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VBWG. Physiology of RAAS: Focus on Angiotensin. VBWG. RAAS: Pathways of ACE inhibition and angiotensin receptor blockade. Angiotensin I. Chymase, tPA, cathepsin. Bradykinin/NO. ACE inhibitor. Inactive fragments. ‘Angiotensin II escape’. Angiotensin II. ARB. AT 2 receptor.

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Physiology of raas focus on angiotensin

VBWG

Physiology of RAAS:Focus on Angiotensin


Raas pathways of ace inhibition and angiotensin receptor blockade

VBWG

RAAS: Pathways of ACE inhibition and angiotensin receptor blockade

Angiotensin I

Chymase,tPA,cathepsin

Bradykinin/NO

ACE inhibitor

Inactivefragments

‘Angiotensin IIescape’

Angiotensin II

ARB

AT2 receptor

AT1 receptor

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


Atherosclerosis promoting actions of ang ii and protective effects of bradykinin

VBWG

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

 Vasodilation

 Prostacyclin

 Nitric oxide

 tPA

Protection against the effects of Ang II

Inactive peptides

Bradykinin

-

ACEinhibitor

  • Vasoconstriction  ICAM-1, VCAM-1

  •  Growth factors

  • Oxyradical formation

  • PAI-1

  • Smooth muscle cell proliferation

  • Matrix degradation

-

  • Endothelial dysfunction

  • Inflammation

  • Coagulation

  • Atherogenesis

Ang I

Ang II

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


Ang ii influence on structure function and atherosclerosis

VBWG

Ang II: Influence on structure, function, and atherosclerosis

Angiotensin II

 Growth

 Thrombosis

 Smooth musclecell growthand migration

 Endothelialdysfunction

 Plateletaggregation

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


Acei proposed continuum of benefits
ACEI: Proposed continuum of benefits

VBWG

Immediate onset

 Blood pressure

Bradykinin preservation:

 NO and vasodilation

Intermediate effects

Fibrinolysis:  PAI-1, tPA

Platelet inhibition

Long-term effects

 Cell proliferation and migration

Atherosclerotic plaque stabilization

Adapted from Bertrand ME.

Curr Med Res Opin. 2004;20:1559-69.


Hypercholesterolemia increases angiotensin peptides and atherosclerosis via at 1a receptor
Hypercholesterolemia increases angiotensin peptides and atherosclerosis via AT1A receptor

VBWG

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

Aortic intimal surface(male)

6

LDL receptor+/+  AT1A receptor+/+

5

LDL receptor–/– AT1A receptor+/+

1200

LDL receptor–/– AT1A receptor–/–

*

4

1000

Lesionareaofarch

(mm2)

800

3

pg/ml

*

600

2

400

1

200

0

0

+/+

–/–

Ang II

Ang III

Ang IV

Sum

Ang 4–8

Ang 5–8

AT1A receptor genotype

Angiotensin peptides

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

‡P < 0.001 between genotypes

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


Reduction in infarct size with ace inhibition involvement of bradykinin
Reduction in infarct size with ACE inhibition: Involvement of bradykinin

VBWG

N = 60 rabbits

Normal-fed

Cholesterol-fed

In this model, AT1 receptor

blockade

had no effect

on infarct size

100

*

Infarct size

(%)

50

0

Quinapril

8

+

9

+

HOE

5

9

+

8

+

HOE

7

+

L-NAME

5

n =

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

Hoshida S et al. Circulation. 1999;99:434-40.

Hoshida S et al. Atherosclerosis. 2000;149:287-94.


Acei reduces atherosclerosis progression
ACEI reduces atherosclerosis progression of bradykinin

VBWG

SECURE

0.025

P= 0.028

0.022

NS

0.020

0.018

Mean maximum IMT slope(mm/y)

37% Reduction

0.015

0.014

0.010

0.005

0

Placebo

Ramipril 2.5 mg

Ramipril

10 mg

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


Acei may exert anti ischemic effects in cad

VBWG of bradykinin

ACEI may exert anti-ischemic effects in CAD

N = 12

ST-segment depression

Exercise-induced LV systolic

dysfunction

6

P < 0.05

5

–42%

P < 0.05

ST-segment

changes (mm)

4

2.5

–39%

2

3

LVmotion score

1.5

2

1

1

0.5

0

0

Before

3 months

Before

3 months

perindopril8 mg

perindopril8 mg

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


Acei is associated with less aortic valve calcification

VBWG of bradykinin

ACEI is associated with less aortic valve calcification

100

P < 0.001

80

75

58

Patientswith AVC scoreprogression

(%)

60

42

40

25

No change

20

Progression

0

No ACEIn = 80

ACEI

n = 43

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


Acei normalizes structure of resistance arteries in cad patients

VBWG of bradykinin

ACEI normalizes structure of resistance arteries in CAD patients

Total

interstitial collagen

Periarteriolar collagen

P = 0.04

P = 0.04

800

8

Coronary reserve

P = 0.001

600

6

558 ± 270

5.5 ± 3.8

22%

µm2

Vv%

4.3 ± 3.2

53%

+67%

400

4

Baseline 2.1

260 ± 173

200

2

Perindopril

3.5

0

0

At treatment end (12 mo)

