ORIGINAL ARTICLE

Effects of amlodipine and candesartan on oxidized LDL level inpatients with mild to moderate essential hypertension

PIIBE MUDA1, PRIIT KAMPUS1,2, REIN TEESALU1, KERSTI ZILMER2,

TIINA RISTIMAE1, KRISTA FISCHER3 & MIHKEL ZILMER2

1Department of Cardiology, University of Tartu, L.Puusepa 8, Tartu 51014, Estonia, 2Department of Biochemistry,

University of Tartu, Ravila 19, Tartu 50411, Estonia, and 3Department of Public Health, University of Tartu, Ravila 19,

Tartu 50411, Estonia

AbstractObjective. To compare the effects of amlodipine and candesartan on oxidized low-density lipoprotein (OxLDL), conjugateddienes (CD) and baseline diene conjugation in circulating low-density lipoproteins (LDL-BDC) level duringantihypertensive treatment. Methods. Forty-nine patients with untreated mild to moderate essential hypertension wererecruited in a randomized double-blind study to receive a daily dose either of 8 mg candesartan or 5 mg amlodipine for 16weeks. Blood pressure, OxLDL, CD, LDL-BDC, triglycerides (TG), total cholesterol and lipoprotein cholesterol weremeasured at baseline, at week 2 and at week 16. Results. During treatment, in addition to a significant decrease in systolicand diastolic blood pressure, high level of OxLDL decreased significantly reaching practically upper kit reference values.Both treatment groups were similar with regard to the studied parameters at all time points. At the same time serum TG,lipoprotein and total cholesterol levels as well as LDL-BDC did not change and CD levels did not exceed endemic normal.Decrease in both systolic and diastolic blood pressure was associated with decrease in LDL-BDC/LDL. Conclusions. Besidestheir antihypertensive effects, both candesartan and amlodipine are efficient drugs for reducing OxLDL level, being neutralwith regard to serum lipids.

Key Words: Amlodipine, candesartan, hypertension, oxidized LDL

Introduction

Angiotensin II type 1 (AT1) receptor antagonists and

calcium-channel blockers are among the first choice

drugs for treatment of essential hypertension (1).

Experimental studies have suggested that both AT II

over the AT1 receptor and calcium have an impact

on low-density lipoprotein (LDL) oxidation (2,3).

The AT1 receptor blocker candesartan and the

calcium-channel blocker amlodipine are effective in

reducing blood pressure in patients with essential

hypertension (4) and also possess some antioxidative

properties (5,6). Essential hypertension is associated

with limitation in antioxidative defence suggesting

that profound oxidative stress is important in the

pathogenesis of essential hypertension (7). LDL

from hypertensive patients was more susceptible to

oxidation than LDL from normotensive controls (8).

Oxidation of LDL plays a significant role in

atherogenesis (9) as these particles are severely

damaged during oxidative processes (10).

Autoantibodies to the epitopes of oxidized LDL

(OxLDL), reflecting the fact that OxLDL is

immunogenic, are found in atherosclerotic lesions

and in the plasma of animals and patients with

various manifestations of atherosclerosis (11–13).

Recently, it was reported that hypertensive patients

have significantly higher OxLDL levels than normo-

tensive controls (14). The initial products of lipid

peroxidation are conjugated dienic hydroperoxides

(15). Baseline diene conjugation in circulating low-

density lipoproteins (LDL-BDC) is an indicator of

Correspondence: Piibe Muda, Department of Cardiology, University of Tartu, L. Puusepa 8, 51014 Tartu, Estonia. Tel: +372 7 318 317. Fax: +372 7 318

317. E-mail: piibe.muda@kliinikum.ee

(Received 15 May 2006; accepted 26 September 2006)

Blood Pressure. 2006; 15: 313–318

ISSN 0803-7051 print/ISSN 1651-1999 online # 2006 Taylor & Francis

DOI: 10.1080/08037050601037844

Blo

od P

ress

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

alif

orni

a Ir

vine

on

10/2

9/14

For

pers

onal

use

onl

y.

