Renin-angiotensin system

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Angiotensin, Hypertension

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CLINICAL IMPLICATION OF RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM AND ROLE OF ACE INHIBITORS Sonu M.Pharma ( P’cology ) RBIP, Mohali campus, Punjab

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The renin-angiotensin aldosterone system (RAAS) A hormonal cascade that functions in the homeostatic control of arterial pressure , tissue perfusion, and extracellular volume primarily via the vasoconstrictor properties of angiotensin II and the sodium-retaining properties of aldosterone . Dysregulation of the RAAS plays an important role in the pathogenesis of cardiovascular and renal disorders .

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Liver Angiotensinogen Angiotensin I Angiotensin II Aldosterone Increased Blood Volume Increase BP Kidney Renin ACE Renin-Angiotensin-aldosterone System Increased TPR Increased CO Salt & Water Retension Increased TPR

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Juxtaglomerular apparatus found between the vascular pole of the renal corpuscle and the returning DCT of the same nephron.

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regulates the function of each nephron by regulating renal blood flow and glomerular filtration rate. The three cellular components of the JG apparatus are juxtaglomerular cells macula densa extra-glomerular mesangial cells Juxtaglomerular cells are modified pericytes (also known as granular cells) of glomerular afferent arterioles .

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This cells secrete Renin , an aspartyl protease, synthesized as prorenin, in response to : Beta1 adrenergic stimulation Decrease in renal perfusion pressure or stretch within the renal afferent arteriole, detected directly by the granular cells ( baroreceptor mechanism ) Decrease in NaCl absorption in the Macula Densa Conversely, renin secretion is inhibited by increased NaCl transport in the thick ascending limb of the loop of Henle, by increased stretch within the renal afferent arteriole, and by beta 1 receptor blockade.

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In addition, angiotensin II directly inhibits renin secretion due to angiotensin II type 1 receptors on juxtaglomerular cells, and renin secretion increases in response to pharmacologic blockade of either ACE or angiotensin II receptors. Macula densa cells columnar epithelium thickening of the distal tubule; senses NaCl concentration in the distal tubule of the kidney and Lacis cells (extraglomerular Mesangial cells) stimulated by renal sympathetic nerves, and modulate the actions of the JG apparatus.

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Angiotensin-converting enzyme Angiotensin II is converted by enzyme angiotensin-converting enzyme (ACE, or kininase), primarily through ACE within the kidney. ACE found in other tissues of the body have no physiological role (ACE has a high density in the lung, but activation here promotes no vasoconstriction, Ang II is below physiological levels of action). Angiotensin III Angiotensin II is degraded to angiotensin III by angiotensinases that are located in red blood cells and the vascular beds of most tissues. Angiotensin III has 40% of the pressor activity of Angiotensin II, but 100% of the aldosterone-producing activity .

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Renin-angiotensin-aldosterone axis Bradykinin counteracts the negative action of AT II Improves endothelial function by increasing expression and activity of the constitutive Nitric Oxide synthase It has also anti-proliferative effect and stimulate synthesis of tissue plasminogen activator Thereby prevents endothelial dysfunction

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Angiotensin Receptors: 2 (two ) subtypes: AT 1 and AT 2 – most of known Physiologic effects are via AT 1 Both are GPCR Actions of angiotensin-II – CVS Powerful vasoconstrictor particularly arteriolar and venular Direct action - release of Adr /NA (adrenal medulla and adrenergic nerve endings) and increase Central sympathetic outflow More potent vasopressor agent than NA –promotes Na+ and water reabsorption and no tachyphylaxis Overall Effect – Pressor effect (Rise in Blood pressure )

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Heart : Increases myocardial force of contraction (CA++ influx promotion) Increases heart rate by sympathetic activity, but reflex bradycardia occurs Increases Cardiac work (by increased Peripheral resistance ) Adrenal cortex : Enhances the synthesis and release of Aldosterone - In distal tubule Na+ reabsorption and K+ excretion Kidney : Enhancement of Na+/H+ exchange in proximal tubule – increased Na+, Cl - and HCO3 reabsorption Also reduces renal blood flow and promotes Na+ and water retention CNS : Drinking behaviour and ADH release Peripheral sympathetic action : Stimulates adrenal medulla to secrete Adr and also releases NA from autonomic ganglia

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Nature Reviews Drug Discovery 1 ; 621-636 (2002); doi:10.1038/nrd873

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Chronic effects of Angiotensin-II: i ll effects on chronic basis of exposure (Mitogenic effect!) Directly : Induces hypertrophy, hyperplasia and increased cellular matrix of myocardium and vascular smooth muscles – by direct cellular effects involving mas proto-oncogenes and transcription of growth factors Indirectly : Volume overload, increased TPVR and long standing hypertension in heart causes Ventricular Hypertrophy and Remodelling (abnormal redistribution of muscle mass) Independent of its hemodynamic effects, angiotensin II may play a role in the pathogenesis of atherosclerosis through a direct cellular action on the vessel wall. Following MI – fibrosis and dilatation in infarcted area and hypertrophy of non-infarcted area of ventricles ( Ventricular Remodelling ) P rogressive fibrotic changes and myocyte death leads to CHF Overall risk of CVS related morbidity and mortality increased ACE inhibitors reverse cardiac and vascular hypertrophy and remodelling

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Angiotensin-II Pharmacological importance: Drugs Increasing Renin release: ACE inhibitors and AT1 antagonists enhance Renin release Vasodilators and diuretics stimulate Renin release Loop diuretics increase renin release Decrease in Renin release: Beta blockers and central sympatholytics NSAIDs and selective COX-2 inhibitors decrease Renin release

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Tissue RAAS and Alternative Pathways of Angiotensin Biosynthesis The prevailing concept is that the RAAS functions both as a circulating system and as a tissue paracrine/autocrine system . There is evidence that local or “tissue” Ang II biosynthesis may be initiated by renin and/or angiotensinogen taken up from the circulation. In addition, independent Ang II generating systems have been postulated to exist in the heart , peripheral blood vessels, kidney, brain, adrenal glands, pituitary , adipose tissue, testes, ovaries, and skin. Serine proteases , including several kallikrein -like enzymes ( tonins ), cathepsin G, and chymase are thought to contribute to Ang II formation in the tissue RAAS.

