1. PHYSIOLOGY & PATHOPHYSIOLOGY OF RAAS
DR.SANDEEP R
SR , DEPT. OF CARDIOLOGY
CMC CALICUT

2. 1) HISTORY
2) ANGIOTENSINOGEN
3) RENIN
4) ACE
5)ANGIOTENSINS
6)ANGIOTENSIN RECEPTORS
7)LOCAL RAAS
8)CARDIAC RAAS
9)ALDOSTERONE
9)PATHOPHYSIOLOGY OF RAAS

3. J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20
HISTORY
Robert Tigerstedt and Per Bergman from Sweden in their seminal 1898 report, Niere und Kreislauf, described the prolonged vasopressor effects of crude rabbit kidney extracts.
Tigerstedt named the unidentified active substance “renin” on the basis of its organ of origin.
Steven A. Atlas, MDJThe Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition
J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20

4. J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20
Goldblatt and colleagues, published in 1934, that showed that renal ischemia induced by clamping of the renal artery could induce hypertension.
Ischemic kidney also released a heat-stable, short-lived pressor substance, in addition to renin.
This finding eventually led to the recognition that renin’s pressor activity was indirect and resulted from its proteolytic action on a plasma substrate (eventually termed “angiotensinogen”) to liberate a direct-acting pressor peptide.
This peptide was initially termed “angiotonin” or “hypertensin” by Page & colleagues(US)
Ultimately named “angiotensin” by Braun-Menendez & colleagues(ARGENTINA)
Steven A. Atlas, MDJThe Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition
J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20

5. J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20
In the early 1950s, during attempts at purification, Skeggs & colleagues discovered that this peptide existed in 2 forms, eventually termed Ang I and II.
In later work, they demonstrated that Ang I was cleaved by a contaminating plasma enzyme,termed “angiotensin-converting enzyme,” to generate the active pressor peptide Ang II.
Laragh, Genest, Davis, Ganong, and their colleagues, culminated in the discovery that Ang II also stimulated the release of the adrenal cortical hormone aldosterone
Steven A. Atlas, MDJThe Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition
J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20

6. ANGIOTENSINOGEN
The primary source of systemic circulating angiotensinogen is the liver particularly the pericentral zone of the hepatic lobules.
It is coded by a single gene, composed of five exons and four introns, that spans approximately13 kb of genomic sequence on chromosome 1 (1q42-q43).
Also detected in many other tissues, including kidney, brain, heart, vascular, adrenal gland, ovary, placenta, and adipose tissue
Rise in response to glucocorticoids, estrogens and other sex steroids, thyroid hormone, inflammatory cytokines (e.g., interleukin-1 and tumor necrosis factor), and Ang II.
Ron D, Brasier AR, Habener JF. Angiotensinogen gene-inducible enhancer-binding protein 1, a member of a new family of large nuclear
proteins that recognize nuclear factor kappa B-binding sites through a zinc finger motif. Mol Cell Biol. 1991;11:

7. RENIN Glycoprotein (Mw 37,326) Renin gene located in CHR.1
Synthesized from preprorenin
Mature active renin is an aspartyl protease secreted by juxtaglomerular cells
Richard E. Gilbert, David S. Game, and Andrew Advani:BRENNERS TEXTBOOK OF NEPHROLOGY;2010;12;