in vivo LDL oxidation. Clinical studies have shown

that LDL-BDC is closely related to coronary,

carotid and brachial atherosclerosis (16). There

exist many pathways resulting in increased produc-

tion of OxLDL (17). LDL may be oxidized by metal

ions, lipoxygenases, myeloperoxidase and reactive

oxygen species (18). However, an excessive lipid

peroxidation is among the most likely mechanisms to

produce OxLDL. The present study was undertaken

to compare the effects of amlodipine and candesar-

tan on OxLDL, on conjugated dienes (CD) and

LDL-BDC with the aim to find out how lipid

peroxidation is associated with antihypertensive

treatment.

Materials and methods

Patients

The study group consisted of 49 outpatients (43

men/six women) with untreated mild to moderate

essential hypertension. All subjects who responded

to the advertisement and met the inclusion criteria

were recruited on a consecutive basis between

September 2000 and December 2002 at the

Department of Cardiology, University of Tartu,

Estonia. The diagnosis of hypertension was estab-

lished on the basis of systolic blood

pressurew140 mmHg and/or diastolic blood

pressurew90 mmHg measured during three differ-

ent visits. The patients who had received previous

antihypertensive treatment had been free of medica-

tion for at least two months, while 34 persons (69%)

had never been treated. The exclusion criteria

included diabetes (based upon a glucose tolerance

test), history of cardiac or cerebrovascular disease,

heart failure (left ventricular ejection frac-

tionv50%), hypercholesterolaemia (total choles-

terol, Total-C, w6.5 mmol/l), other systemic

diseases, recent/current infection, anaemia, current

smoking, obesity (body mass index, BMIw30 kg/

m2) and secondary hypertension. None of the

patients had clinical evidence suggestive of coronary

artery disease based upon history, electrocardiogra-

phy, exercise test and echocardiography. Routine

clinical, haematological and radiological examina-

tions excluded the secondary forms of hypertension.

All patients had normal renal function and there was

no microalbuminuria on urinanalysis. The subjects

who were taking any medical vitamin preparations or

drugs were not included. No dietary restrictions

were imposed.

Three patients did not complete the study: two

(one from either study group) left the study because

of personal reasons unrelated to the study, and one

patient in the amlodipine group discontinued treat-

ment at week 6 because of a skin reaction; thus data

from 46 patients were available for analysis. Twenty-

four patients [22 men/two women, mean¡SD age

53.9¡6.9 years; BMI 27.0¡2.1 kg/m2, duration of

hypertension 16.0 years (range 0.5–35 years)] were

treated with candesartan, and 22 patients [19 men/

three women, mean age 50.9¡6.6 years; BMI

27.0¡2.1 kg/m2, duration of hypertension 12.4

years (range 0.5–44 years)] were treated with

amlodipine. There were no differences in the

demographic data between the groups. The Ethics

Committee of the Medical Faculty, University of

Tartu, approved the study protocol, and informed

consent was obtained from all participants before the

study.

Study protocol

During the 4-week run-in period, patients did not

receive any treatment and were seen for repeated

measurements of blood pressure, for the performing

exercise stress test, glucose tolerance test, echocar-

diography and ultrasound investigation of the renal

arteries. After run-in period, a total of 49 patients

with mild to moderate essential hypertension were

recruited in a randomized double-blind study to

receive a daily dose of 8 mg candesartan or 5 mg

amlodipine for 16 weeks. The patients who did not

respond (systolic blood pressure >140 mmHg and/

or diastolic blood pressure >90 mmHg) to the

above-mentioned doses at week 2 or 6 of treatment

received a double dose of either drug for the

remaining trial period.

The subjects were studied and the blood samples

were collected between 08.00 and 09.00 h, after

overnight fast. Blood pressure was measured in both

arms with the individual in the sitting position after

10 min of rest using a conventional mercury

sphygmomanometer and a normal size cuff; the

mean of three readings with 2-min intervals was

taken, with diastolic blood pressure at Korotkov

phase V. Each individual’s height and weight were

recorded, and their BMI calculated.

