8/3/2019 Heart-2000-Lscher-i20-2

1/4

Endothelial dysfunction: the role and impact ofthe renin-angiotensin system

Thomas F Lscher

A complex chain of events leads to the

development of end stage heart disease (fig 1).

It starts with seemingly normal subjects with

certain risk factors, such as high cholesterol,

hypertension, and diabetes. Atherosclerosis is

the final common pathway, aVecting blood

vessels in the brain, the coronary circulation,

and the peripheral circulation. What deter-

mines the prognosis for these patients is not the

presence of myocardial ischaemia or angina

pectoris, but the development of myocardial

infarctiona complex disease involving coron-

ary thrombosis, plaque rupture and vasospasm.

As cardiac remodelling occurs in heart failure,

other mechanisms also come into play.

Throughout these stages of heart failure devel-

opment, the renin-angiotensin system plays an

important role and provides a valuable targetfor therapeutic intervention.

Ten to 20 years ago the cardiovascularsystem was thought to be controlled bycirculating factors such as the renin-angiotensin system and the sympathetic nerv-ous system which were able to regulate theheart, the kidney, and the blood vessels. Morerecently, however, it has become evident thatthe blood vessel itself plays an important rolethat involves many factors including nitricoxide, which is a vasodilator, and endothelin, avasoconstrictor. In fact, the endothelium isaltered morphologically as a result of coronaryartery disease.

Renin-angiotensin system and theendotheliumInterestingly, angiotensin converting enzyme(ACE) is expressed at the endothelial cellmembrane. As angiotensin II is created it mayactivate endothelial receptors or those ex-pressed on smooth muscle cells. The receptorsfound on the endothelium are linked to theproduction of endothelin, a coagulation factor,and many other molecules including freeradicals. The action of angiotensin II onsmooth muscle cells produces contraction andalso proliferation. These actions are supportedby endothelin, which is itself stimulated by

angiotensin II (fig 2).

NITRIC OXIDE

ACE inhibitors have several properties thatmay increase the bioavailability of endotheliumderived nitric oxidean important antiathero-genic molecule. For example, ACE inhibitorsblock the breakdown of bradykinin and inde-pendently stabilise the activity of the bradyki-nin receptor, thereby increasing the activity ofthe nitric oxide pathway. This shifts the balancefrom vasoconstriction to vasodilation. This hasbeen illustrated in a number of studies.

In an in vitro study looking at human mam-mary resistance arteries, the addition of angio-

tensin I resulted in contraction (as the vesselwall is capable of converting angiotensin I intoangiotensin II via ACE).1 If a high concentra-tion of ACE inhibitor was added to the prepa-ration, the contraction was notably reduced.The addition of an angiotensin receptorantagonist reduced the contraction even moreeVectively.

In a study in which the human saphenousvein was constricted using norepinephrine(noradrenaline), it was found that increasingconcentrations of bradykinin produced a dosedependent relaxation.2 Interestingly, whenthese vessels were treated with an ACE inhibi-

Figure 1 Chain of events leading to end stage heart disease.

StrokeCAD

PVD

AtherosclerosisLVH

Sudden death

Myocardialinfarction

Coronarythrombosis

Myocardialischaemia

SilentAnginaHibernation

Arrhythmia andloss of muscle

Remodelling

Ventriculardilatation

Congestiveheart failure

Endstageheart

disease

Risk factors(cholesterol, BP diabetes mellitus, smoking)

platelets, fibrinogen

,

Figure 2 The endothelium plays an important role in the control of the vascular system.

Angiotensin I Angiotensin II

AIPrepro ET Big ET ATGACE

ECE AACygNOSc

Renin

Angiotensin IINO PGI2

Endothelin I

Bradykinin

ACE

Inactiveproducts

AT B2

ETA

AT1

cGMP cAMP

Relaxation

Contraction

L-Arginine

Heart 2000;84(Suppl I):i20i22i20

Division of Cardiology,

Universittsspital

Zurich, CH-8091

Zurich, Switzerland

T F Lscher

Correspondence to:

Professor Lscher

www.heartjnl.com

group.bmj.comon January 23, 2012 - Published byheart.bmj.comDownloaded from

http://group.bmj.com/http://group.bmj.com/http://group.bmj.com/http://heart.bmj.com/http://heart.bmj.com/http://group.bmj.com/http://heart.bmj.com/

8/3/2019 Heart-2000-Lscher-i20-2

2/4

8/3/2019 Heart-2000-Lscher-i20-2

3/4

of acetylcholine. There was a major improve-ment in coronary vasomotion in the quinapriltreated patients, indicating that the renin-angiotensin system contributes to endothelialdysfunction in patients with coronary arterydisease.

