UPDATES OF RENIN ANGIOTENSIN SYTEM INTERVENTION

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UPDATES IN RENIN ANGIOTENSIN SYSTEM INTERVENTION

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UPDATES OF RENIN ANGIOTENSIN SYTEM INTERVENTION

  1. 1. The Renin-Angiotensin Aldosterone System: Conventional RAS &Established Facts. Dr Ramachandra Barik
  2. 2. INTRODUCTIONIn the quest to keep our self updated in the aura of 21st century- newer molecules and newer trials being poring ineveryday, we the upcoming cardiologists are forgetting/confused or do not give importance to the landmarks orlandmark trials in our day to day practice due to lack of time. In the rush of everything should be evidence baseMedicine to do everything at patient best and make oneself safest in bar, This is a tiny attempt to afresh ourknowledge of conventional RAS and established facts. “We repeat the same mistake again and again because we like practice without history.”
  3. 3. Bird’s eye View THE MOST POTENT VASOCONSTRICTOR SYSTEM IN THE BODY.
  4. 4. Manipulating RAS
  5. 5. 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.
  6. 6. 1836 :Robert Tigerstedt and Per Bergman → kidney–hypertension-LVH.A thermolabile peptide from kidney extracts into rabbits→HTN=Renin=in kidney. Renin
  7. 7. Harry Goldblatt – 100 Yrs. later a characteristic narrowing of the renal blood vessels inpatients 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 Test result a reproducible and persistent Goldblatt’s explanation for his rise in blood pressure, in the results was similar to that of absence of overt renal failure. Tigerstedt and Bergman: Clamping other large arteries ischemia causes the kidneys to —splenic or femoral—had no produce an “internal secretion” effect, indicating that that triggers vasoconstriction hypertension resulted specifically from kidney ischemia(Journal of Experimental Medicine-1934)
  8. 8. “Goldblatt’s discovery was spectacular, but nobody believedit,” recalls cardiologist John Laragh. The skepticism, Laragh says, was largely because of thetechnical 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 higherthe purity lesser the HTN effect .Hence pressure-raising substance not Renin itself rather acatalyst for angiotensinogen. Purifying renin away from its substrate had abolished its activity .They named “hypertensin” and “angiotonin,” respectively. They later compromised andrenamed 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 convertedinto angiotensin I, which is then processed by angiotensin converting enzyme (ACE) intoangiotensin II. Angiotensin II is the true culprit of hypertension.
  9. 9. 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.
  10. 10. Affects → heart & systemic RESULTSvasculature Vasoconstriction, Atherosclerosis,HTN,cardiacAthesclerosis, vascular Hypertrophy.etcremodeling, hypertrophy,interstitial fibrosis, apoptosis,inflammation, thrombosis,Angiotensin II–stimulatedsecretion of aldosterone by theadrenal cortex and argininevasopressin , sympatheticactivation and aldosterone.
  11. 11. Renin –Hormonal peptide-340 AA,an enzyme .T½ -15 min ,prepared and stored ingranular JG cells in kidney and alsoother tisuue–the main source of plasmaRenin (active) and 90% in prorenin(inactive but immune reactive ).it issynthesized In both constitutive and ratelimiting pathway. It catalyzes the ratelimiting step of RAS – attract activefuture target.Stretch receptors(pressure sensor) inthe afferent arteriole, local SNS , Nacontent of the tubular fluid reaching themacula Desna cell - release aroundJGA→Renin .
  12. 12. ↑ RELEASE
  13. 13. Renin production is ↓ indomethacin,b-Blocker,Ang II receptor and pepstatin.
  14. 14. Rate-limiting step : α2globulin, angiotensinogen(453AAs-↑ by glucocorticoids,thyroid hormones, estrogens,several cytokines, andangiotensin II) by Renin →inert decapeptide Ang- I(1/100th potency of Ang II)→ AngII(T½-1 min).Source ofAngiotensinogen- liver, kidney,brain, heart, vascular, adrenalgland, ovary, placenta, andadipose tissue.ACE-ectoenzyme two forms:a somatic - throughout thebody and a germinal cell. Onegene chromosome 17. (DD/II/DI) . Angi I→Ang II.Localized inplasma membrane ofendothelial cells and other cells in unbound form in plasma.Angi II - III and IV.Angi II -T½ IS1-2 min .
  15. 15. Conventional/tissue RAS