Blood samples and assays

The blood samples were drawn from the antecubital

vein for the measurement of serum Total-C, HDL-

cholesterol (HDL), LDL-cholesterol (LDL) and

triglycerides (TG), as well as lipid peroxidation

markers OxLDL, LDL-BDC and CD. The blood

samples were processed within 30 in. Serum was

separated from the cells by centrifugation at 3000g

for 15 min. Serum Total-C (Human, Germany),

314 P. Muda et al.

Blo

od P

ress

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

alif

orni

a Ir

vine

on

10/2

9/14

For

pers

onal

use

onl

y.

LDL, HDL and TG (Roche Diagnostics, Germany)

were measured with an automated analyser Hitachi

912.

For the measurement of OxLDL, blood was

drawn into tubes containing EDTA. The blood

samples for the measurement of lipid peroxidation

markers were stored at 270˚C until analysis.

OxLDL levels were measured using an enzyme-

linked immunosorbent assay kit (Mercodia, AB,

Uppsala, Sweden, kit upper reference limit 117 U/l).

For LDL-BDC measurement, first LDL was

precipitated as described by Ahotupa et al. (19).

Before precipitation of LDL, the serum samples (to

which 1 mg/ml of EDTA was added) and the

precipitation reagents were allowed to equilibrate

at room temperature; 1 ml of the sample was added

to 7 ml of the heparin-citrate buffer. The precipita-

tion buffer consisted of 0.064 M trisodium citrate

adjusted to pH 5.05 with 5 M HCl, and contained

50,000 IU/l heparin. After mixing with a Vortex

mixer, the suspension was allowed to stand for

10 min at room temperature. The insoluble lipo-

proteins were sedimented by centrifugation at 1000g

for 10 min. The pellet was resuspended in 1 ml of

0.1 M Na-phosphate buffer, pH 8.0, containing

0.9% NaCl. Thereafter the lipids were extracted

from the LDL samples (100 Microl) by chloro-

form–methanol (2:1), dried under nitrogen, then

redissolved in cyclohexane, and analysed spectro-

photometrically at 234 nm. The absorbance units

(difference A234–A300) were converted to the molar

units using the molar extinction coefficient

2.956104 M21cm21. The ratio LDL-BDC to

LDL-C (LDL-BDC/LDL-C was calculated. The

level of blood CD was measured according to the

method described previously (20).

Statistical analysis

Normally distributed data are presented as

mean¡SD; non-normally distributed data are pre-

sented as geometric mean with 95% confidence

intervals. To account for repeated measures, multi-

level linear regression analysis was used to test for

treatment differences in average blood pressures and

biochemical variables over three different time

points. Error bar graphs were used to plot the mean

and 95% confidence interval of biochemical vari-

ables at different timepoints.

Changes in blood pressure values and biochemical

variables were calculated as the difference between

the baseline values and the values at the end of the

study. Pearson coefficients of correlation were

obtained to estimate the associations between

the changes in blood pressures and biochemical

variables. To test whether the associations remain

the same after adjusting for treatment group

indicator, multiple linear regression analysis was

used. All statistical analyses were conducted using

the software R version 1.9.0 for Windows. The level

of significance was defined as pv0.05 (two-tailed).

Results

Forty-nine patients with untreated hypertension (43

men, six women) were studied. The data of three

patients who did not complete the study were not

included in analysis. The study variables for the

hypertensive patients at baseline and during treat-

ment are shown in Table I. Throughout the study,

the treatment groups did not differ significantly with

regard to the parameters studied. According to

multilevel linear regression analysis, both drugs

Table I. Changes in blood pressure and in the biochemical variables during antihypertensive treatment with candesartan or amlodipine.