Interestingly, the SOLVD trial found that,compared to placebo, the ACE inhibitorenalapril reduced the incidence of myocardialinfarction.11 Possibly, some of the eVects ofACE inhibitors may be related to an improve-ment in endothelial function. The HOPE trial,which showed a significant reduction ofmorbidity and mortality in patients with main-tained left ventricular function, provides fur-ther confirmation of this concept.12

ConclusionCardiovascular haemostasis is a complex proc-ess. While several years ago only the circulatingrenin-angiotensin system and sympatheticnervous system were considered, it is nowknown that the blood vessels also contribute tovascular disease. In fact, the endothelium is animportant player because of the release ofendothelin, a potent peptide closely linked tothe renin-angiotensin and sympathetic nervoussystems. Moreover, the enzyme regulating therenin-angiotensin system not only has eVects atthe level of the smooth muscle cells within the

blood vessel wall, but also at the endothelium,by regulating the release of the protective sub-

stance, nitric oxide.ACE inhibitors are valuable tools for inter-

fering with this complex mechanism, but in the

future other approaches will be discoveredinvolving systems of the nitric oxide axis andthe endothelin pressure system.

1 Tschudi MR, Lscher TF. Characterization of contractileendothelin and angiotensin receptors in human resistancearteries: evidence for two endothelin and one angiotensinreceptor. Biophys Biochem Res 1994;204:68590.

2 Yang Z, Arnet U, von Segesser L, et al. DiVerent eVects ofangiotensin-converting enzyme inhibition in human arter-ies and veins.J Cardiovasc Pharmacol 1993;22(suppl 5):1722.

3 Auch Schwelk W, Bossaller C, Claus C, et al . Localpotentiation of bradykinin-induced vasodilation byconverting-enzyme inhibition in isolated coronary arteries.

J Cardiovasc Pharmacol 1992;20(suppl 9):S627.4 Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent

vasoconstrictor peptide produced by vascular endothelialcells. Nature 1988;332:41115.

5 Lscher TF, Barton M. Endothelin and endothelin receptorantagonists. Circulation In press.

6 Moreau P, dUscio LV, Shaw S, et al. Angiotensin IIincreases tissue endothelin and induces vascular hypertro-phy in vivo: reversal by ETA-receptor antagonist. Circula-tion 1997;96:15937.

7 dUscio L, Shaw S, Barton M, et al. Losartan but not vera-pamil inhibits angiotensin II-induced tissue endothelial-1

increase: role of blood pressure and endothelial function.Hypertension 1998;31:130510.

8 Liu G, Espinosa E, Oemar BS, et al. Bi-modal eVects ofangiotensin II on migration of human and rat smooth mus-cle cells: direct stimulation and indirect inhibition viatransforming growth factor beta-1. Arterioscler Thromb VascBiol 1997;17:12517.

9 Yang Z, Krasnici N, Lscher TF. Endothelin-1 potentiateshuman smooth muscle cell growth to PDGF: eVects ofETA and ETB receptor blockade. Circulation 1999;100:58.

10 Mancini GBJ, Henry GC, Macaya C, et al. Angiotensin-converting enzyme inhibition with quinapril improvesendothelial vasomotor dysfunction in patients with coron-ary artery disease: the TREND (trial on reversing endothe-lial dysfunction) study. Circulation 1996; 94:25865.

11 The SOLVD Investigators. EVect of enalapril on survival inpatients with reduced left ventricular ejection fractions andcongestive heart failure. N Engl J Med 1991;325:293302.

