Newer Concepts in RAAS:Tissue, and Cardiac RAAS

Dr Amarpal Singh GulatiAsst. Prof. Dept. of Cardiology

Nizam’s Institute of medical Sciences

Definition

“The renin-angiotensin system (RAS) is a peptidergic system with endocrine characteristics.”

How the RAAS Was Seen in the Past

•Substrate : Angiotensinogen, an α-glycoprotein, released from the liver

•In the circulation, enzyme renin, secreted from the juxtaglomerular apparatus of the kidney forms the decapeptide angiotensin (ANG) I.

•ANG I is then activated to the octapeptide ANG II by angiotensin converting enzyme (ACE), amembrane-bound metalloproteinase, which is predominantly expressed in high concentrations on the surface of endothelial cells in the pulmonary circulation.

•ANG II, considered the main effector peptide of the RAS, which acts on specific receptors on vascular smooth muscle cells to induce vasoconstriction or, by stimulating the release of aldosterone from the adrenal cortex.

Vascular Disease Prevention, 2009, 6, 65-74

Circulating Ang II “main effector”

Involved in • global regulation of sympathetic

activity• Regulation of blood pressure• Fluid and electrolyte balance

POSITIVE FEEDBACK EXISTS BETWEEN DISEASE PROCESSES IN THE CARDIORENAL CONTINUUM

Kopyt NP. JAOA. 2005;105:207–15.

Predicts stroke,CHD, CVD risk

ESRD

GFRSCr

Glomerular sclerosis

MAUUAER

Glomerular pressure

IGTDM riskCVD risk

HTN RAAS activityAng IIOxidative stress/Vasoconstriction

CKD

CHD=coronary heart disease; IGT=impaired glucose tolerance; UAER=urinary albumin excretion rate

Macro-albuminuriaproteinuria

4

CHD=coronary heart disease; IGT=impaired glucose tolerance; UAER=urinary albumin excretion rate

Kopyt NP. JAOA. 2005;105:207–15.

Technical Advances1. molecular biology

2. Availability of transgenic and knock-out rat modelswith altered expression of RAS components.

•Atherosclerosis•cardiac hypertrophy•fibrosis,

• nephropathy of diabetic and nondiabetic etiology.

• Circulating Ang II levels tend to increase in patients taking ACE inhibitors over long periods.

• “ACE is not the only enzyme implicated in the generation of Ang II”

Different ANG receptors and signal transduction

pathways

Additional truncated peptides

(1-9) & (1-7)

Concept of “local” or “tissue” renin

angiotensin systems

Interplay of recently discovered components of the renin – angiotensin – aldosterone system.

Alternative pathways of ANG II formation

European Heart Journal (2011) 32, 2739–2747

•Prorenin can be activated by • Proteolytic :Endopeptidases/trypsin/cathepsin B or• Nonproteolytic :low pH

• Three receptors• Mannose-6-phosphate receptor (M6P)

• Endothelial cells • Clearance mechanism

• Prorenin binding protein• Cardiac cells• Local tissue RAAS

• 45-kDa membrane protein binding both prorenin and renin• Angiotensin independent effects• Cofactor in increase production of Ang I• Activation of

• promyelocytic zinc finger (PLZF)• protein-phosphatidylinositol-3-kinase• mitogen-activated protein kinases (MAPKs)

• localized in the mesangium (kidney) and in the subendothelium of renal, uterine, and cardiac blood vessels

Newer Theraupeutic Targets“1”

DRI’s

“2”Angiotensin

Independent Effects

•Direct renin inhibitors • like aliskiren • attenuate the plasma renin activity which is increased

by ACE inhibition or AT1R blockade• High renin levels cause ‘escape’ from renin inhibition• Do not prevent binding of renin to the (P)RR.