8. JUXTAGLOMERULAR APPARATUS
The Juxtaglomerular Apparatus consists of:
The juxtaglomerular cells
(2) The macula densa
(3) The lacis cells or agranular cells
Granular cells are modified pericytes of glomerular arterioles
Macula densa cells are columnar epithelium thickening of the distal tubule. The macula densa senses any increase in the sodium chloride concentration in the distal tubule of the kidney and secretes a locally active (paracrine) vasopressor which acts on the adjacent afferent arteriole to decrease glomerular filtration rate (GFR), as part of the tubuloglomerular feedback loop. Specifically, excessive filtration at the glomerulus or inadequate sodium uptake in the proximal tubule / thick ascending loop of Henle brings fluid to the distal convoluted tubule that has an abnormally high concentration of sodium. Apical Na-K-2Cl cotransporters move sodium into the cells of the macula densa. The macula densa cells do not have enough basolateral Na/K ATPases to excrete this added sodium, so the cell's osmolarity increases. Water flows into the cell to bring the osmolarity back down, causing the cell to swell. When the cell swells, a stretch-activated non-selective anion channel is opened on the basolateral surface. ATP escapes through this channel and is subsequently converted to adenosine. Adenosine vasoconstricts the afferent arteriole via A1 receptors and vasodilates (to a lesser degree) efferent arterioles via A2 receptors which decreases GFR. Also, adenosine inhibits renin release in JG cells via A2 receptors on JG cells using Gi pathway. Also, when macula densa cells detect higher concentrations of Na and Cl they inhibit Nitric Oxide Synthetase (decreasing renin release) with an unknown pathway.
A decrease in GFR means less solute in the tubular lumen. As the filtrate reaches the macula densa, less NaCl is re-absorbed. The macula densa cells detect lower concentrations in Na and Cl and upregulate Nitric Oxide Synthetase (NOS). NOS creates NO which catalyses the formation of prostaglandins. These prostaglandins diffuse to the granular cells and activate a prostaglandin specific Gs receptor. This receptor activates adenylate cyclase which increases levels of cAMP. cAMP augments renin release. Prostaglandins and NO also vasodilate the afferent arterioles. Efferent arterioles are spared from this effect by renin release

9. RENIN -SYNTHESIS PREPRORENIN( 406 aminoacid) PRORENIN (383 aminoacid)
Whereas the kidneys produce both renin and prorenin, a range of extrarenal tissues—including the adrenal glands, gonads, and placenta—produce prorenin and contribute to its presence in plasma. (293). Renin is also produced locally in organs that exhibita blood-tissue barrier, such as the brain or the testes . In these organs, the local renin operates independently of the systemic RAAS. On the otherhand, in organs such as the heart and the large arterialvessels, significant amounts of renin are taken up from the plasma to support the paracrine activity of the locally produced enzyme
RENIN (340 aminoacid)
Renin is also synthesized In brain, adrenal gland, ovary, visceral adipose tissue, heart and vasculature
Half life of renin is 80 mt
Only action of renin is conversion of angiotensinogen to angiotensin I

10. REGULATION OF RENIN
Active renin secretion is regulated principally by 4 interdependent factors:
(1) A renal baroreceptor mechanism in the afferent arteriole that senses changes in renal perfusion pressure,
(2) Changes in delivery of NaCl to the macula densa cells of the distal tubule
(3) Sympathetic nerve stimulation via beta-1 adrenergic receptors
(4) Negative feedback by a direct action of Ang II on the JG cells.
HAYO CASTROP, KLAUS HO ¨ CHERL, ARMIN KURTZ, FRANK SCHWEDA, VLADIMIR TODOROV,
AND CHARLOTTE WAGNER; Physiology of Kidney Renin: Physiol Rev 90: 607–673, 2010;

