Physiology of RAAS:Focus on Angiotensin

VBWG

RAAS: Pathways of ACE inhibition and angiotensin receptor blockade

Dzau V. J Hypertens. 2005;23(suppl 1):S9-S17.

ACE inhibitor

Bradykinin/NO

Inactivefragments

Chymase,tPA,

cathepsin

‘Angiotensin IIescape’

ARB

AT1 receptor AT2 receptor

Angiotensin I

Angiotensin II

VBWG

Atherosclerosis-promoting actions of Ang II and protective effects of bradykinin

VasodilationVasodilation ProstacyclinProstacyclin Nitric oxideNitric oxide tPAtPA

Vasoconstriction Vasoconstriction ICAM-1, VCAM-1 ICAM-1, VCAM-1 Growth factorsGrowth factors Oxyradical formationOxyradical formation PAI-1PAI-1 Smooth muscle cellSmooth muscle cell proliferation proliferation Matrix degradationMatrix degradation

Protection against Protection against the effects the effects

of Ang IIof Ang II

Endothelial dysfunctionEndothelial dysfunction Inflammation Inflammation CoagulationCoagulation AtherogenesisAtherogenesis

BradykininBradykinin

Ang IIAng II

Inactive peptidesInactive peptides

Ang IAng I

--

--

ACEinhibitor

Ferrari R. Expert Rev Cardiovasc Ther. 2005;3:15-29.

VBWG

Ang II: Influence on structure, function, and atherosclerosis

Weir MR, Dzau VJ. Am J Hypertens. 1999;12:205S-213S.

Angiotensin II

Growth

Smooth musclecell growth

and migration

Plateletaggregation

Endothelialdysfunction

Thrombosis

VBWG

Adapted from Bertrand ME.Curr Med Res Opin. 2004;20:1559-69.

Blood pressureBlood pressureBradykinin preservation:Bradykinin preservation: NO and vasodilationNO and vasodilation

Fibrinolysis: Fibrinolysis: PAI-1, PAI-1, tPAtPA Platelet inhibitionPlatelet inhibition

Cell proliferation and migrationCell proliferation and migrationAtherosclerotic plaque stabilizationAtherosclerotic plaque stabilization

Intermediate effectsIntermediate effects

Immediate onsetImmediate onset

Long-term effectsLong-term effects

ACEI: Proposed continuum of benefitsVBWG

Daugherty A et al. Circulation. 2004;110:3849-57.

LDL-receptor–deficient mice (LDL receptor–/–)

*P < 0.001, †P < 0.01 for LDL receptor–/– AT1A receptor+/+

‡P < 0.001 between genotypes

1

2

3

4

5

0

Aortic intimal surface(male)

AT1A receptor genotype

200

400

600

800

1000

1200

0

*

Angiotensin peptides

pg/ml

Lesionarea

ofarch

(mm2) ‡

6

LDL receptor+/+ AT1A receptor+/+

LDL receptor–/– AT1A receptor+/+

LDL receptor–/– AT1A receptor–/–

Ang II Ang III Ang IV Ang 4–8

Ang 5–8

Sum +/+ –/–

Hypercholesterolemia increases angiotensin peptides and atherosclerosis via AT1A receptor

*

†

VBWG

Hoshida S et al. Circulation. 1999;99:434-40.Hoshida S et al. Atherosclerosis. 2000;149:287-94.

HOE = bradykinin B2 receptor blockerL-NAME = NO synthase inhibitor*P < 0.05 vs normal-fed†P < 0.05 vs without quinapril‡P < 0.05 vs without HOE or L-NAME

In this model, AT1 receptor

blockadehad no effect

on infarct size

Normal-fed100

50

0

Infarct size(%)

Quinapril

n =

––8

Cholesterol-fed

+

HOE

7

+–9

+L-NAME

5

+–8

––9

+

HOE

5

†

‡‡*

Reduction in infarct size with ACE inhibition: Involvement of bradykininN = 60 rabbits

VBWG

Lonn EM et al. Circulation. 2001;103:919-25.