•A handling region peptide (HRP) inhibiting the binding of prorenin to (P)RR, • completely abolished diabetic nephropathy in AT1R knockout mice• Reduced cardiac fibrosis in stroke-prone Spontaneously Hypertensive

Rats• reduced cardiac hypertrophy and fibrosis• HRP were only effective in low-renin conditions

Ichihara A et al. Hypert ens Res 2010;33:177 – 180Susic D et al. Am J Physiol Heart Circ Physiol 2008;295:H1117 – H1121.

Angiotensin converting enzyme ACE independent enzyme activity• chymases,

– high substrate specificity– Cellular localization largely restricted to

mast cells– Normally remains inactivated– Selective chymase inhibitors used in animal

models

• carboxypeptidases,

• cathepsin G

• tonin.

• neprylisin

• In circulation

• Locally expressed

• Mediate > 80% of AngII formation in the heart and >60% in the vessels

• Not inhibited by ACE inhibitors

• Upregulation during pathologic conditions causing increased local Ang

II generation

• Also form Alternative cleavage products

cleavage of the COOH-terminal dipeptide

Quantification of hamster chymase and ACE mRNA in the kidney by real-time PCR. Results are shown as a percentage of controls.

White bars : nondiabetic controls (control)

Black bars : streptozotocin (STZ)-induced diabetic hamsters (STZ)

Hatched bars : STZ hamsters rendered normoglycemic by continuous intraperitoneal insulin infusion (STZ

CIPII).

ACE (dipeptidyl-carboxypeptidase) subtypes

• Two distinct forms of ACE – Somatic form on the endothelial

cells(lung, smooth muscle cells, monocytes, T lymphocytes, and adipocytes)

– Germinal form (testis)• glycosylphosphatidylinositol (GPI) hydrolase

activity not inhibited by ACE inhibitors• capacitation, formation of the sperm

membrane,

• Two types of Existence– At the cell surface (ectoenzymes)

hydrolyzing circulating peptides– Soluble form (plasma ACE) after action of

ACE secretase• lungs have traditionally been considered to

be an integral part of the circulating RAS• 10% of total ACE• Risk factor for coronary stent restenosis,

CAD, MI and post MI LV dilation

• Two active sites– N-terminal domain

• Ang 1-7 cleavage

– C-terminal domain• Responsible for Ang I

conversion • Selective C domain

inhibition is sufficient to prevent Ang I–induced vasoconstriction

• Both sites required for degradation of bradykinin

located on the 1. endotheliumof all blood vessels 2. In the parenchyma of the heart, kidneys, brain, and adrenal glands. 2. Also in non-endothelial cells such as macrophage

Anchored to the plasma membrane

“Local” or “tissue” renin angiotensin systems

• RAS components in “unlikely” places– such as the “kidney enzyme” renin in the brain– Local expression of angiotensinogen, renin, renin-binding protein,

ACE, chymase, as well as Ang II receptors and secretion of Ang II.

• “Tissue-based synthesis of ANG II”– Angiotensin and renin messenger RNA (mRNA) has been discovered

in 12 different extrahepatic tissues of rats, strongly suggesting that there is local synthesis of angiotensinogen and renin

• Local synthesis or Uptake from the circulation• Clinical relevance : “Dissociating from the class effect”

• Both Local and systemic actions of the RAS integrate and cause ANG-mediated effects

Though

• An independent function of local RAS (for example, in the brain, inside the blood-brain barrier as well as in testis/ovary/bonemarrow and so on)

• Local RAAS at the cellular level– Paracrine– Autocrine effects

• cell growth, proliferation, and metabolism

– Intracellular or intracrine RAS sffects• ANG binding in the cell nucleus

The renin-angiotensin system(RAS) in the heart.

Physiol Rev • VOL 86 • JULY 2006

endothelium

Inducers of ACE1. Vol or press overload2. Wall stress3. CHF4. MI5. aging

•Contractility•Chronotropy•Hypertrophy•Apoptosis•Fibrosis

•Van Kats et al. used infusions of radiolabeled ANG I and ANG II peptides in pigs and measured plasma and tissue levels of endogenous as well as the radiolabeledpeptides.