11. REGULATION OF RENIN SECRETION
1.INTRARENAL MECHANISM
Renal baroreceptor mechanism
Renin secretion increases as the blood pressure falls below 90mmhg
The precise mechanism , how the pressure signal is transduced into renin release is still unknown, although postulated mediators include stretch-activated calcium channels, endothelins, and prostaglandins
JG cells are strongly electrically coupled to the neighboring cells of the afferent arteriole .
Interestingly, their resting membrane potential changes in situ from -60 to -80 mV in nonpressurized arterioles to approximately -40 mV in pressurized arterioles
Since the depolarization of JG cells is accompanied by the suppression of renin release, the depolarization in response to an increase in perfusion pressure might directly or indirectly contribute to the known pressure-dependent inhibition of renin secretion
As part of a negative-feedback loop, blood pressure in turn affects the synthesis and release of renin from the JG cells of the kidney: an increase in the arterial blood pressure inhibits, whereas a decrease stimulates, the synthesis and secretion of renin (925). This pressure-dependent mechanism, which controls renin synthesis and release, was denoted the “long negative-feedback loop”. Increases in the systemic blood pressure can inhibit renin release via intrarenal as well as extrarenal mechanisms. Both mechanisms have been suggested to be involved in the pressure-dependent regulation of the renin
system. With regard to intrarenal mechanisms, high blood pressure 1) induces pressure-dependent natriuresis,which increases the NaCl load at the macula densa, and2) increases the renal perfusion pressure and therefore influences the renal baroreceptor mechanism.
ANP can modulate the renin release through direct and indirect mechanisms. The activation of the natriuretic peptide receptor-1 (NPR1) can directly inhibit the renin release by increasing the cGMP formation. Although it is generally believed that the tubular action of ANP is predominantly exerted in the more distal segments of the nephron, ANP may also indirectly reduce the renin release via a possible effect on the proximaltubular salt reabsorption (314), which may lead to anincreased NaCl load at the MD.
Vassopressin inhibits renin through V1a mediated vasoconstrn may stimulate renin V2
Oxytocin stimulates renin thrgh sympathetic activation. The
stimulation of angiotensin II and aldosterone formation increases the sodium reabsorption and consequently increases the body sodium content, which, in `turn, inhibit the renin gene expression.recent discovery that the Mineralocorticoid receptors in Jg cells whichmay increase renin synthesis
Obesity causes increase leptin synthesis which increases renal symp activity increase renin and adiponectin may decrease renin. Vasoconstrictors, which are known to suppress renin release, depolarize JG cells in situ . In addition, An increase in the extracellular K concentration or an inhibition of K channels not only depolarizes JG cells, but also suppresses renin release. On the other hand, the membrane hyperpolarization induced by K channel activation or Cl channel inhibition is accompanied by a stimulated renin secretion
HAYO CASTROP ET AL; Physiology of Kidney Renin: Physiol Rev 90: 607–673, 2010;

12. 2.NEURAL CONTROL
The JGA is endowed with a rich network of noradrenergic nerve endings and their β1 receptors
Stimulation of the renal sympathetic nerve activity leads to renin secretion that is independent of changes in renal blood flow, glomerular filtration rate (GFR), or Na+ resorption
Moreover, this effect can be blocked surgically by denervation and pharmacologically by the administration of β blockers

13. 3.TUBULAR CONTROL
Chronic diminution in luminal NaCl delivery to the macula densa is a potent stimulus for renin secretion
This mechanism is thought to account for the chronically high plasma renin activity (PRA) in subjects who adhere to a low-salt diet
The initial step of the MD-dependent control of renin secretion is the detection of the NaCl concentration in the tubular lumen by the MD cells. .
HAYO CASTROP ET AL; Physiology of Kidney Renin: Physiol Rev 90: 607–673, 2010;

14. DISTAL TUBULAR SODIUM ↑
INCREASED UPTAKE INTO MACULA DENSA
THROUGH NA/K+/2CL CHANNEL
MACULA DENSA Na+ & FLUID CONTENT↑
SWELLING OF MACULA DENSA & STRETCH
STRETCH CAUSES ADENOSINE RELEASE
A2 CAUSES ↓
RENIN SECRN
NO SYNTHETASE ↓
DECREASES RENIN

15. DISTAL TUBULAR SODIUM ↓
Na+ UPTAKE IN MACULA DENSA ↓
ACTIVN OF NO
SYNTHETASE
PG SYNTHESIS
STIMULATE RENIN
RELEASE

16. Three mediators - prostanoids, NO, and adenosine/ATP
The detection done by Na-K-2Cl cotransporter in the apical membrane of tubular cells
Three mediators - prostanoids, NO, and adenosine/ATP
Increased tal activity in barter loop diuretics and low sodium diet by increased cox 1 2 expression.The increased sodium uptake from NKCC causes increased production of PGI2 and PGE2 from COX 2 enzyme.Similarily, increased tubular sodium load can increase ATP production in tubular cells causing increase adenosine synthesis which inturn causes decreased renin secretion.NO synthesized in JG cells increase renin.
Castrop et al ; Physiology of Kidney ReninPhysiol Rev 90: 607–673, 2010

17. REGULATION OF RENIN

18. FACTORS THAT INCREASE RENIN RELEASE
1)Catecholamines
2)Bradykinin
3)Dopamine
4)NO
5)Prostaglandins
FACTORS THAT DECREASE
RENIN RELEASE
ANG II
VASOPRESSIN
A N P
IL6
5) TNF - ALPHA
6) ADENOSINE
Castrop et al ; Physiology of Kidney ReninPhysiol Rev 90: 607–673, 2010