0

0.005

0.010

0.015

0.020

0.025

Ramipril 10 mg

Ramipril 2.5 mg

Placebo

0.022

0.018

0.014

NS

37% Reduction

P = 0.028

Mean maximum IMT slope

(mm/y)

SECURE

ACEI reduces atherosclerosis progressionVBWG

ST-segment depression

Exercise-induced LV systolicdysfunction

0

1

2

3

4

5

6

Before 3 monthsperindopril

8 mg

ST-segmentchanges

(mm)

P < 0.05

0

0.5

1

1.5

2

2.5

Before 3 monthsperindopril

8 mg

LVmotion score

P < 0.05

–42%

–39%

N = 12

Morishita T el al. Jpn J Pharmacol. 2002;88:100-7.

ACEI may exert anti-ischemic effects in CAD

VBWG

ACEI is associated with less aortic valve calcification

O’Brien KD et al. Arch Intern Med. 2005;165:858-62.

P < 0.001

0

20

40

60

80

No ACEIn = 80

ACEIn = 43

No change

Progression

Patientswith AVC

scoreprogression

(%)

100

25

75

58

42

VBWG

Schwartzkopff B et al. Hypertension. 2000;36:220-5.

0

200

400

600

800

Periarteriolar collagen

P = 0.04

53%

558 ± 270

260 ± 173

µm2

0

2

4

6

8

Total interstitial collagen

P = 0.04

22%5.5 ± 3.8

4.3 ± 3.2Vv%

Pretreatment(n = 14)

Post-treatment*(n = 14)

Coronary reserve

+67%

P = 0.001

Baseline 2.1

3.5Perindopril

*Perindopril 4–8 mg for 12 months

ACEI normalizes structure of resistance arteries in CAD patients

At treatment end (12 mo)

VBWG

Short term ACEI does not improve transient ischemia in CAD

Pepine CJ et al. J Am Coll Cardiol. 2003;42:2049-59.

QUinapril Anti-ischemia and Symptoms of Angina Reduction (QUASAR) trial

N = 336*Time to induce during exercise treadmill testing after 8-week treatment

40

60

80

100

20

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Placebo

Quinapril 40 mg

Log rank P = 0.07

Level 2angina

(%)

Time (minutes)*

VBWG

Adipocyte and vasculature interactionsAdipocyte and vasculature interactions

Courtesy of W. Hseuh; 2005.

IL-6

PAI-1TNF-

AdiponectinLeptin

Insulin sensitivity Insulin resistance

Vascular inflammation Endothelial dysfunction

Angiotensinogen

FFA

Visfatin

VBWG

Furuhashi M et al. Hypertension. 2003;42:76-81.

• Insulin sensitivity, BMI, and HDL-C independent determinants of adiponectin concentrations

• ACEI and ARB increased insulin sensitivity and adiponectin (P < 0.05)

• Changes in insulin sensitivity correlated with changes in adiponectin (r = 0.59, P < 0.05)

*P < 0.05

N = 16 with essential hypertension and insulin resistance

RAAS blockade increases adiponectin

6

4

10

Adiponectin(µg/mL)

0

8

2

Before After Before After

6

4

10

0

8

2

Temocapril 4 mg(n = 9)

Candesartan 8 mg(n = 7)

*

*

VBWG

Pretorius M et al. Circulation. 2003;107:579-85.

*P < 0.05 vs baseline†P < 0.05 vs vehicle or baseline‡P < 0.05 vs enalaprilat + vehicleHOE 140 = bradykinin B2 receptor antagonist

Greater effect in women vs men

Women (n = 7) Men (n = 5)

Baseline

‡

HOE 140 + Enalaprilat

HOE 140

2

1

0

3

Net tPArelease(ng/min/100 mL)

2

1

0Baseline

*†

Vehicle + Enalaprilat

Vehicle

3

ACEI increases tPA release through endogenous bradykinin

VBWG

Brown NJ et al. Hypertension. 2002;40:859-65.P = 0.043, drug time interaction

ACE inhibition (ramipril) AT1 receptor blockade (losartan)

10

0

–10

20

Week 1

–20

PAI-1

antigen(ng/mL)

30

Week 3 Week 4

Sustained decrease in PAI-1 antigen over time with ACEI vs ARB

Week 6

VBWG

Greater decrease in PAI-1 over time with ACEI vs ARB 85 Hypertensive diabetic patients treated for 12 weeks

Fogari R et al. Am J Hypertens. 2002;15:316-20.

