UPDATES OF RENIN ANGIOTENSIN SYTEM INTERVENTION

The Renin-Angiotensin Aldosterone System: Conventional

RAS &Established Facts.

Dr Ramachandra Barik

INTRODUCTION

In the quest to keep our self updated in the aura of 21st century- newer molecules and newer trials being poring in everyday, we the upcoming cardiologists are forgetting/confused or do not give importance to the landmarks or landmark trials in our day to day practice due to lack of time. In the rush of everything should be evidence base Medicine to do everything at patient 'best and make oneself safest in bar, This is a tiny attempt to afresh our knowledge of conventional RAS and established facts.

“We repeat the same mistake again and again because we like practice without history.”

Bird’s eye View

THE MOST POTENT VASOCONSTRICTOR SYSTEMIN THE BODY.

Manipulating RAS

Recapitulation

• In 1934, pathologist Harry Goldblatt established the first animal model of hypertension. This model provided researchers with the tools to delineate the

• RAS -of blood pressure control and, eventually, to design enzyme inhibitors for the treatment of chronic hypertension.

Renin

1836 :Robert Tigerstedt and Per Bergman → kidney–hypertension-LVH.A thermolabile peptide from kidney extracts into rabbits→HTN=Renin=in kidney.

Harry Goldblatt – 100 Yrs. later a characteristic narrowing of the renal blood vessels in patients who had died of hypertension-made him think ?????

Homework- constricted the major renal arteries of dogs using a self-styled adjustable silver clamp. Partial constriction of both renal arteries resulted in a reproducible and persistent rise in blood pressure, in the absence of overt renal failure. Clamping other large arteries—splenic or femoral—had no effect, indicating that hypertension resulted specifically from kidney ischemia(Journal of Experimental Medicine-1934)

Test resultGoldblatt’s explanation for his results was similar to that of Tigerstedt and Bergman: ischemia causes the kidneys to produce an “internal secretion” that triggers vasoconstriction

“Goldblatt’s discovery was spectacular, but nobody believed it,” recalls cardiologist John Laragh. The skepticism, Laragh says, was largely because of the technical difficulty of Goldblatt’s procedure, which few could reproduce.

Goldblatt’s confirmed- determining the identity of the “internal secretion”→ Renin.

1939 -Eduardo Braun-Menendez and Irvine Page— purified Renin but found that the higher the purity lesser the HTN effect .Hence pressure-raising substance not Renin itself rather a catalyst for angiotensinogen. Purifying renin away from its substrate had abolished its activity . They named “hypertensin” and “angiotonin,” respectively. They later compromised and renamed it “angiotensin” and its precursor “Angiotensinogen”.

Leonard Skeggs et al.→ confirmed 2 forms of angiotensin .

It is now known - Renin initiates an enzymatic cascade in which Angiotensinogen is converted into angiotensin I, which is then processed by angiotensin converting enzyme (ACE) into

angiotensin II. Angiotensin II is the true culprit of hypertension.

CONVENTIONAL RAS(CIRCULATING)

The RAS –endocrine-paracrine-auto crine (circulatory and local tissue) - true band master of neurohormonal regulators of the for circulation in long run.

Renin← JGA cells ← hypo perfusion, ↓& SNS . Angiotensinogen ← liver cleaved by Renin→ inactive ANG I→ ACE→ANG II→ATR for effect by directlyor indirectly.

All of the necessary components of the RAS also exist in several organs and tissues, including the heart, kidneys, and vasculature.

Affects → heart & systemic vasculature Vasoconstriction, Athesclerosis, vascular remodeling, hypertrophy, interstitial fibrosis, apoptosis, inflammation, thrombosis, Angiotensin II–stimulated secretion of aldosterone by the adrenal cortex and arginine vasopressin , sympathetic activation and aldosterone.

RESULTSAtherosclerosis,HTN,cardiac Hypertrophy.etc

Renin –Hormonal peptide-340 AA,an enzyme . T½ -15 min ,prepared and stored in granular JG cells in kidney and also other tisuue–the main source of plasma Renin (active) and 90% in prorenin (inactive but immune reactive ).it is synthesized In both constitutive and rate limiting pathway. It catalyzes the rate limiting step of RAS – attract active future target.

Stretch receptors(pressure sensor) in the afferent arteriole, local SNS , Na content of the tubular fluid reaching the macula Desna cell - release around JGA→Renin .

↑ RELEASE

Renin production is ↓ indomethacin,b-Blocker,Ang II receptor and pepstatin.