19. TUBULOGLOMERULAR FEEDBACK
↓ ARTERIAL PRESSURE
( _ )
( _ )
↓GLOMERULAR FILTRN.PRESSURE
↓GFR
↓MACULA DENSA NaCL
RENIN& ANG II ↑
EFFERENT ARTERIOLAR RESISTANCE ↑
AFFERENT ARTERIOLAR RESISTANCE ↓

20. MOLECULAR MECHANISM OF RENIN RELEASE
C-amp mediated - sympathetic, prostaglandin E2 & I2,dopamine
Calcium paradox - increase in intracellular Ca2+ decrease renin release-endothelin,vasopressin,Ang II
C-GMP
Low consc. stimulates &
High consc. Inhibits - NO
While cAMP is the main stimulator of renin release,the free cytosolic Ca2 concentration is considered as the primary inhibitor. Notably, an increase in the intracellular Ca2 concentration initiates and supports exocytosis in all other secretory cells, excluding parathyroid gland cells(165). Accordingly, the unusual effect of Ca2 in the renin-secreting JG cells has been termed as the “calcium para-dox” of renin release. The term renal baroreceptor describes the inverse
relationship between the intrarenal (perfusion) pressure
and renin secretion. Although it is still difficult to pinpoint
the exact nature of the renal baroreceptor, it appears
likely that the adenosine/ATP from vascular and tubular
sources is crucially involved in the suppression of renin
secretion during increased intrarenal pressure, as men-
tioned above. In addition, mechanical stretching results in
the release of ATP from JG cells (973). This release of ATP from JG cells may provide a tubule-independent link between renal perfusion pressure and renin secretion and may participate in the still elusive local “baroreceptor.” Proposed mech.is increased afferent artery stretch causes increase adenosine synthesis and decreased renin,also endothelins.decreased flow cause increase prostagndin
Castrop et al ; Physiology of Kidney Renin Physiol Rev 90: 607–673, 2010

21. PRORENIN
Traditionally, prorenin was considered the inactive precursor of renin
The Current studies implicate prorenin and renin as direct cardiac and renal toxins
Prorenin is inactive because a 43–amino acid hinge is closed and prevents it from binding to angiotensInogen
Prorenin & renin levels increased by ACE inhibitor , ARB , DRI
Richard E. Gilbert, David S. Game, and Andrew Advani:BRENNERS TEXTBOOK OF NEPHROLOGY;2010;12;

22. PRORENIN RECEPTOR
The kidneys convert inactive prorenin to active renin by enzymatic cleavage of this inhibitory hinge region
When circulating prorenin binds to a newly discovered (pro)renin receptor in the heart and kidneys, the hinge is opened (but not cleaved), and this nonenzymatic process fully activates prorenin
Direct Renin Inhibition: Focus on Aliskiren James L. Pool, MD JMCP October Vol. 13, No. 8, S-b

23. RENIN/PRORENIN RECEPTOR
The existence of high-affinity cell surface receptors that bind both renin and prorenin in several tissues, including heart, brain placenta, and kidney but its significance still unknown
The binding of renin to its receptor resulted in a fivefold increase in the catalytic activity compared with renin in solution
The binding of pro-renin to the receptor increased its enzymatic activity from virtually zero to values comparable to those of active renin in solution
Activation of the (pro)renin receptor increases TGF-β production, leading to collagen deposition and fibrosis
Direct Renin Inhibition: Focus on Aliskiren James L. Pool, MD JMCP October Vol. 13, No. 8, S-b

24. ACE
ACE is responsible for the cleavage of Ang I to form the octapeptide Ang II
ACE cleaves bradykinin into inactive fragments
Human ACE in encoded by a single gene located on chromosome 17
The majority (∼90%) of ACE activity in the body is found in tissues; the remaining 10% of ACE activity is found in a soluble (non–membrane bound) form in the interstitium of the heart and vessel wall
It is seen pulmonary vascular endothelium, endothelium of vasculature ,cell membrane of heart , kidneys & brain

