Angiotensin Receptor Blockers and Glutathione

[Guest guest]

Hi, all.

In the past there has been discussion on some of the lists about

whether making efforts to build glutathione would be compatible with

taking an angiotensin receptor blocker (ARB).

I found four papers in the literature that report investigations

into the effect of ARBs on the glutathione status in rats and in

humans. The abstracts of these papers are pasted below.

All four papers report that it was found that ARBs raised

glutathione and decreased the state of oxidative stress.

I think that this suggests that glutathione building is compatible

with taking ARBs.

In addition, it may also suggest that one of the ways in which ARBs

are beneficial to some people might be their effect on raising

glutathione and lowering oxidative stress.

Please note that I am neither advocating the use of ARBs or opposing

them, only trying to understand the interactions.

Rich

Jpn J Physiol. 2002 Oct;52(5):435-40.

The effects of losartan and enalapril therapies on the levels of

nitric oxide, malondialdehyde, and glutathione in patients with

essential hypertension.

Donmez G, Derici U, Erbas D, Arinsoy T, Onk A, Sindel S, Hasanoglu E.

Department of Physiology, Gazi University Faculty of Medicine,

Ankara, 06510 Turkey.

Several recent studies have shown that essential hypertension is

associated with increased oxidative stress, which may cause

hypertension via enhanced oxidation and inactivation of nitric

oxide. In this study, we investigated the malondialdehyde, nitric

oxide, and glutathione levels in newly diagnosed essential

hypertensive patients and whether or not there was any effect of

antihypertensive treatment with angiotensin II type 1 receptor

antagonist, losartan or angiotensin converting enzyme inhibitor,

enalapril on plasma malondialdehyde, nitric oxide, and glutathione

values. We selected 17 patients (F/M: 10/7, mean age: 46.12 +/- 9.2

years) for enalapril therapy (10-20 mg/d) and 14 patients (F/M: 8/6,

mean age: 47.7 +/- 7.5 years) for losartan therapy (50-100 mg/d),

and compared them with 12 normotensive controls. At the beginning of

the study, both treated groups showed significantly higher plasma

malondialdehyde and lower glutathione and nitric oxide in exhaled

air compared to the control group. After 9 weeks of enalapril and

losartan treatment, both systolic and diastolic pressure were

significantly reduced. Both enalapril and losartan produced a

significant decrease in plasma malondialdehyde and a significant

increase in plasma glutathione levels and nitric oxide in exhaled

air after 9 weeks. Initial values of plasma nitrate levels in

patient groups were similar to the control group and increased

significantly after the treatment period. In conclusion, both

losartan and enalapril may be regulators between oxidant stress and

the antioxidant system.

PMID: 12533248 [PubMed - indexed for MEDLINE]

FASEB J. 2003 Jun;17(9):1096-8. Epub 2003 Apr 22.

Enalapril and losartan attenuate mitochondrial dysfunction in aged

rats.

de Cavanagh EM, Piotrkowski B, Basso N, Stella I, Inserra F, Ferder

L, Fraga CG.

Physical Chemistry-PRALIB, School of Pharmacy and Biochemistry,

University of Buenos Aires, Argentina.

Renin-angiotensin system (RAS) inhibition can attenuate the effects

of aging on renal function and structure; however, its effect on

mitochondrial aging is unknown. To investigate whether an

angiotensin-converting enzyme inhibitor (enalapril) or an

angiotensin II receptor blocker (losartan) could mitigate age-

associated changes in kidney mitochondria, male Wistar rats (14 mo

old) received during 8 mo water containing either enalapril (10

mg/kg/day) (Enal), or losartan (30 mg/kg/day) (Los), or no additions

(Old). Four-month-old untreated rats (Young) were also studied. In

old rats mitochondrial respiratory control, ADP/O, nitric oxide

synthase activity, and uncoupling protein 2 levels were lower (46,

42, 27, and 76%, respectively), and Mn-SOD activity was higher (70%)

than in Young, Enal, and Los rats. In Old rats mitochondrial

hydrogen peroxide production was higher than in both Young (197%)

and Enal or Los (40%) rats. In Old rats, kidney GSH/GSSG was lower

than in both Young (80%) and Enal (57%) or Los (68%) rats. In Old

rats electron microscopy showed effacement of microvilli in tubular

epithelial cells, ill-defined mitochondrial cristae, lower

mitochondrial numbers, and enhanced number of osmiophilic bodies

relative to Young, Enal, or Los rats. In conclusion, enalapril and

losartan can protect against both age-related mitochondrial

dysfunction and ultrastructural alterations, underscoring the role

of RAS in the aging process. An association with oxidative stress

modulation is suggested.