•>90% of cardiac ANG I is synthesized locally in the heart

•>75% of cardiac ANG II is synthesized locally, most of it using local ANG I generation as a basis.

•Concept of a cardiac RAS is not dependent only on the local synthesis of angiotensinogen and renin.

•Tissue ACE is regarded as the vital rate limiting enzyme in the local elaboration of AII

•. Even partial inhibition of cardiac ACE has been shown to contribute to the beneficial effects associated with ACE inhibitors in patients with heart failure, hypertension, or coronary artery disease

1) Clinically, ACE inhibitors are extremely efficient in the treatment of cardiac disease;

2) Most of the ANG II generated by intact cardiac blood vessels can be blocked by ACE inhibitors;

3) Expression of human heart chymase is highly compartmentalized and mostly restricted to

mast cells

ACE independent pathways are particularly important in disease states such as cardiac hypertrophy and heart failure

e.g,ACE expression is higher in ruptured plaque as well as in the macrophages around ruptured plaque

Activation of a local renin-angiotensin system (RAS) in heart

•~50,000 mast cells/g human heart tissue in close proximity to vessels and nerves

• Density further increases in heart failure, ischemic cardiomyopathy and experimental infarct models

Circulation. 2010 August 24; 122(8): 771–781

IPC

RAS after LVAD

European Heart Journal (2009) 30, 805–812

Local RASS in Kidney1. Unlike heart Ang II is required

for normal renal development

2. Activated by• Hyperglycemia• Proteinuria• Renal injury• Reduction in calcitriol

3. ACEI’s do not significantly reduce intrarenal AngII production which is regionally compart-mentalized and in endosomes

Wolf G et al. Nephron Physiol 93: 3–13, 2003

4. Never the less, antihypertensive therapy with ACE inhibitors, successfully ameliorates proteinuria suggesting beneficial effects independent of reductions in blood pressure.

5. Also decreases risk associated with death, dialysis, increased creatinine, and transplantation

Proximal tubular cell

Tissue ACE and the Vasculature• Endothelial cells cover 700 m2 and weigh 1 to

1.5 kg in a 70-kg individual

• Vascular homeostasis – relaxation and contraction; – thrombogenesis and fibrinolysis;– platelet activation and inhibition;– Cellular growth stimulation and inhibition.

• The vascular wall is the effector organ for the hormonal or plasma RAS

• The substrate mRNA levels are abundantly expressed in periadventitial fat cells

• Renin uptake also takes place via unspecified binding sites on endothelial cells or specific prorenin/renin receptors– Clearance mechanism as well as pathological

• Locally produced AII is responsible for endothelial dysfunction.

• Local renin production as well as endothelial ACE upregulation occurs in response to injury– Hypercholesterolemia,– smoking, – hypertension, – aging, – Diabetes

• Expression of ACE is further modulated by– steroids, – calcium ionophores, – growth factors

Tissue ACE and Endothelial Dysfunction

• Ang II ↑ NADPH+, producing superoxide anion and hydrogen peroxide that inactivate NO

• Oxidative stress also activates the transcription of factor NF-κ B that induces the expression of genes controlling cytokine formation and leukocyte adhesion to the vessel wall

• ACE degrades and inactivates bradykinin, hence vasoconstriction and inflammation– ↓ NO and other endothelial derived vasodilators– ↑ vascular smooth muscle cell growth and

migration– ↑ expression of VCAM-1 & monocyte

chemoattractant protein-1 – ↓ plasminogen activator

• AngII also stimulates the production of endothelin-1 (potent vasoconstrictor) and plasminogen activator inhibitor-1 (PAI-1)

The reduction of tissue AngII and increased NO bioavailability may underlie the mechanisms by which ACE inhibitors exert their vasculoprotective effects.