25. ACE 2
ACE2 represents a zinc metalloprotease with carboxypeptidase activity that shares 42% identity with the catalytic site of somatic ACE and can be shed from cells
ACE2 can convert ANGII to ANG 1-7 & ANG I to ANG 1-9
Preferable physiological substrate for ACE2 seems to be ANG II
The expression of ACE2 is (in comparison with ACE) relatively restricted to cardiac blood vessels and tubular epithelia of the kidneys
ACE 2 cannot hydrolyze bradykinin and is not inhibited by ACE inhibitors
Actual function and significance is still unknown
ACE2 is the functional receptor for coronavirus associated with the acute respiratory syndrome, i.e., SARS

27. Steven A. Atlas, MDJThe Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20

28. ANGIOTENSIN SYNTHESIS

29. ANGIOTENSIN RECEPTORS
1)AT1
2)AT2
3)AT3
4)AT4
5)Mas receptor

30. AT1 RECEPTOR AT1 - G protein coupled receptor Chromosome 3
AT1A receptors are found predominantly in kidney, lung, liver and vascular smooth muscle
AT1B receptors are expressed mainly in the adrenal and anterior pituitary glands.
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492

31. AT1 receptors are primarily found in the
1)Brain-hypothalamus,NTS and ventrolateral medulla in the hindbrain,ant.pituitary
2)Adrenals- the zona glomerulosa of the adrenal cortex and chromaffin cells of the adrenal medulla
3) Heart - in the conducting system , nerves of myocardium
4)Vasculature-the aorta, pulmonary and mesenteric arteries, are present in high levels on smooth muscle cells and low levels in the adventitia
5) Kidney – glomerular mesangial cells and renal interstitial cells
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492

32. AT1 RECEPTOR
The predominant angiotensin receptor in the vasculature is the AT1 receptor
Although both the AT1 and AT2 receptor subtypes are present in human myocardium
Ratio of AT1 to AT2 receptors decreases in heart failure
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492

33. ACTIONS OF AT1 RECEPTOR 1) Blood vessels –
vasoconstriction leading to an increase in peripheral vascular tone and systemic blood pressure
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492

34. 1)INCREASED SYMPATHETIC ACTIVITY
2)Heart
Positive ionotropic and chronotropic effects of Ang II on cardiomyocyte
1)INCREASED SYMPATHETIC ACTIVITY
2)INCREASED CA2+ INFLUX
Ang II is also known to mediate cell growth and proliferation in cardiac myocytes and fibroblasts, as well as in vascular smooth muscle cells via TGF,PDGF etc
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492

35. Trophic factor for zona glomerusa
3) Adrenal -Ang II stimulates the release of catecholamines from the adrenal medulla and aldosterone from the adrenal cortex
Trophic factor for zona glomerusa
4) Brain- thirst , salt appetite, central control of blood pressure, stimulation of pituitary hormone release and has effects on learning and memory
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492

36. It increases salt reabsorbtion – direct & indirect Direct effect
5)RENAL
It increases salt reabsorbtion – direct & indirect
Direct effect
Renal arterioles constriction
Proximal Tubular
Epithelial cells
Peritubular capillary pressure
Sodium
reabsorbtion
Fluid reabsorption
From tubules

37. INDIRECT ACTION OF ANG II IN KIDNEY
ANGIOTENSIN II
ADRENAL
CORTEX STIMLN.
SYMPATHETIC ACTIVATION
ALDOSTERONE
SECRETION
MESANGIAL CONTRN
GFR
SALT & WATER
RETENTION

39. AT2 RECEPTOR
The AT2 receptor is also a seven transmembrane domain receptor, encoded by a 363-amino-acid protein( MW 41 kDa)
Shares only 34% sequence identity with the AT 1 receptor
The AT2 receptor -highly expressed in foetus but rapidly declines at birth
AT2 receptors are present in brain, heart, adrenal medulla, kidney and reproductive tissues
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492

40. Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492

41. AT2 RECEPOR & ITS ACTIONS
Brain – cerebellum
Heart - fibroblasts in interstitial regions
Adrenal- adrenal medulla
Kidney- the AT2 receptor is localized to glomeruli, tubules and renal blood vessel
ACTIONS
Vasodilation
Antiproliferative
Apoptosis
Thirst
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492

