.8-5.7 ± 4.7-2.3 ± 6.3
3.7 ± 4.8
7.5 ± 4.2
6.2 ± 8.3

0.1

13.9 ± 3.00.001

2.3 ± 4.8

0.01
0.1

0.01

0.001

6.0 ± 6.4
7.1 ± 3.7

-5.0 ± 14.4
-3.9 ± 8.3

IC 50
2.28 ± 2.37

None

None

> 100

None

None

None

None

None

None

None

None

None

None

None

None

Data are expressed as mean ± standard deviation. None, non-dose dependent; AGEs, advanced glycation end products; ARBs, angiotensin receptor blockers;
ACE, angiotensin-converting enzyme; IC 50, 50% inhibitory concentration expressed in mg/mL.*Samples were prepared from commercially available tablets thatwere grounded into powder. Aminoguanidine IC50 was 0.063 mg/mL in our previous study 9).

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Anti-glycative effect of ARBs, ACEIs, and statinsassociation with improved renal function and reactive oxygen
species (ROS) inhibition 20) whereas our study was limited to
examining the direct inhibitory effect of losartan on in-vitro
AGEs generation.
The ARB valsartan also has renoprotective effects, which
are independent of blood pressure in type 2 diabetes mellitus
patients 16, 21). Valsartan treatment also decreases serum AGEs
in type 2 diabetic subjects with hypertension 16) though an
unknown mechanism, although the anti-oxidative activity ofvalsartan may contribute to this response 22). Consistent withthis finding, valsartan exhibited anti-glycation activity inthe present HSA assay. The ARB olmesartan was recently
reported to inhibit the formation and accumulation of AGEs
in vitro 10) and in diabetic rat models 12,15). Valsartan treatment
also decreases serum AGEs in type 2 diabetic subjects withhypertension 16) through an unknown mechanism, although
the anti-oxidative activity of valsartan may contribute to this
response 22).
Statins, which are competitive inhibitors of 3-hydroxy3-methylglutaryl coenzyme A ( HMGCoA) reductase, may
decrease the formation of AGEs and slow the aging process
through several potential mechanisms. Evidence suggeststhat statins are involved in a positive feedback regulation
mechanism between C-reactive protein and the AGE-RAGE
axis, reduce the AGE-induced formation of intracellular
reactive oxygen species ROS, and due to their cholesterollowering effects, increase the level of soluble RAGE by
inducing RAGE shedding 23-25). These findings indicate thatstatins reduce serum levels of AGEs, lower RAGE expression,and increase soluble RAGE levels by inducing RAGE shedding
in diabetic patients 25). Statins are also reported to play a keyrole in the treatment of AGE-induced diabetic vasculopathy
by blocking RAGE-AGE interaction and inhibiting ROS
generation 24). Our present findings demonstrate that statins(fluvastatin and simvastatin / Lipovas) directly inhibit glycationin vitro, and suggest that these compounds may also reduce
AGEs formation in vivo.
In the present HSA assay results, several differences inReferences

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Conclusion

We have shown that ARBs and statins possess antiglycation activity in vitro, suggesting that these anti-hypertensive
drugs may have AGEs inhibitory activity and therefore beeffective for preventing AGE-related complications in diabetic
and cardiovascular patients. However, because the differencein chemical structures and glucose absorbance mechanism oftested compounds, their in-vivo effects may differ from the invitro activities determined using the HSA. Therefore, althoughpromising, caution is needed when interpreting the present
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Conflicts of interest statement

The authors have no conflicts of interest related to thisstudy to declare.

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