Balloon angioplasty induced endothelial dysfunction

• Percutaneous transluminal coronary angioplasty (PTCA) injury in humans results in upregulation of ACE at sites of active repair

• After pretreatment with perindopril, there was a reduced neointima formation after balloon injury of rabbit carotid artery

• Trial on Reversing Endothelial Dysfunction (TREND)– CAD patients

• normotensive, • had no heart failure, • no major lipid abnormalities;

– randomized to placebo or quinapril and followed for 6 months– quinapril experienced significant improvement in endothelial response over those

patients who had received placebo ( P = 0. 002).

Ohishi M et al.Circulation 96: 3328 –3337, 1997Circulation 1996;94:258–265.

Free of RAS activation

RAAS: BENEFICIAL EFFECTS OF INHIBITION ON THE CVS AND KIDNEY

Cardiovascular system (CVS)• ↓ Elevated BP• ↓ Vascular smooth muscle cell

growth• ↓ LVH• Prevents LV remodeling after MI• Prevents HF after MI• ↓ Sympathetic NS activity• Stabilization of atherosclerotic plaque• Normalization of endothelial function• ↑ Fibrinolytic system

Kidney• ↓ Sodium and water reabsorption• ↓ Proteinuria• ↓ Glomerular and tubulointerstitial fibrosis• Stabilization of renal function in CKD

Cowie MR. In Cardiovascular Medicine. Eds: Willerson JT, et al. 2007.

LVH=left ventricular hypertrophy; NS=nervous system

Other organs/systems

• Skin

• Digestive organs

• Sensory organs

• Lymphatic tissue

• Bone marrow

• Adipose tissue

RAS in the brain.

RAS in the ovary

RAS in the testis and epididymis

Pharmokinetics of Angiotensin-Converting Enzyme Inhibitors

• 2-methylpropranolol-L-proline moiety is common (active site)

• Functional group :Adherence to the zinc component of the active site of ACE (potency dependent on strength of binding)1. carboxyl-containing2. Sulphydryl containing3. phosphoryl-containing

• Drug lipophilicity– tissue penetration– differences in clinical effect ?

Clin. Cardiol. Vol. 28, December 2005

quinaprilat =benazeprilat > ramiprilat > perindoprilat > lisino-pril > enalaprilat > fosinoprilat > captopril

•Hemodynamic effects: well proven as in trials of CHF/MI

•Local vasculoprotective effects: CAD / endothelial dysfunction, validated 1st by HOPE

OR

•Peripheral drug effects e.g decreasing afterload

•Cardiac drug effects as in CHF (as seen in aorta clipped model )

Issues • Lipophilicity (α ACEI activity)

• Potency

• Bioavailability

• bradykinin selectivity and potentiation

• effects on endothelial-cell apoptosis

• Co-morbidity

• Evidence based

• Tolerability

• Prodrugs

• Plasma levels

• intermediary metabolism

• half-lives

• Elimination

• durations of action

• trough:peak plasma concentration relationships

• Design

• Demographics

• Prostaglandins & free radicle scavanger

Major morbidity – mortality studies of angiotensin-converting enzyme inhibitors across the continuum of cardiovascular disease

Relative tissue affinity of various angiotensin-convertingenzyme inhibitors

Relative selectivity of angiotensin-converting enzyme (ACE) inhibitors for bradykinin vs. angiotensin I binding sites on ACE

Ferrari R et al.Dialogues Cardiovasc Med 2004; 9 :71 –89Ceconi C et al.Eur J Pharmaco l 2007; 577 :1– 6.

Effects of ACE Inhibitor administration on Decreasing lipopolysaccharide (LPS)-induced endothelial apoptosis in rat aorta

Ceconi C et al.Cardiovasc Drugs Ther 2007; 21 :423 – 429.

•Quinapril Ische-mic Event Trial (QUIET)• CAD without left ventricular dysfunction • quinapril failed to reduce cardiovascular events overall• Subset with increased concentration of LDL cholesterol improvement seen.