Variable

Candesartan,

baseline

Candesartan,

week 2

Candesartan,

week 16

Amlodipine,

baseline

Amlodipine,

week 2

Amlodipine,

week 16

SBP, mmHg 150.3¡12.3 135.2¡8.9 132.2¡7.8* 151.6¡8.4 133.8¡9.5 131.2¡9.1*

DBP, mmHg 96.6¡6.0 88.1¡7.1 86.3¡5.8* 96.5¡6.4 85.6¡8.0 84.6¡5.1*

Total-C, mmol/l 5.4¡0.7 5.5¡1.0 5.3¡0.9 5.5¡0.8 5.5¡0.8 5.4¡0.9

LDL, mmol/l 3.6¡0.7 3.6¡0.8 3.6¡0.6 3.5¡0.8 3.4¡0.8 3.5¡0.9

HDL, mmol/l 1.3¡0.3 1.4¡0.2 1.4¡0.3 1.5¡0.4 1.6¡0.4 1.5¡0.4

TG, mmol/l 1.2 (1.0–1.5) 1.3 (1.2–1.6) 1.3 (1.1–1.9) 1.1 (0.9–1.7) 1.1 (0.8–1.9) 1.2 (1.0–1.8)

LDL-BDC, mmol/l 18.8 (16.9–22.6) 18.8 (16.9–22.6) 18.9 (17.2–22.8) 18.8 (16.3–27.1) 17.3 (14.4–23.9) 17.6 (15.2–24.7)

CD, mmol/l 33.2 (30.5–41.6) 35.9 (33.2–41.2) 39.8 (36.5–46.4)* 33.7 (29.1–47.1) 34.6 (28.6–47.5) 41.3 (36.9–50.2)*

LDL-BCD/LDL,

mmol/mmol

5.4 (4.9–6.4) 5.9 (5.3–7.2) 5.4 (4.8–6.6) 5.6 (4.8–8.2) 5.2 (4.3–7.0) 5.2 (4.5–7.4)

The normally distributed data are presented as mean¡standard deviation; the non-normally distributed data are presented as geometric

mean with the 95% confidence intervals. SBP, systolic blood pressure; DBP, diastolic blood pressure; Total-C, total cholesterol; LDL, low-

density lipoprotein cholesterol; HDL, high-density lipoprotein cholesterol; TG, triglycerides. There were no differences between the

treatment groups. *denotes a significant difference from a baseline value. pv0.05 was considered significant.

Antihypertensive therapy and lipid peroxidation 315

Blo

od P

ress

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

alif

orni

a Ir

vine

on

10/2

9/14

For

pers

onal

use

onl

y.

caused a highly significant decrease in both mean

systolic blood pressure and mean diastolic blood

pressure (pv0.0001), with no significant differences

between the drugs. The decrease was most pro-

nounced during the first 2 weeks. Further decrease

in blood pressure in the course of the treatment was

insignificant. Doubling of the dose was required for

12 patients in the candesartan group and for nine

patients in the amlodipine group.

Serum TG and lipoprotein cholesterol levels did

not change significantly throughout the study in

either treatment group. A substantial and significant

decrease (pv0.0001) occurred in OxLDL level

(Figure 1) reaching almost the kit upper reference

value (117 U/l). Elevation of mean CD (pv0.006)

did not exceed the population-based upper reference

limit for CD (45 mmol/l, data on file). LDL-BDC

and LDL-BDC-/LDL did not change significantly

remaining within reference limits (10.1–29.9 mmol/l

for LDL-BDC and 3.1–7.9 mmol/mmol for LDL-

BDC/LDL).

The changes in OxLDL and CD were neither

correlated with the changes in blood pressure in

whole study group nor in both treatment groups.

The changes in LDL-BDC were positively asso-

ciated with changes in diastolic blood pressure

(r50.30, p50.045). The changes in the LDL-

BDC/LDL ratio were positively correlated with the

changes in diastolic blood pressure (r50.39,

pv0.01), and there was borderline positive correla-

tion present with the changes in systolic blood

pressure (r50.28, p50.058). After adjusting for the

drug used, the correlations between the changes in

LDL-BDC/LDL ratio and the changes in systolic

blood pressure and diastolic blood pressure

remained significant.

