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Renin angiotensin aldosterone-   Updates
 

Renin angiotensin aldosterone- Updates

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renin angitensin aldosterone system- updates

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    Renin angiotensin aldosterone-   Updates Renin angiotensin aldosterone- Updates Presentation Transcript

    • UPDATE ON RAASDr Vijay Amaranth Dr R. Barik
    • 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.
    •  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
    • 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”.
    • 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.
    • Stretch receptors in the afferent arteriole, the sympathetic nerves ending in thejuxtaglomerular cells, and the composition of the tubular fluid reaching the macula densa
    •  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.
    •  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
    • 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
    •  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.
    •  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.
    • 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.
    •  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
    • 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.
    •  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)
    •  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
    • (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.
    • “receptor-associated prorenin system” (RAPS) pathogenic mechanims dually activates the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling via the receptor.
    • (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
    • 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.
    • 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
    • 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.
    •  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.
    • Localization and Functional Aspects RENAL RAS CARDIAC RAS Vasculature Nervous system Adipose tissue
    • 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
    •  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
    • FUNCTION INOTROPIC EFFECTS HYPERTROPHIC EFFECTS - activation of MAP kinase and JAK/STAT pathways; MECHANICAL STRETCH
    •  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
    •  APOPTOSIS - cardiac remodeling for example, after myocardial infarction , hypertensive cardiomyopathy , and diabetic cardiomyopathy
    • RAAS and cardiac arrhythmias Electrical remodeling cardiac hypertrophy, fibrosis, and heterogeneity of the cardiac tissue RAAS, oxidative stress, and arrhythmias RAAS and ion channels
    • RAAS and cardiac arrhythmias
    • 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.
    • 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.
    • 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)
    • Aldosterone antagonism
    • Aldosterone antagonism
    • 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.
    •  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 .
    • 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
    • Aliskiren Binding to Renin ReninAliskiren bound to Active siteWood et al. BBRC 2003.
    •  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
    • 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)
    • 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
    • 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
    • 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.
    • 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.
    • 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