Rate-limiting step : α2 globulin, angiotensinogen(453 AAs-↑ by glucocorticoids, thyroid hormones, estrogens, several cytokines, and angiotensin II) by Renin → inert decapeptide Ang- I(1/100 th potency of Ang II)→ Ang II(T½-1 min).Source of Angiotensinogen- liver, kidney, brain, heart, vascular, adrenal gland, ovary, placenta, and adipose tissue.ACE-ectoenzyme two forms: a somatic - throughout the body and a germinal cell. One gene chromosome 17. (DD/II/DI) . Angi I→Ang II.Localized in plasma membrane of endothelial cells and other cells in unbound form in plasma. Angi II - III and IV.Angi II -T½ IS 1-2 min .

Conventional/tissue RAS

RAS WORKS-Renin –rate limiting enzyme.Angiotensinogen-renin substrate from liver.Angiotensinogen I–no action.Angiotensin II=hypertensin = angiotonin— most potent vasoconstrictors X8 NA.its pressure activity ↓in Na+, cirrhosis .Angiotensin II ↑adrenal cortex Aldosterone secretion, nor epinephrine by a direct action on postganglionic sympathetic neurons, contraction of mesangial cells (↓ GFR),direct renal tubules to increase Na+ reabsorption.Angiotensin II → brain to decrease the sensitivity of the baroreflex→potentiates the pressure effect of Angiotensin II/↑ H20 intake/ vasopressin and ACTH. It does not penetrate the blood–brain barrier, but it triggers these responses by acting on the circumventricular organs, One of these structures, the area postrema- pressure ↑ subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT), cause-dispogenic effect.

Angiotensin II Receptors-AT1- (chromosome 3/Gq- phospholipase C-IP3/DAG - intracellular ↑ cytosolic Ca2+ -vasopressor and contraction of heart and tyrosine kinase/MAP kinase /PKC-protooncogene activation for growth and hyperplasia.)- effects of Ang II.

AT2—( X chromosome/ G protein /phosphatases -antagonize growth effects and open K+ channel/production of NO and ↑intracellular cyclic 3,5-guanosine monophosphate (cGMP). . AT2 receptors - plentiful in fetal /neonatal life / also in brain and other organs in adults.The AT1 receptors in the arterioles and the AT1 receptors in the adrenal cortex are regulated in opposite ways: an excess of angiotensin II down-regulates the vascular receptors, but it up-regulates the adrenocortical receptors, making the gland more sensitive to the Aldosterone-stimulating effect of the peptide.

Angiotensin III –has 40% of the pressure activity of Angiotensin II, but 100% of the Aldosterone-stimulating activity. It has been suggested that Angiotensin III is the natural Aldosterone-stimulating peptide, whereas Angiotensin II is the blood-pressure-regulating peptide. However, this appears not to be the case, and instead Angiotensin III is simply a breakdown product with some biologic activity. Angiotensin IV- unique effects in the brain.

AT-2 receptorA single gene on the X chromosome.highly expressed in fetal mesenchyme tissues

clearly detectable in the adult kidney, heart, and blood vessels.

mediate vasodilation by stimulating the production of BK, NO, and cGMP.activates phospholipase A2 and prostaglandin generation.

In the heart, the AT2 receptor inhibits growth and remodeling, induces vasodilation, and is up-regulated in pathological states Activation of the AT2 receptor mediates at least some of the beneficial effects of AT1 receptor blockade via a BK/NO/cGMP pathway.

This paradigm opens the door for potential synergistic therapeutic effects of AT2 receptor agonists in combination with AT1 receptor blockers.Activation of the AT2 receptor mediates at least some of the beneficial effects of AT1 receptor blockade via a BK/NO/cGMP pathway.

This paradigm opens the door for potential synergistic therapeutic effects of AT2 receptor agonists in combination with AT1 receptor blockers.

AT-III AND AT –IV RECEPTOR

The type 4 (AT4) receptors- mediate the release of plasminogen activator inhibitor 1 by Ang II and by the N-terminal truncated peptides (Ang III and Ang IV).

The AT4 receptor appears to be involved in memory acquisition and recall.

but the function of the type 3 (AT3) receptors is unknown.

2000 AD -ACE 2 a zinc metalloprotease was discovered and gene mapped X-chromosomeACE 2 may be a candidate gene in hypertension.