Discussion

The main finding of the present study was that

OxLDL levels decreased substantially and to an

equal degree in both treatment groups, almost

reaching the upper normal reference limit (117 U/

L). Another finding was that neither LDL-BDC and

LDL nor their ratio (LDL-BDC/LDL-C) changed

during antihypertensive treatment with candesartan

or amlodipine. Whether candesartan and amlodipine

have an impact on LDL-BDC level was not

previously known and the effect of candesartan on

CD was not studied before. The ratio of LDL-BDC

to LDL is thought to characterize the degree of LDL

oxidation (21), hence indicating stability of the LDL

particle. The fact that LDL-BDC, LDL-BDC/LDL

and CD were within endemic norm throughout the

study indicates that both studied drugs are neutral in

this regard. This is consistent with previous findings

where both candesartan and amlodipine were

reported to be similar to placebo with regard to

serum lipid levels (22,23). It shows that the positive

effects of both drugs did not involve predominating

lipid peroxidation-targeted influence on OxLDL

levels. Our study confirmed the high antihyperten-

sive efficacy of both candesartan and amlodipine,

well known from several previous reports (4,22,23).

The decrease in OxLDL levels was not correlated

with the changes in blood pressure irrespective of the

drug used. It is reported that the AT1 receptor

blocker losartan shows that prevention or retardation

of atherosclerosis is reached beyond reduction in

blood pressure (24). Dohi et al. showed that

candesartan reduces oxidative stress and inflamma-

tion in patients with essential hypertension indepen-

dently of its effects on blood pressure (25). It has

been demonstrated in hypertensive patients with

type II diabetes that use of amlodipine is associated

with slowing down of progression of carotid athero-

sclerosis irrespective of blood pressure changes (26).

In our study, irrespective of the drug used, the

decrease in blood pressure was associated with

decrease in the LDL-BDC/LDL ratio, suggesting

that lowering of blood pressure may have LDL

particle stabilizing influence.

For both studied drugs (candesartan and amlodi-

pine) several mechanisms are suggested for reduc-

tion of oxidative stress-related hypertension.

Candesartan attenuated the cell-injurious effects of

OxLDL (27), restored nitric oxide availability and

decreased production of reactive oxygen species in

Figure 1. The oxidized low-density lipoprotein (mean with 95%

CI) in hypertensive patients treated with candesartan or amlodi-

pine at different timepoints (p for trendv0.0001). OxLDL,

oxidized low-density lipoprotein.

316 P. Muda et al.

Blo

od P

ress

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

alif

orni

a Ir

vine

on

10/2

9/14

For

pers

onal

use

onl

y.

vascular endothelial cells (28) and lowered OxLDL

level in vascular smooth muscle cells (29). In

hypertensive patients candesartan reduced lipid

peroxidation as measured by malondialdehyde (5).

It is reported that the effects of amlodipine may be

mediated in part by the prostanoid endothelium-

derived factor and nitric oxide, via preservation of

endogenous antioxidant activity, via smooth muscle

cell membrane stabilization, via endothelial cell

protection (6). It has been shown in experimental

studies that amlodipine is able to suppress oxidiz-

ability of LDL in vitro (30) and to inhibit binding of

OxLDL lipids to model membranes (31). Both

studied drugs have favourable effects on the intra-

cellular glutathione system (32). All these findings

support the suggestion that although candesartan

and amlodipine decrease significantly OxLDL level,

evidently, mechanisms other than direct lipid per-

oxidation suppression may have a stronger impact

on the human body.

The main study limitation is relatively small

number of patients. Further studies are needed to

clarify antioxidative mechanisms of these antihyper-

tensive drugs.

We conclude that in addition to their antihyper-

tensive effects, both candesartan and amlodipine are

efficient drugs for reducing OxLDL level, being

neutral with regard to serum lipids.

Acknowledgements

This study was supported by the Estonian Scientific

Foundation, grants No. 4442 and 5327. The

authors thank AstraZeneca AB for providing the

study drugs in a double dummy formula.

This work was supported by the Estonian

Scientific Foundation, grants No. 5833 and 6588.

References

1. 2003 European Society of Hypertension – European Society

of Cardiology guidelines for the management of hypertension.

J Hypertens. 2003;21:1011–1053.