Pretreatment

(n = 14)

Post-treatment*

(n = 14)

*Perindopril 4–8 mg for 12 months

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


Short term acei does not improve transient ischemia in cad

VBWG of bradykinin

Short term ACEI does not improve transient ischemia in CAD

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

Log rank P = 0.07

Placebo

100

Quinapril 40 mg

80

Level 2

angina(%)

60

40

20

0

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Time (minutes)*

N = 336

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

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


Adipocyte and vasculature interactions

VBWG of bradykinin

Adipocyte and vasculature interactions

Visfatin

Adipocyte

Angiotensinogen

IL-6

TNF-

PAI-1

Adiponectin

Leptin

FFA

Insulin sensitivity

Insulin resistance

Vascular inflammation

Endothelial dysfunction

Courtesy of W. Hseuh; 2005.


Raas blockade increases adiponectin

VBWG of bradykinin

RAAS blockade increases adiponectin

N = 16 with essential hypertension and insulin resistance

*

  • 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)

10

10

*

8

8

6

6

Adiponectin

(µg/mL)

4

4

2

2

0

0

Before

After

Before

After

Candesartan 8 mg

(n = 7)

Temocapril 4 mg

(n = 9)

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

*P < 0.05


Acei increases tpa release through endogenous bradykinin
ACEI increases tPA release through endogenous bradykinin of bradykinin

VBWG

Greater effect in women vs men

3

3

*†

Net tPArelease(ng/min/100 mL)

2

2

1

1

0

0

Vehicle + Enalaprilat

HOE 140 + Enalaprilat

Baseline

Vehicle

Baseline

HOE 140

Women (n = 7)

Men (n = 5)

*P < 0.05 vs baseline

†P < 0.05 vs vehicle or baseline

‡P < 0.05 vs enalaprilat + vehicle

HOE 140 = bradykinin B2 receptor antagonist

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


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

VBWG

30

20

Week 6

10

PAI-1

antigen

(ng/mL)

Week 3

Week 1

Week 4

0

–10

–20

AT1 receptor blockade (losartan)

ACE inhibition (ramipril)

P = 0.043, drug  time interaction

Brown NJ et al. Hypertension. 2002;40:859-65.


Greater decrease in pai 1 over time with acei vs arb

VBWG ARB

Greater decrease in PAI-1 over time with ACEI vs ARB

85 Hypertensive diabetic patients treated for 12 weeks

P < 0.01

10

5

PAI-1

ng/dL

4

Perindopril 4 mg

0

Losartan 50 mg

–5

–10

–10

*

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

*P = 0.028 perindopril vs placebo


Differing effects of acei and arb on tpa release

VBWG ARB

Differing effects of ACEI and ARB on tPA release

25

*

20

*

P < 0.05

*

*

tPA antigen

in coronary

sinus (ng/mL)

15

*

10

*

*

5

0

0

0.2

0.6

2.0

Bradykinin (µg/min)

Perindopril 4 mg

(n = 16)

Losartan 50 mg

(n = 15)

Control

(n = 14)

Matsumoto T et al. J Am Coll Cardiol. 2003;41:1373-9.

*P < 0.05 vs baseline


Effects of acei on endothelial function europa substudies

VBWG ARB

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.


Pertinent study design

VBWG ARB

PERTINENT: Study design

EUROPA substudy

Objective:

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

Endothelial cell (EC) studies

ECs incubated with serum from CAD patients at baseline and at 1 year*

Plasma studies

Measure substances in plasma that modulate ecNOS and apoptosis

Levels measured at baseline vs 1 year

Ang II

Bradykinin

TNF-

von Willebrand factor

ecNOS

EC apoptosis rate

*Human umbilical vein ECs

ecNOS = EC nitric oxide synthase

Ferrari R. ESC 2004; Munich.


Pertinent effects of treatment with perindopril for 1 year

 ecNOS activity ARB

 Endothelial cell apoptosis

VBWG

PERTINENT: Effects of treatment with perindopril for 1 year

EUROPA substudy

Endothelial cells*

Patients’ plasma

 Ang II

 Bradykinin

 TNF-

 von Willebrand factor

  • The only significant correlation was between bradykinin and ecNOS

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

Ferrari R. ESC 2004; Munich.

*Incubated with patients’ serum


Perfect study design

VBWG ARB

PERFECT: Study design

EUROPA substudy

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

Bots ML et al. J Am Coll Cardiol. 2005;45A(suppl):409A.

Bots ML et al. Cardiovasc Drugs Ther. 2002;16:227-36.


Perfect acei and endothelial function preliminary results

Mean FMD* increased (baseline vs 36 months) ARB 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

VBWG

PERFECT: ACEI and endothelial function—Preliminary results

EUROPA substudy

*Brachial artery vasodilation in response to reactive hyperemia

Bots ML et al. J Am Coll Cardiol. 2005;45A(suppl A):409A.


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