42. AT3 & AT4 Type 3 (AT3) receptors – Function unknown
The type 4 (AT4) receptors - mainly mapped in brain & kidney
Thought to mediate the release of plasminogen activator inhibitor 1 by Ang II and by the N-terminal truncated peptides (Ang III and Ang IV)
Suggested a role in mediating cerebral and renal blood flow, memory retention and neuronal development
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492

43. Mas RECEPTOR Mas receptor - Acted upon by ANG1-7 Causes Vasodilatation
Natriuresis
Antiproliferation
Cardiac protection
Castrop et al ; Physiology of Kidney ReninPhysiol Rev 90: 607–673, 2010

44. LOCAL RAS
Angiotensin II is found to be synthesized in the various tissues through ACE & non ACE pathways
Independent Ang II - heart, peripheral blood vessels, kidney, brain, adrenal glands, pituitary, adipose tissue, testes, ovaries, and skin.
COMPONENTS :
1) Renin and Prorenin receptor
2) Serine proteases, including several kallikrein-like enzymes (tonins), cathepsin G, and chymase are thought to contribute to Ang II
3) Non-ACE pathways- chymase is the dominant Ang II-generating pathway in the human heart, coronary arteries, and atherosclerotic aorta in vitro
4)ACE 2 ,Mas receptor,AT2 , AT4
The Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition Vol. 13, No. 8, S-b October JMCP

45. LOCAL RAS

46. CARDIAC RAAS 1)RENIN 2)RENIN RECEPTOR 3)ANGIOTENSINOGEN 4)CHYMASE
5)ACE 2
6)AT1& AT2
RECEPTOR 1
MARTIN PAUL et alPhysiology of Local Renin-Angiotensin Systems :Physiology of Local Renin-Angiotensin Systems Physiol Rev 86: 747–803, 2006

47. CARDIAC RAS
Predominant physiological role of the cardiac RAS appears to be the maintenance of an appropriate cellular milieu balancing stimuli inducing and inhibiting cell growth and proliferation as well as mediating adaptive
responses to myocardial stress, for example, after myocyte stretch

49. EFFECTS OF CARDIAC RAAS
1)Ionotropic Effect
Positive ionotropic and chronotropic effects of Ang II on cardiomyocyte
1)INCREASED SYMPATHETIC ACTIVITY
2)INCREASED CA2+ INFLUX
2)Hypertrophy
Ang II is also known to mediate cell growth and proliferation in cardiac myocytes and fibroblasts, as well as in vascular smooth muscle cells via TGF,PDGF
MARTIN PAUL et alPhysiology of Local Renin-Angiotensin Systems :Physiology of Local Renin-Angiotensin Systems Physiol Rev 86: 747–803, 2006

50. 5) Apoptosis – remodelling during M.I , DCMPY etc
3)Mechanical stretch- stretch can cause release of ANG II causing hypertrophy and remodelling
4)Cardiac remodelling – stretch causing fibroblast activation through AT1 receptor.
Increased activity of the system has also been linked to changes in the electrical physiology that lead to arrhythmias both in the ventricle and atria
5) Apoptosis – remodelling during M.I , DCMPY etc
MARTIN PAUL et alPhysiology of Local Renin-Angiotensin Systems :Physiology of Local Renin-Angiotensin Systems Physiol Rev 86: 747–803, 2006

51. VASCULATURE RAS 1) Vasoconstriction
2) Oxygen free radicals causing endothelial dysfunction
The production of ROS by NAD(P)H oxidase in reponse to ANG II stimulation in endothelial and vascular smooth muscle cells activates signal pathways such as MAP kinases, tyrosine kinases may lead to inflammation , artherosclerosis, hypertrophy
3)Angiogenesis
MARTIN PAUL et alPhysiology of Local Renin-Angiotensin Systems :Physiology of Local Renin-Angiotensin Systems Physiol Rev 86: 747–803, 2006