  16. 16. RAS WORKS-Renin –rate limiting enzyme.Angiotensinogen-renin substrate from liver.Angiotensinogen I–no action.Angiotensin II=hypertensin = angiotonin—most potent vasoconstrictors X8 NA.itspressure activity ↓in Na+, cirrhosis .Angiotensin II ↑adrenal cortex Aldosteronesecretion, nor epinephrine by a direct actionon postganglionic sympathetic neurons,contraction of mesangial cells (↓ GFR),directrenal tubules to increase Na+ reabsorption.Angiotensin II → brain to decrease thesensitivity of the baroreflex→potentiates thepressure effect of Angiotensin II/↑ H20intake/ vasopressin and ACTH. It does notpenetrate the blood–brain barrier, but ittriggers these responses by acting on thecircumventricular organs, One of thesestructures, the area postrema- pressure ↑subfornical organ (SFO) and the organumvasculosum of the lamina terminalis (OVLT),cause-dispogenic effect.
  17. 17. Angiotensin II Receptors-AT1- (chromosome 3/Gq- phospholipase C-IP3/DAG - intracellular ↑ cytosolic Ca2+-vasopressor and contraction of heart andtyrosine kinase/MAP kinase /PKC-protooncogene activation for growth andhyperplasia.)- effects of Ang II. AT2—( X chromosome/ G protein/phosphatases -antagonize growth effects andopen K+ channel/production of NO and↑intracellular cyclic 3,5-guanosinemonophosphate (cGMP). . AT2 receptors -plentiful in fetal /neonatal life / also in brainand other organs in adults.The AT1 receptors in the arterioles and the AT1receptors in the adrenal cortex are regulated inopposite ways: an excess of angiotensin IIdown-regulates the vascular receptors, but itup-regulates the adrenocortical receptors,making the gland more sensitive to theAldosterone-stimulating effect of the peptide.
  18. 18. Angiotensin III –has 40% ofthe pressure activity ofAngiotensin II, but 100% of theAldosterone-stimulatingactivity. It has been suggestedthat Angiotensin III is thenatural Aldosterone-stimulating peptide, whereasAngiotensin II is the blood-pressure-regulating peptide.However, this appears not tobe the case, and insteadAngiotensin III is simply abreakdown product with somebiologic activity.Angiotensin IV- unique effectsin the brain.
  19. 19. AT-2 receptorA 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 receptorblockade via a BK/NO/cGMP pathway.This paradigm opens the door for potential synergistic therapeutic effects of AT2 receptoragonists in combination with AT1 receptor blockers.Activation of the AT2 receptor mediates at least some of the beneficial effects of AT1 receptorblockade via a BK/NO/cGMP pathway.This paradigm opens the door for potential synergistic therapeutic effects of AT2 receptoragonists in combination with AT1 receptor blockers.
  20. 20. AT-III AND AT –IV RECEPTORThe type 4 (AT4) receptors- mediate the release of plasminogen activator inhibitor 1 by Ang IIand 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.
  21. 21. 2000 AD -ACE 2 a zinc metalloprotease was discovered and gene mapped X-chromosomeACE 2 may be a candidate gene in hypertension.
  22. 22. 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 ACEinhibitorsMAS -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 proteinthat 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
  23. 23. 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 intheir 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 extracellularmatrix components, fibronectin and collagenreceptor acts as a cofactor by increasing the efficiency of ANG I generation on the cell surfaceby 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 extracellularmatrix components, fibronectin and collagenreceptor acts as a cofactor by increasing the efficiency of ANG I generation on the cell surfaceby receptor-bound prorenin and renin
  24. 24. Tissue RAS.In addition to circulating Angiotensin II, many different tissues contain independentrenin–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 theeyes, exocrine portion of the pancreas, heart, fat, adrenal cortex, testis, ovary,anterior and intermediate lobes of the pituitary, pineal, and brain. Tissue Renincontributes very little to the circulating Renin pool, because plasma Renin activityfalls to undetectable levels after the kidneys are removed. The functions of thesetissue renin–angiotensin systems are unsettled, though evidence is accumulatingthat Angiotensin II is a significant growth factor in the heart and blood vessels. ACEinhibitors or AT1 receptor blockers are now the treatment of choice for congestiveheart failure, and part of their value may be due to inhibition of the growth effectsof Angiotensin II.
  25. 25. Manipulating RAS-Towards establishing facts1.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 ?
  26. 26. Renin inhibitor
  27. 27. Renin blocker-alskerin
  28. 28. 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.
  29. 29. THANK U

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