10

–10

5

0

–5

Losartan 50 mg

4Perindopril 4 mg

–10

P < 0.01

*P = 0.028 perindopril vs placebo

PAI-1ng/dL

*

VBWG

Differing effects of ACEI and ARB on tPA release

Matsumoto T et al. J Am Coll Cardiol. 2003;41:1373-9.*P < 0.05 vs baseline

20

10

15

5

0.2

0

0 0.6 2.0

tPA antigenin coronary

sinus (ng/mL)

Bradykinin (µg/min)

Perindopril 4 mg(n = 16)

Losartan 50 mg(n = 15)

Control(n = 14)

P < 0.05*

**

**

* *

25

VBWG

Effects of ACEI on endothelial function: EUROPA substudies

• PERTINENT: PERindopril Thrombosis, InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial

– Determined the mechanisms by which the ACEI perindopril improved outcomes in patients with stable coronary artery disease

• PERFECT: PERindopril-Function of the Endothelium in Coronary artery disease Trial

– Evaluated whether long-term administration of perindopril improves endothelial dysfunction

Ferrari R. ESC 2004; Munich.Bots ML et al. Cardiovasc Drugs Ther. 2002;16:227-36.

VBWG

PERTINENT: Study design

Endothelial cell (EC) studiesEndothelial cell (EC) studiesECs incubated with serum from CAD ECs incubated with serum from CAD patients at baseline and at 1 year* patients at baseline and at 1 year*

Plasma studiesPlasma studiesMeasure substances in plasma that Measure substances in plasma that modulate ecNOS and apoptosismodulate ecNOS and apoptosis

Ang IIAng IIBradykininBradykininTNF-TNF-von Willebrand factorvon Willebrand factor

ecNOSecNOSEC apoptosis rateEC apoptosis rate

*Human umbilical vein ECsecNOS = EC nitric oxide synthase Ferrari R. ESC 2004; Munich.

Levels measured at baseline vs 1 year

Objective: Objective: Evaluate effects of perindopril on endothelial function and markers of Evaluate effects of perindopril on endothelial function and markers of inflammation and thrombosis in EUROPA subgroup of CAD patientsinflammation and thrombosis in EUROPA subgroup of CAD patients

EUROPA substudy

VBWG

ecNOS activity

Endothelial cell apoptosis

Ang II

Bradykinin

TNF- von Willebrand factor

Ferrari R. ESC 2004; Munich.*Incubated with patients’ serum

Endothelial cells* Patients’ plasma

EUROPA substudy

• The only significant correlation was between bradykinin and ecNOS

• Results suggest perindopril modifies inflammation and thrombosis and endothelial function through bradykinin-dependent mechanisms

PERTINENT: Effects of treatment with perindopril for 1 year

VBWG

PERFECT: Study design

Objective: Determine effect of perindopril on brachial artery endothelial function in patients

with stable CAD and without clinical HF

Design: Double-blind randomized controlled trial

Population: N = 333 at 20 centers

Treatment: Perindopril 8 mg or placebo

Follow-up: 3 years

Primary outcome: Change in flow-mediated vasodilation of

brachial artery assessed over 36 months

EUROPA substudy

Bots ML et al. J Am Coll Cardiol. 2005;45A(suppl):409A.Bots ML et al. Cardiovasc Drugs Ther. 2002;16:227-36.

VBWG

• Mean FMD* increased (baseline vs 36 months) Perindopril 2.7% to 3.3% (+37%)Placebo 2.8% to 3.0% (+7%)

• Endothelial function (rate of change per 6 months) Perindopril 0.14% (P < 0.05 vs baseline) Placebo 0.02% (P = 0.74 vs baseline) (P = 0.07 for perindopril vs placebo)

• Conclusion: Part of the beneficial effect of perindopril on CV morbidity and mortality in the EUROPA study may be explained by improvement in endothelial function

*Brachial artery vasodilation in response to reactive hyperemia Bots ML et al. J Am Coll Cardiol. 2005;45A(suppl A):409A.

PERFECT: ACEI and endothelial function—Preliminary resultsEUROPA substudy

VBWG