Renin angiotensin aldosterone- Updates

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Renin angiotensin aldosterone- Updates

  1. 1. UPDATE ON RAASDr Vijay Amaranth Dr R. Barik
  2. 2. RAAS - INTRODUCTION Coordinated hormonal cascade in the control of cardiovascular, renal, and adrenal function that governs fluid and electrolyte balance and arterial pressure. Exciting new concepts: new peptides, new enzymes , novel receptors, receptor-receptor interactions, and the local tissue RAS ,intracellular RAS.
  3. 3.  The new expanded view covers both endocrine, paracrine ,autocrine and intracrine functions. Discovery of SNPs in RAS - enhanced comprehension of the pathophysiology of complex disease . RAS - complex and multilayered
  4. 4. Historical Perspective In 1898, Tigerstedt and Bergmann : heat- labile substance in crude extracts of rabbit renal cortex termed “renin”. heat-stable, short-lived pressor substance - termed “angiotonin” or “hypertensin” by competing investigators Page et al and Braun- Menendez et al who ultimately compromised on the term “angiotensin”.
  5. 5. The Classical Renin-Angiotensin System Renin is produced and stored in granular JG cells in kidney. Preprorenin >>> prorenin >>> renin . sequential cleavage of the N-terminal 20 and 46 amino acids of preprorenin. kidney also releases unprocessed prorenin via a constitutive pathway prorenin accounts for about 70% to 90% of the immunoreactive renin.
  6. 6. Stretch receptors in the afferent arteriole, the sympathetic nerves ending in thejuxtaglomerular cells, and the composition of the tubular fluid reaching the macula densa
  7. 7.  Rate-limiting step : cleaving the N-terminal portion of a large molecular weight globulin, angiotensinogen, to form the biologically inert decapeptide Ang- 1(1-10) primary source is liver, also in kidney, brain, heart, vascular, adrenal gland, ovary, placenta, and adipose tissue.
  8. 8.  Ang III and IV- in tissue with high levels of aminopeptidases A and N, such as brain and kidney tissue. Ang III - in CNS , play an important role in tonic blood pressure maintenance and in hypertension. Ang IV [(3-8)] is a hexapeptide . Some report that Ang IV is a vasorelaxative agent and this effect is contributed to activation of endothelial NOS others: Cooperative effect of Ang IV on angiotensin II type 1 (AT1)-receptor signaling
  9. 9. The AT2 Receptor gene - a single copy on the X chrmosome. highly expressed in fetal mesenchymal tissues clearly detectable in the adult kidney, heart, and blood vessels. mediate vasodilation by stimulating the production of BK, NO, and cGMP
  10. 10.  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
  11. 11.  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.
  12. 12.  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.
  13. 13. Angiotensin-Converting Enzyme-2 In the year 2000, ACE 2 a zinc metalloprotease was discovered gene mapped to the X chromosome in humans ACE 2 may be a candidate gene in hypertension.
  14. 14.  Pedominantely 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 inhibitors
  15. 15. Angiotensin (1–7) IN 1988 major biologically active peptide product of the RAS ANG I by neutral-endopeptidase (NEP) 24.11 or prolyl- endopeptidase (PEP) ANG II via PEP or prolyl-carboxypeptidase NEP 24.11 plays a major role in both circulating and tissue ANG (1–7) formation cleaved to biologically inactive fragments by aminopeptidases or ACE.
  16. 16.  G protein-coupled receptor Mas originally described as a protooncogene 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)
  17. 17.  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
  18. 18. (pro)renin receptor Transmembrane 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.
  19. 19. “receptor-associated prorenin system” (RAPS) pathogenic mechanims dually activates the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling via the receptor.
  20. 20. (pro)renin 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 collagen receptor acts as a cofactor by increasing the efficiency of ANG I generation on the cell surface by receptor-bound prorenin and renin
  21. 21. Angiotensin Receptor Heterodimerization AT1 receptor and the BK B2 receptor associate to form stable heterodimers ; in vivo was shown to be potentially important in the mediation of increased ANG II responsiveness in preeclampsia AT1 and AT2 receptors heterodimerize: no longer activate G proteins by AT1 . Thus, it appears that the AT2 receptor can be a direct AT1 receptor-specific antagonist.
  22. 22. Local [tissue] RAS New hypotheses and functional concept- based on the tissue-based synthesis of ANG II. Convinced and strengthened by two major technical advances :the use of molecular biology and the availability of transgenic and knock-out models
  23. 23. local synthesis versus uptake from the circulation Should not threaten the concept , since either mechanism could contribute to local ANG synthesis and actions. Modern concepts of the tissue RAS, therefore, are function oriented.