• ↓LDL

• Statins

• relatively lower-

risk pt population.

•High tissue affinity alone cannot determine the effectiveness of an ACE inhibitor in preventing cardiovascular events though it is an important component

•Other pharmacologic and structural characteristics of ACE inhibitors result in differences in effectiveness.

•Perindopril or ramipril is likely to be a better therapeutic option than certain other ACE inhibitors in the setting of stable CAD.

Quinapril is known to decrease vol overload hypertrophy compared to enalapril

Circulation 1995;91:16–19.

Am J Physiol 1997;273:H641–H646.

BANFF •High-resolution usg used for brachial art flow mediated vasodilation (FMD) before & after 8 wks of treatment.

•CAD pts had impaired FMD compared to pts without CAD.

•Among the antihypertensive agents tested (quinapril, enalapril, losartan, amlodipine), only quinapril significantly improved FMD

J Am Coll Cardiol 2000;35:60–66.78].

RAAS Blockade with ARB;ACEI and ARB : Is there difference?

• Ang II

• AT1

•X• Proliferation

• Vasoconstriction

• AT2

• Antiproliferation Vasodilation

• Bradykinin • NOS

• NO

• cGMP

• Ang II

The Blood Pressure Lowering Treatment Trialists’ Collaboration—• meta-regression analyses of 26 large-scale trials

• Almost 150 000 patients with hypertension or ↑ CVD risk

• ACE inhibitors and ARBs produced similar BP-dependent decreases in the risks of major coronary heart disease (CHD) events, such as stroke and heart failure

• However, ACE inhibitors, but not ARBs, had effects beyond BP lowering

• (9%) of ACE inhibitor efficacy in reducing CHD risk was attributed to BP-independent effects( P =0.002)

J Hype rtens 2007; 25 :951 –958.

Angiotensin 1 -9 (Ang1-9) & Ang1-7

• Ang 1-9– reduces AngII – increases Ang1-7 levels – Stimulates bradykinin

release– Directly binds the AT 2R

• Ang1-7 blocks the effects of AngII via the G protein-coupled receptor Mas

ACE 2

•Novel enzyme similar to ACE, called angiotensin-converting enzyme 2 (ACE2)

•Removes the COOH-terminal amino acid phenylalanine and has 400-fold less affinity to Ang I than to Ang II

•ACE2 can cleave des-Arg(9)-bradykinin

•Insensitive to ACE inhibitors

•AT2R• Inhibits MAPKs, activates

NO/cGMP and phospho-lipase A2 pathways

• Stimulation with non-peptide agonist, compound 21, improved myocardial function in rats with myocardial infarction independently of BP effects, along with anti-inflammatory action and NF-k B inhibition

Funke-Kaiser H et al. J Renin Angiotensin Aldosterone Syst 2010;11:7 – 17Rompe F et al. Hypertension 2010;55:924 – 931

•Mas • Promotes Akt

phosphorylation,NO release.

• Stimulation with a synthetic peptide induced vasorelaxation, reduced BP in spontaneously hypertensive rats (SHR) and showed antiarrhythmic effects.

Savergnini SQ et al.Hyp ertension 2010;56:112 – 120

Cardiac ACE2/Ang-(1–7)/Mas Axis

• Protective role of ACE2 in the heart

• Vascular endothelial cells( including kidney, lung & small intestine), cardiomyocytes, fibroblasts & myofibroblasts

• ACEi, ARBs, and aldosterone receptor blockers, increase ACE2 activity/ expression

• Ang-(1–7) causes vasodilation in forearm circulation of normotensive subjects and patients with essential hypertension but no significant effect in the same vascular territory in ACEi-treated patients

• Activation of Endogenous ACE2 (XNT) causes a dose-dependent hypotensive effect in normotensive and hypertensive rats but no significant effect in response to the administration of Ang II or Losartan