Predominantly in endothiuelm of coronary and renal vasculature

ACE 2 probably counterbalances the enzymatic actions of ACE

Unlike ACE, this enzyme does not convert Ang I to Ang II and its activity is not affected by ACE inhibitorsMAS -G protein-coupled receptor originally described as a proto-oncogene

expressed in several organs including heart, kidney, blood vessels, and brain

intracellular signaling mechanisms are largely unknown may be coupled to a Gq/11 protein that activates phospholipase C (PLC).

BRADYKININ-In addition to BK potentiation at B2 receptor, promotes release of prostaglandins release of NO { PI3K/Akt pathway} vasodilation, inhibition of vascular cell growth, attenuation of ANG II-induced vasoconstriction In addition to BK potentiation at B2 receptor, promotes release of prostaglandins release of NO { PI3K/Akt pathway} vasodilation, inhibition of vascular cell growth, attenuation of ANG II-induced vasoconstriction

Prorenin receptorTransmembrane protein consisting of 350 amino acids ;cloned from mesangial cells

Prorenin/renin - not only aspartyl proteases but also hormones with specific cellular actions in their own right.

Relevant to the pathophysiology of hypertension, preeclampsia, and diabetes mellitus.pathogenic mechanism dually activates the tissue Renin-Angiotensin system (RAS) and RAS-independent intracellular signaling via the receptor.

pathogenic mechanism dually activates the tissue Renin-Angiotensin system (RAS) and RAS-independent intracellular signaling via the receptor. Activates mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) pathway and increases several profibrotic mediators- (TGF-β), and (PAI-1), and the extracellular matrix components, fibronectin and collagenreceptor acts as a cofactor by increasing the efficiency of ANG I generation on the cell surface by receptor-bound prorenin and renin

Activates mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) pathway and increases several profibrotic mediators- (TGF-β), and (PAI-1), and the extracellular matrix components, fibronectin and collagenreceptor acts as a cofactor by increasing the efficiency of ANG I generation on the cell surface by receptor-bound prorenin and renin

Tissue RAS.

In addition to circulating Angiotensin II, many different tissues contain independent renin–angiotensin systems that generate Angiotensin II, local use account for 90% of total ANG II. found in the walls of blood vessels and in the uterus, the placenta, and the fetal membranes. Amniotic fluid has a high concentration of prorenin. n the eyes, exocrine portion of the pancreas, heart, fat, adrenal cortex, testis, ovary, anterior and intermediate lobes of the pituitary, pineal, and brain. Tissue Renin contributes very little to the circulating Renin pool, because plasma Renin activity falls to undetectable levels after the kidneys are removed. The functions of these tissue renin–angiotensin systems are unsettled, though evidence is accumulating that Angiotensin II is a significant growth factor in the heart and blood vessels. ACE inhibitors or AT1 receptor blockers are now the treatment of choice for congestive heart failure, and part of their value may be due to inhibition of the growth effects of Angiotensin II.

Manipulating RAS-Towards establishing facts

1.Sympathetic blocker-ᵦ blocker, adrenergic neuron blocker, central sympatholytic ↓renin. and interventional therapy-SNS radio frequency ablation for RAS.2.Renin inhibitory peptides and antibody ↓ Renin3.ACEI4.Ang AT1 receptor blocker5.Ang II activator6.Aldosterone antagonist7.AT2 receptor agonist8.Prorenin receptor blocker?7.Vasopeptidase inhibitor.?7.Vaccines?8.Genetic ?

Renin inhibitor

Renin blocker-alskerin

Established facts1.RAS INHIBITION IS BENIFICIAL2.CHF-VERY USUFUL IN MILD/MOD/SEV HF3.HTN-BEST RESULTS WITH LONG TERM USE AND WITH HIGH RISK PATIENTS4.EARLY MI START WITHIN 24 HOURS.5.ASYMPTOMATIC LV DYSFN-SAVE,SOLVED6.JUVENILE DM7.NON DM NEPHROPATHY8.PROPHYLAXIS-HIGH RISK-HOPE/EUROPA,ONTARGET9.ARB/HF-VALIANT10.COMBINATION THERAPY-VAL-HeFT,CHARM ,ON TARGET11.LESS NEW DM-COMPAIRED b –blocker/diuretic.12.B/L RAS,PREGNANCY,HYPERKALEMIA,HIGH CREATINE13.ALDACTONE/SPIRONOLACTONE IN HF/MI14.ALISKERIN-ALTITUDE/ASPIRE14.QUADRUPLE THERAPY.

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