2. Hayek T, Attias J, Coleman R, Brodsky S, Smith J,

Breslow JL, et al. The angiotensin-converting enzyme

inhibitor, fosinopril, and the angiotensin II receptor antago-

nist, losartan, inhibit LDL oxidation and attenuate athero-

sclerosis independent of lowering blood pressure in

apolipoprotein E deficient mice. Cardiovasc Res. 1999;44:

579–587.

3. Wells KE, Miguel R, Alexander JJ. Transmembrane calcium

flux regulates LDL oxidation by arterial smooth muscle cells.

J Surg Res. 1997;67:126–131.

4. Kloner RA, Weinberger M, Pool JL, Chrysant SG, Prasad R,

Harris SM, et al. Comparison of Candesartan and

Amlodipine for Safety, Tolerability and Efficacy (CASTLE)

Study Investigators. Comparative effects of candesartan

cilexetil and amlodipine in patients with mild systemic

hypertension. Am J Cardiol. 2001;86:727–731.

5. Koh KK, Ahn JY, Han SH, Kim DS, Jin DK, Kim HS, et al.

Pleiotropic effects of angiotensin II receptor blocker in

hypertensive patients. J Am Coll Cardiol. 2003;42:905–910.

6. Mason RP. Mechanisms of plaque stabilization for the

dihydropyridine calcium channel blocker amlodipine:

Review of the evidence. Atherosclerosis. 2002;165:191–199.

7. Russo C, Olivieri O, Girelli D, Faccini G, Zenari ML,

Lombardi S, et al. Anti-oxidant status and lipid peroxidation

in patients with essential hypertension. J Hypertens.

1998;16:1267–1271.

8. Keidar S, Kaplan M, Shapira C, Brook JG, Aviram M. Low

density lipoprotein isolated from patients with essential

hypertension exhibits increased propensity for oxidation and

enhanced uptake by macrophages: A possible role for

angiotensin II. Atherosclerosis. 1994;107:71–84.

9. Witztum JL, Steinberg D. The oxidative modification

hypothesis of atherosclerosis: Does it hold for humans?

Trends Cardiovasc Med. 2001;11:93–102.

10. Parthasarathy S, Santanam N, Auge N. Oxidized low-density

lipoprotein, a two-faced Janus in coronary artery disease?

Biochem Pharmacol. 1998;56:279–284.

11. Tsimikas S, Palinski W, Witztum JL. Circulating autoanti-

bodies to oxidized LDL correlate with arterial accumulation

and depletion of oxidized LDL in LDL receptor-deficient

mice. Arterioscler Thromb Vasc Biol. 2001;21:95–100.

12. Shaw PX, Horkko S, Tsimikas S, Chang MK, Palinski W,

Silverman GJ, et al. Human-derived anti-oxidized LDL

autoantibody blocks uptake of oxidized LDL by macrophages

and localizes to atherosclerotic lesions in vivo. Arterioscler

Thromb Vasc Biol. 2001;21:1333–1339.

13. Tsimikas S, Bergmark C, Beyer RW, Patel R, Pattison J,

Miller E, et al. Temporal increases in plasma markers of

oxidized low-density lipoprotein strongly reflect the presence

of acute coronary syndromes. J Am Coll Cardiol. 2003;41:

360–370.

14. Frostegard J, Wu R, Lemne C, Thulin T, Witztum JL, de

Faire U. Circulating oxidized low-density lipoprotein is

increased in hypertension. Clin Sci. 2003;105:615–620.

15. Dotan Y, Lichtenberg D, Pinchuk I. Lipid peroxidation

cannot be used as a universal criterion of oxidative stress.

Prog Lipid Res. 2004;43:200–227.

16. Ahotupa M, Asankari TJ. Baseline diene conjugation in LDL

lipids: An indicator of circulating oxidized LDL. Free Radic

Biol Med. 1999;27:1141–1150.

17. Halliwell B, Gutteridge JMC. Free radicals in biology and

medicine. New York: Oxford University Press, 1999:

617–639.

18. Mertens A, Holvoet P. Oxidized LDL and HDL: Antagonists

in atherothrombosis. FASEB J. 2001;15:2073–2084.