International Journal of HypertensionVolume 2012 (2012), Article ID 147825, 13 pagesdoi:10.1155/2012/147825

Ang II

With XNT

Without XNT

Metabolism of bradykinin [BK-1-9]

Kinins• Vasodilators• Promote diuresis• Natriuresis• Cardioprotective actions• Prevention of cardiac hypertrophy• Reduction in infarct size• Regulate coronary vascular tone and BP• Contribute to the vasodilation in heart failure

•High levels of kinin peptides produce• inflammation• Angioedema

Hypertension. 2003;41:383-389

Removal of two C-terminal dipeptides

•Captopril + bradykinin receptor antagonist HOE140 given to both normotensive and hypertensive subjects

•HOE140• reduced the hypotensive effect of captopril,• renal hemodynamic response to captopril was not

changed,• response of plasma renin activity to captopril was

significantly altered

N Engl J Med 1998;339:1285–1292.

•Doppler imaging used to measure radial artery blood flow effects of • high tissue-affinity ACE inhibitor (quinaprilat) • HOE140, • Combination.

•Quinaprilat increased flow nearly 50% over baseline,

•HOE140 decreased flow from baseline by 33%. •Coadministration yielded results similar to those obtained with the B2 antagonist alone

Circulation 1997;95:1115–1118.

Contribute/Support/Mediate the cardiac effects of ACEI

ACE & NEP• ACE and NEP are 2 membrane-bound zinc-

containing metallopeptidases involved in the metabolism of a variety of biological peptides.

• Tissue distribution– The vascular endothelium– smooth muscle cells– cardiac myocytes– fibroblasts,– Brush border of proximal tubule cells of the kidney, – Brain

Erdos Eget al. FASEB J. 1989;3:145–151.

Ferrario CM et al.Hypertension. 1997;30:535–541.

ACE NEP

Angiotensin (Ang) I Natriuretic peptides

Ang-(1-7) Ang I

Kinin peptides bradykininand kallidin

Ang II

Chemotactic peptide Kinin peptides

Enkephalins Substance P

Neurotensin Adrenomedullin

Substance P Endothelin

LH–releasing hormone Chemotactic peptide

Hemoregulatory peptide N-acetyl-Ser-Asp-Lys-Pro

Enkephalins, and the Amyloid peptide.

Effects of ACE Inhibition

↑Renin

ACE Independent

pathways

Hypertension. 2003;41:383-389.

Vasopeptidase Inhibitors: Dual ACE/NEPInhibition by a Single Molecule

OCTAVEIMPRESS

OVERTURE

•Major concerns were • Angioedema

• upto 4 times• Particularly in HTN rather in HF

• More of ACE inhibition rather than NEP inhibition

•Angiotensin type 1 receptor (AT1R) • mediates most of the

Ang II effects

• Trigerrs aldosterone release

• Telmisartan or losartan with its metabolite XP 3179, might offer even more metabolic protection as they have peroxisome proliferator-activated receptor-γ activating properties.

•AT4R : predominantly in kidney (endothelial cells and tubules)

Kappert K et al.Hypertension 2009;54:738 – 743.J Physiol 589.4 (2011) pp 939–951

Lower Affinity

Aldosterone receptor antagonists

Spironolactone•Reduce BP (Resistant hypertension)•Diminish urine protein excretion•Confer CV gain in heart failure apparently independently of volume alterations•Reduces the apnoea-hypopnea index in patients with OSA

Eplerenone•Selective for MR•200 mg b.i.d. required to achieve BP reduction comparable with 50 mg spironolactone b.i.d.

Nishizaka MK et al. Am J Hypertens 2003;16:925 – 930.Sica DA et al. J Clin Hypertens (Greenwich) 2011;13:65 – 69.