  24. 24.  Plasma RAS takes up the role of an acute “response unit,” whereas tissue-based ANG II formation is more linked to subacute and chronic modulation. local RAS: should not be considered as an opposing or alternative but rather as a complimentary or integrated functional concept of ANG formation and function.
  25. 25. Localization and Functional Aspects RENAL RAS CARDIAC RAS Vasculature Nervous system Adipose tissue
  26. 26. CARDIAC RAS Maintenance of an appropriate cellular milieu balancing stimuli inducing and inhibiting cell growth and proliferation as well as mediating adaptive responses to myocardial stress
  27. 27.  Human heart chymase activates ANG I to ANG II but is not inhibited by ACEI Normal fibroblasts express AT1 only but can recruit the AT2 receptor under certain pathological conditions
  28. 28. FUNCTION INOTROPIC EFFECTS HYPERTROPHIC EFFECTS - activation of MAP kinase and JAK/STAT pathways; MECHANICAL STRETCH
  29. 29.  REMODELING: mediated through growth factor pathways induced by AT1 . osteopontin - vascular smooth muscle cell remodeling , cardiac fibroblast behavior AC-SDKP: a hematopoetic stem cell regulator, plasma marker for efficient ACE inhibition antiproliferative effects
  30. 30.  APOPTOSIS - cardiac remodeling for example, after myocardial infarction , hypertensive cardiomyopathy , and diabetic cardiomyopathy
  31. 31. RAAS and cardiac arrhythmias Electrical remodeling cardiac hypertrophy, fibrosis, and heterogeneity of the cardiac tissue RAAS, oxidative stress, and arrhythmias RAAS and ion channels
  32. 32. RAAS and cardiac arrhythmias
  33. 33. INTRACELLULAR RAS INTRACRINE HORMONAL SYSTEM : Although controversial none of the components would have to be secreted into the extracellular space to engender a biological action. renin and prorenin might have the capability to act intracellularly, as well as ANG II and other ANG peptides.
  34. 34. ACE Escape With Long-Term ACE Inhibitor Treatment Angiotensin II Returns to Baseline Levels 100 PlasmaAngiotensin- 75 Converting 50 Enzyme,nmol/mL/min 25 * * * * * * * * 0 30 Plasma 20Angiotensin II, pg/mL 10 * 0 Placebo 4 h 24 h 1 2 3 4 5 6 Time, months *P<.001 vs placebo. ACEI, angiotensin-converting enzyme inhibitor; Ang, angiotensin. Biollaz J et al. J Cardiovasc Pharmacol. 1982;4:966-972.
  35. 35. AT1-Receptor Blocker (ARB) Clinical Outcome Studies HBP VASCULAR MI HF LIFE (ONTARGET) OPTIMAAL ELITE II SCOPE (TRANSCEND) VALIANT Val-Heft VALUE JIKEI CHARM (I-PRESERVE)PRE-DIABETES DIABETES DIABETES RENAL(NAVIGATOR) OPTHAL (DIRECT) RENAAL ATRIAL FIB IDNT (ACTIVE)
  36. 36. Aldosterone antagonism
  37. 37. Aldosterone antagonism
  38. 38. ACEI/ARB combinations different cardiovascular outcomes [ CHARM- Added, Val-HeFT, VALIANT vs RESOLVD Pilot Study Investigators ] may relate to different patient populations, previous or concurrent successful treatment with other drugs, or study design PRA is related to adverse clinical outcomes further raises the possibility that DRIs may be useful.
  39. 39.  Pepstatin - The first synthetic renin inhibitor but required parenteral administration. Oral agents : enalkiren, remikiren, and zankiren had limited clinical use poor bioavailability (<2%) short halflives weak antihypertensive activity .
  40. 40. ALISKIREN Octanamide, new class of nonpeptide, low molecular weight, orally renin inhibitors At a dose of 300 mg decreases PRA by 50%–80 The plasma half-life of 23–70 hours
  41. 41. Aliskiren Binding to Renin ReninAliskiren bound to Active siteWood et al. BBRC 2003.
  42. 42.  Metabolism by Cytochrome P450 (CYP3A4) No change of dose in hepatic and renal insufficiency Adverse events : diarrhea, headache, nasopharyngitis, dizziness, fatigue, back pain, gastrointestinal disorders, rash, and renal stone cough and angioedema
  43. 43. PRORENIN RECEPTOR handling region peptide (HRP) inhibiting the binding of prorenin to (P)RR non-peptide (P)RR antagonist (i.e. a renin/prorenin receptor blocker, RERB)
  44. 44. AT2R agonists Recently discovered non-peptide agonist, compound 21 Inhibits MAPKs, activates NO/cGMP and phospholipase A2 pathways- mediating anti- proliferation, vasodilation, and anti-inflammation. Mas may also partially antagonize the AT1R effects- some therapeutic potential In rat studies
  45. 45. Vasopeptidase inhibitors OCTAVE and OVERTURE : ACE/NEP inhibition omapatrilat but higher incidence of angioedema . Dual AT1R/NEP antagonism (angiotensin receptor and neprilysin inhibitors, ARNI) could show a more favourable tolerance profile
  46. 46. Gene-based therapies aOverexpression of ACE2 and AT2R delivered in viral vectors reduced cardiac remodelling. Exciting, but more safe and reliable methods of nucleic acid transfer re required.
  47. 47. Vaccine-based strategies Two antihypertensive vaccines were developed: PMD3117 against Ang I and Cyt006 against Ang II Seems feasible and preventive employment against CV diseases.
  48. 48. Molecular therapy Ang-(1-7) inhibited mitogen-stimulated VSMC growth and reduced neointimal formation after vascular injury. Increased the vascular content of cAMP in VSMCs Inhibits angiogenesis - role in treatment of various tumors

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