19. Ahotupa M, Marniemi J, Lehtimaki T, Talvinen K,

Raitakari OT, Vasankari T, et al. Baseline diene conjugation

in LDL lipids as a direct measure of in vivo LDL oxidation.

Clin Biochem. 1998;31:257–261.

20. Starkopf J, Zilmer K, Vihalemm T, Kullisaar T, Zilmer M,

Samarutel J. Time course study of oxidative stress during

open heart surgery. Scand J Thorac Cardiovasc Surg.

1995;29:181–186.

21. Brizzi P, Tonolo G, Bertrand G, Carusillo F, Severino C,

Maioli M, et al. Autoantibodies against oxidized low-density

lipoprotein (ox-LDL) and LDL oxidation status. Clin Chem

Lab Med. 2004;42:164–170.

22. McClellan KJ, Goa KL. Candesartan cilexetil. A review of its

use in essential hypertension. Drugs. 1998;56:847–869.

Antihypertensive therapy and lipid peroxidation 317

Blo

od P

ress

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

alif

orni

a Ir

vine

on

10/2

9/14

For

pers

onal

use

onl

y.

23. Haria M, Wagstaff AJ. Amlodipine. A reappraisal of its

pharmacological properties and therapeutic use in cardiovas-

cular disease. Drugs. 1995;50:560–586.

24. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G,

de Faire U, et al. LIFE Study Group. Cardiovascular

morbidity and mortality in the Losartan Intervention

For Endpoint reduction in hypertension study (LIFE): A

randomised trial against atenolol. Lancet. 2002;359:

995–1003.

25. Dohi Y, Ohashi M, Sugiyama M, Takase H, Sato K, Ueda R.

Candesartan reduces oxidative stress and inflammation in

patients with essential hypertension. Hypertens Res. 2003;26:

691–697.

26. Pitt B, Byington RP, Furberg CD, Hunninghake DB,

Mancini GB, Miller ME, et al. PREVENT Investigators.

Effect of amlodipine on the progression of atherosclerosis and

the occurrence of clinical events. Circulation. 2000;102:

1503–1510.

27. Li D, Saldeen T, Romeo F, Mehta JL. Oxidized LDL

upregulates angiotensin II type 1 receptor expression in

cultured human coronary artery endothelial cells: The

potential role of transcription factor NF-kappaB.

Circulation. 2000;102:1970–1976.

28. Desideri G, Bravi MC, Tucci M, Croce G, Marinucci MC,

Santucci A, et al. Angiotensin II inhibits endothelial cell

motility through an AT1-dependent oxidant-sensitive decre-

ment of nitric oxide availability. Arterioscler Thromb Vasc

Biol. 2003;23:1218–1223.

29. Watanabe T, Pakala R, Katagiri T, Benedict CR. Mildly

oxidized low-density lipoprotein acts synergistically with

angiotensin II in inducing vascular smooth muscle cell

proliferation. J Hypertens. 2001;19:1065–1073.

30. Chen L, Haught WH, Yang B, Saldeen TG, Parathasarathy S,

Mehta JL. Preservation of endogenous antioxidant activity

and inhibition of lipid peroxidation as common mechanisms

of antiatherosclerotic effects of vitamin E, lovastatin and

amlodipine. J Am Coll Cardiol. 1997;30:569–575.

31. Phillips JE, Preston Mason R. Inhibition of oxidized LDL

aggregation with the calcium channel blocker amlodipine:

Role of electrostatic interactions. Atherosclerosis. 2003;168:

239–244.

32. Muda P, Kampus P, Zilmer M, Ristimae T, Fischer K,

Zilmer K, et al. Effect of antihypertensive treatment with

candesartan or amlodipine on glutathione and its redox

status, homocysteine and vitamin concentrations in patients

with essential hypertension. J Hypertens. 2005;23:105–11.

318 P. Muda et al.

Blo

od P

ress

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity o

f C

alif

orni

a Ir

vine

on

10/2

9/14

For

pers

onal

use

onl

y.