• Aldosterone is generated in many tissues besides the adrenal cortex and is involved in endothelial dysfunction, inflammation, proteinuria, and fibrosis

•Blockade of mineralocorticoid receptors presumably is beneficial even in situations with high AngII, because of common signal transduction pathways

Non-steroid generation of MRAs.

NimodipineWO2005097118; DE102005034267

Dietz JD et al. Hyp ertension 2008;51:742 – 748.Arhancet GB et al. J Med Chem 2010;53:4300 – 4304.

Aldosterone synthase inhibitors•Fadrozole• Aromatase inhibitor or its dextroenantiomer

(FAD286)• Reduces mortality, cardiac hypertrophy,

albuminuria, cell infiltration, and matrix deposition in the kidney in double transgenic renin rats (dTGR)

• Both FAD286 and MRAs comparably reduced hypertrophy and interstitial fibrosis of the kidney and heart induced by Ang II and a high-salt intake

• No profound effect on BP

•LCI699• Reduced 24 h-ambulatory systolic BP by - 4.1

mmHg after 4 weeks of treatment • Suppressed supine plasma aldosterone

concentrations• ACTH concentrations were also elevated though

cortisol remained same

Fiebeler A et al. Circulation 2005;111:3087 – 3094.Amar L etal.Hyperte nsion 2010;56:831 – 838

Cross-talk between statin and RAASCross-talk between PPARs and RAAS

Koh KK et al. Int J Cardiol 2009;132:297–9. [PubMed: 19136168]Vascular Disease Prevention, 2009, 6, 65-74

•Statins, thiazolidinediones (PPARγ agonists) and RAAS blockade may have additive beneficial effects on endothelial function, insulin resistance, and atherosclerosis

•Telmisartan and losartan also have additional inbuilt PPARγ agonist activity

•Hypercholesterolemia is associated with AT1-receptor upregulation and increased O2-production secondary to an activation of vascular NADPH oxidase.

•Pioglitazone inhibits gp91phox expression, and attenuatsed toxic peroxynitrite (ONOO-) formation

Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline)

• The breakdown of Ac-SDKP can be blocked by ACE inhibitor treatment resulting in an increase of its plasma levels

• Measurement of Ac-SDKP could be a marker for the clinical efficiency of ACE inhibition

• N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), is a hematopoetic factor (acts

on the cell cycle and prevents the activation of pluripotent stem cells)

• Increased levels of Ac-SDKP have recently been associated with anemia in heart failure patients treated with ACE inhibitors

Van der Meer P et al.Circulation 112: 1743–1747, 2005.

ACE Inhibitor and ARB Effects“Independent of the RAAS”

• ACE inhibitors as well as AT1 receptor blockers can influence cellular functions independent of inhibition of the RAAS. – ACE inhibitors block the hydrolysis of Ac-SDKP

• Hence inhibition of fibrosis, reduction of inflammatory cell infiltration

– Ramiprilat and perindoprilat increase CK2-mediated phosphorylation of serine1270 and increase the activity of N-terminal kinase in endothelial cells (↑NO)• Hence mediate cellular function by “outside-in” signaling directly

through ACE

– The PPAR-γ activating properties of certain sartanes (molecular structure of the specific sartanes)

Peng H et al. Circulation 112: 2436 –2445, 2005Fleming I et al. Curr Opin Neph-rol Hypertens 15: 8 –13, 2006

Conclusion

• With overexpression of RAS components or inhibition of others, the RAS becomes a mediator of pathophysiological stimuli:– Most importantly “progression of atherosclerosis

in multiple organs”

• The search for new members/components / pathways still continues.

• It offers new and promising drug targets

Conclusion

• The concept of tissue RAS, should not be considered as an opposing or alternative but rather as a complimentary or integrated functional concept of ANG formation and function.

• The plasma RAS : Acute “response unit”

• Tissue RAS : Subacute and chronic modulation

• Tissue ACE inhibition results in vasculoprotection beyond blood pressure reduction alone

“There is clearly no basis for any controversy”T H A N K Y O U