Physiology of RAAS: Focus on Angiotensin
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Transcript of Physiology of RAAS: Focus on Angiotensin
Physiology of RAAS:Focus on Angiotensin
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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
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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.
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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
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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
*
†
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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
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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
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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
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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)
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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)*
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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
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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)
*
*
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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
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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
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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
*
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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
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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.
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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
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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
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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.
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• 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
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