52. GENDER DIFFERENCES IN CARDIAC RAS
1)AT1 receptor downregulated by estrogen
2)Increased pdn. Of ANG 1-7 –vasodilator peptide
3)Ventricular ACE activity is more in males
4)Estrogen decreases renin production
5)Angiotensinogen production is stimulated by testosterone
MARTIN PAUL et alPhysiology of Local Renin-Angiotensin Systems :Physiology of Local Renin-Angiotensin Systems Physiol Rev 86: 747–803, 2006

53. ALDOSTERONE Mineralocorticoid
It is synthesized in the zona glomerulosa of adrenal cortex
It is stimulated by
1)ACTH
2)ANG II
3)HYPERKALEMIA
4) HYPONATREMIA

54. Cholesterol ACTH/AII Pregnenolone Progesterone Deoxycorticosterone
ALDOSTERONE SYNTHASE
Corticosterone
ALDOSTERONE SYNTHASE/AII
18-Hydroxycorticosterone
ALDOSTERONE SYNTHASE
Aldosterone

55. MINERALOCORTICOID RECEPTOR
Mineralocorticoid receptor can bind cortisol, aldosterone & deoxycortisone
The affinity of cortisol to MR receptor is ten times its affinity to GR receptor
This is prevented by the presence of 11 beta dehydrogenase 2 which converts cortisol to cortisone( inactive )
This is the basis of syndrome of apparent mineralocorticoid excess (AME)
PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383

56. ALDOSTERONE ACTION Acts on P cells in Collecting duct
Causes increased activity of Enac
Causes Na/K exchangers
PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383

57. REGULATION OF ALDOSTERONE
ANP DECREASES RENIN THUS ALDO IS INHIBITED.HEPARIN CAUSES DECREASED AFFINITY OF ANGII RECEPTORS TO ALDO SYNTHESIS.
OUBAIN INHIBIT NA/K THUS DEACTIVATING ALDOSTERONE
INCREASE OF 1MEQ OF K+-STIMULATES THE CA CHANNEL INCREASE INTRACELLULAR CA2+
PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383

58. FEEDBACK REGULATION OF ALDOSTERONE

59. HARMFUL EFFECT OF ALDOSTERONE
PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383

60. EFFECTS OF ALDOSTERONE ON HEART
1)Cardiac fibrosis - by acting through mineralocorticoid receptor in cardiac fibroblast causing activation of MAP kinase
2)Perivascular inflammation- endothelial dysfunction permitting adhesion of inflammatory cells to the vascular wall and egress into the perivascular space
Indeed, aldosterone causes endothelial dysfunction in humans in vivo possibly by decreasing NO through superoxide generation
PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383

61. Increase ACE activity causing ANGII causing hypertrophy
3)Cardiac hypertrophy
Increased intracellular calcium might ultimately cause cardiac hypertrophy by increasing the expression of calcineurin, a calcium/calmodulin-dependent protein phosphatase
Increase ACE activity causing ANGII causing hypertrophy
PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383

62. 4) Electrophysiologic abnormalities in heart
Aldosterone causes increase in intracellular calcium/increase in sodium flux which may cause arrythmia
All enzymes required for synthesis of deoxycorticosterone and (in the atria) corticosterone are expressed in the normal human heart
PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383

63. J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20
Steven A. Atlas, MDJThe Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition
J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20

64. ‘ONE KIDNEY’ GOLDBLATT HYPERTENSION
Initial rise in hypertension is due to renin secretion leading to angiotensin II
Secretion of renin peaks in one day but gradually decreases over 5-7 days as the renal perfusion improves
Second rise is due to increase in aldosterone

65. “TWO KIDNEY” GOLDBLATT HYPERTENSION
If there are two kidneys and one is clamped
Then the ischaemic kidney releases the renin
This renin causes fluid and salt retention in both the normal and abnormal kidney
This leads to hypertension

66. RAS IN HEART FAILURE
In contrast to the sympathetic nervous system, the components of the RAS are activated comparatively later in HF
The presumptive mechanisms for RAS activation in HF include
1) Renal hypoperfusion
2)Decreased filtered sodium reaching the macula densa in the distal tubule
3)Increased sympathetic stimulation of the kidney, leading to increased renin release from the juxtaglomerular apparatus

68. J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20
Steven A. Atlas, MDJThe Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition
J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20

69. NATRIURETIC PEPTIDES & RENIN

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