PMID: 12709417 [PubMed - indexed for MEDLINE]

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Mol Aspects Med. 2004 Feb-Apr;25(1-2):27-36.

Concerted action of the renin-angiotensin system, mitochondria, and

antioxidant defenses in aging.

de Cavanagh EM, Piotrkowski B, Fraga CG.

Physical Chemistry-PRALIB, School of Pharmacy and Biochemistry,

University of Buenos Aires, Junin 956, 1113 Buenos Aires, Argentina.

Angiotensin-converting enzyme inhibitors (ACEi) and AT-1 receptor

blockers (ARB) are two types of drugs that inhibit the renin-

angiotensin system (RAS), and can attenuate the progression to

cardiac and/or renal functional impairment, secondary to diverse

pathologies. Some of the beneficial effects of ACEi and ARB occur

independently of the ability of these drugs to reduce arterial blood

pressure. Both, in animals, and in humans, we observed an

enhancement of antioxidant defenses that occurred after treatment

with ACEi. Based on these results, we postulate that some of the

beneficial health effects associated to RAS inhibition can be

ascribed to the prevention of oxidant-mediated damage. Furthermore,

considering that: (i). RAS inhibition attenuates certain age-

associated degenerative changes; (ii). aging was postulated to

result from the accumulation of oxidant-mediated damage; and (iii).

mitochondria are a major source of oxidants, we studied potential

associations among RAS inhibition, mitochondrial function and

production of oxidants and nitric oxide, and aging. The results

obtained suggest, that RAS inhibitors, i.e. enalapril and losartan,

can protect against the effects of aging by attenuating oxidant

damage to mitochondria, and in consequence, they preserve

mitochondrial function. The mechanism(s) explaining such attenuation

of oxidant damage can relay on a reduction of the ANG-II-dependent

generation of superoxide and/or an increased detoxification of

reactive nitrogen and oxygen species by recomposition of antioxidant

defense levels.

PMID: 15051314 [PubMed - indexed for MEDLINE]

Am J Hypertens. 2004 Sep;17(9):809-16.

Factors related to the impact of antihypertensive treatment in

antioxidant activities and oxidative stress by-products in human

hypertension.

Saez GT, Tormos C, Giner V, Chaves J, Lozano JV, Iradi A, Redon J.

Department of Biochemistry and Molecular Biology, Medical School,

Valencia, Spain.

The objective was to study factors related to the changes induced by

antihypertensive treatment on oxidative status, antioxidant

activities, and reactive oxygen species by-products in whole blood

and mononuclear peripheral cells. Eighty-nine hypertensive patients

(mean age 46 years, 46 men, average 24-h blood pressure 139/88 mm

Hg, body mass index 29) were included. After 3 months of

nonrandomized allocation to antihypertensive treatment (20

nonpharmacologic, 36 beta-blockers, 33 angiotensin receptor

blocker), oxidized/reduced glutathione ratio and malondialdehyde

were significantly reduced, and the activity of superoxide

dismutase, catalase, and glutathione peroxidase was significantly

increased in both whole blood and peripheral mononuclear cells. The

content of damaged base 8-oxo-2'-deoxyguanosine in nuclear and

mitochondrial DNA in hypertensive subjects was also significantly

reduced during the antihypertensive treatment. In a group of 42

subjects, the oxidative stress was further reduced and the

antioxidant enzyme activities further increased after 12 months of

antihypertensive treatment. The changes were independent of the kind

of antihypertensive treatment. In conclusion, antihypertensive

treatment improved the increased oxidative stress and the decreased

antioxidant mechanisms. It is independent of the type of treatment

and the beneficial effect of treatment increases over time.

Copyright 2004 American Journal of Hypertension, Ltd.

PMID: 15363824 [PubMed - indexed for MEDLINE]