12 The Heart Outcomes Prevention Evaluation Study Investi-gators. N Engl J Med2000;342:14553.

Trial acronymsTREND: Trial on Reversing Endothelial

DysfunctionHOPE: Heart Outcomes Prevention

Evaluation studySOLVD: Studies Of Left Ventricular

Dysfunction

i22 Lscher

www.heartjnl.com

group.bmj.comon January 23, 2012 - Published byheart.bmj.comDownloaded from

http://group.bmj.com/http://group.bmj.com/http://group.bmj.com/http://heart.bmj.com/http://heart.bmj.com/http://group.bmj.com/http://heart.bmj.com/

8/3/2019 Heart-2000-Lscher-i20-2

4/4

doi: 10.1136/heart.84.suppl_1.i20

2000 84: i20-i22HeartThomas F Lscherthe renin-angiotensin systemEndothelial dysfunction: the role and impact of

http://heart.bmj.com/content/84/suppl_1/i20.full.htmlUpdated information and services can be found at:

These include:

References

http://heart.bmj.com/content/84/suppl_1/i20.full.html#related-urlsArticle cited in:

http://heart.bmj.com/content/84/suppl_1/i20.full.html#ref-list-1

This article cites 10 articles, 5 of which can be accessed free at:

serviceEmail alerting

box at the top right corner of the online article.Receive free email alerts when new articles cite this article. Sign up in the

CollectionsTopic

(593 articles)Diabetes(139 articles)Stable coronary heart disease

(1740 articles)Acute coronary syndromes(5431 articles)Drugs: cardiovascular system

(1769 articles)HypertensionArticles on similar topics can be found in the following collections

Notes

http://group.bmj.com/group/rights-licensing/permissionsTo request permissions go to:

http://journals.bmj.com/cgi/reprintformTo order reprints go to:

http://group.bmj.com/subscribe/To subscribe to BMJ go to:

group.bmj.comon January 23, 2012 - Published byheart.bmj.comDownloaded from

http://heart.bmj.com/content/84/suppl_1/i20.full.htmlhttp://heart.bmj.com/content/84/suppl_1/i20.full.htmlhttp://heart.bmj.com/content/84/suppl_1/i20.full.html#related-urlshttp://heart.bmj.com/content/84/suppl_1/i20.full.html#related-urlshttp://heart.bmj.com/content/84/suppl_1/i20.full.html#ref-list-1http://heart.bmj.com/cgi/collection/diabeteshttp://heart.bmj.com/cgi/collection/diabeteshttp://heart.bmj.com/cgi/collection/diabeteshttp://heart.bmj.com/cgi/collection/diabeteshttp://heart.bmj.com/cgi/collection/stable_coronary_heart_diseasehttp://heart.bmj.com/cgi/collection/diabeteshttp://heart.bmj.com/cgi/collection/stable_coronary_heart_diseasehttp://heart.bmj.com/cgi/collection/stable_coronary_heart_diseasehttp://heart.bmj.com/cgi/collection/stable_coronary_heart_diseasehttp://heart.bmj.com/cgi/collection/acute_coronary_syndromeshttp://heart.bmj.com/cgi/collection/drugs_cardiovascular_systemhttp://heart.bmj.com/cgi/collection/acute_coronary_syndromeshttp://heart.bmj.com/cgi/collection/drugs_cardiovascular_systemhttp://heart.bmj.com/cgi/collection/drugs_cardiovascular_systemhttp://heart.bmj.com/cgi/collection/drugs_cardiovascular_systemhttp://group.bmj.com/group/rights-licensing/permissionshttp://group.bmj.com/group/rights-licensing/permissionshttp://journals.bmj.com/cgi/reprintformhttp://journals.bmj.com/cgi/reprintformhttp://group.bmj.com/subscribe/http://group.bmj.com/http://group.bmj.com/http://group.bmj.com/http://heart.bmj.com/http://heart.bmj.com/http://group.bmj.com/http://heart.bmj.com/http://group.bmj.com/subscribe/http://journals.bmj.com/cgi/reprintformhttp://group.bmj.com/group/rights-licensing/permissionshttp://heart.bmj.com/cgi/collection/diabeteshttp://heart.bmj.com/cgi/collection/stable_coronary_heart_diseasehttp://heart.bmj.com/cgi/collection/acute_coronary_syndromeshttp://heart.bmj.com/cgi/collection/drugs_cardiovascular_systemhttp://heart.bmj.com/cgi/collection/hypertensionhttp://heart.bmj.com/content/84/suppl_1/i20.full.html#related-urlshttp://heart.bmj.com/content/84/suppl_1/i20.full.html#ref-list-1http://heart.bmj.com/content/84/suppl_1/i20.full.html