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angiotensin II type 2 (AT 2 ) receptor widely distributed in the kidney and has the opposite functional effects of the AT 1 receptor. The AT 2 receptor induces vasodilation, sodium excretion, and inhibition of cell growth and matrix formation. Experimental evidence suggests that the AT 2 receptor improves vascular remodelling by stimulating smooth muscle cell apoptosis and contributes to the regulation of glomerular filtration rate. AT 1 receptor blockade induces an increase in AT 2 receptor activity.

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Renin-secreting tumors A clear examples of renin-dependent hypertension. In the kidney, these tumors include benign hemangiopericytomas of the juxtaglomerular apparatus and, infrequently renal carcinomas, including Wilms' tumors. Renin-producing carcinomas also have been described in lung, liver, pancreas, colon, and adrenals. In these instances, in addition to excision and/or ablation of the tumor, treatment of hypertension includes pharmacologic therapies targeted to inhibit angiotensin II production or action. Reno-vascular hypertension another renin-mediated form of hypertension. Obstruction of the renal artery leads to decreased renal perfusion pressure, thereby stimulating renin secretion. Over time, as a consequence of secondary renal damage, this form of hypertension may become less renin dependent .

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Increased activity of the renin-angiotensin-aldosterone axis is not invariably associated with hypertension. ------------------------------------------------------------------------------- In response to a low- NaCl diet or to volume contraction, arterial pressure and volume homeostasis may be maintained by increased activity of the renin-angiotensin-aldosterone axis. Secondary aldosteronism (i.e., increased aldosterone secondary to increased renin-angiotensin), but not hypertension, also is observed in edematous states such as CHF and liver disease.

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Inhibitors of RAS: Sympathetic blockade ACE inhibitors AT 1 receptor antagonists Aldosterone antagonists Renin inhibitory peptides and Renin specific antibodies

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A ldosterone Secretion: Angiotensin II is the primary tropic factor regulating the synthesis and secretion of aldosterone by the zona glomerulosa of the adrenal cortex. Aldosterone synthesis is also dependent on potassium, and aldosterone secretion may be decreased in potassium-depleted individuals. Although acute elevations of adrenocorticotropic hormone (ACTH) levels also increase aldosterone secretion, ACTH is not an important tropic factor for the chronic regulation of aldosterone.

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Effects: Aldosterone is a potent mineralocorticoid that increases sodium reabsorption by amiloride-sensitive epithelial sodium channels (ENaC) on the apical surface of the principal cells of the renal cortical collecting duct. Aldosterone synthesis is stimulated by several factors : increase in the plasma concentration of Angiotensin II and Angiotensin III; plasma acidosis; plasma ACTH; or potassium levels( most sensitive); sympathetic overactivity ; etc. The secretion of aldosterone has a diurnal rhythm . Consequently, increased aldosterone secretion may result in hypokalemia and alkalosis. Because potassium depletion may inhibit aldosterone synthesis, clinically, hypokalemia should be corrected before a patient is evaluated for hyperaldosteronism.

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Primary hyper-aldosteronism is a compelling example of mineralocorticoid-mediated hypertension. In this disorder, adrenal aldosterone synthesis and release are independent of renin-angiotensin, and renin release is suppressed by the resulting volume expansion. Aldosterone and/or mineralocorticoid receptor activation induces structural and functional alterations in the heart, kidney, and blood vessels, leading to myocardial fibrosis, nephrosclerosis, and vascular inflammation and remodeling, perhaps as a consequence of oxidative stress. These effects are amplified by a high salt intake. In animal models, high circulating aldosterone levels stimulate cardiac fibrosis and left ventricular hypertrophy, and spironolactone (an aldosterone antagonist) prevents aldosterone-induced myocardial fibrosis .

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Pathologic patterns of left ventricular geometry also have been associated with elevations of plasma aldosterone concentration in patients with essential hypertension as well as in patients with primary aldosteronism. In patients with CHF, low-dose spironolactone reduces the risk of progressive heart failure and sudden death from cardiac causes by 30%. Owing to a renal hemodynamic effect, in patients with primary aldosteronism, high circulating levels of aldosterone also may cause glomerular hyperfiltration and albuminuria. These renal effects are reversible after removal of the effects of excess aldosterone by adrenalectomy or spironolactone.

Hypertensive Disorders Involving Dysregulation of the Renin-Angiotensin Aldosterone System :

Hypertensive Disorders Involving Dysregulation of the Renin-Angiotensin Aldosterone System

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Hypertensive Disorders RAAS Dysregulation Clinical Manifestations Renin-secreting neoplasms Primary hypersecretion of renin by renal hemangiopericytomas (“JG cell tumors ”), some Wilms ’ tumors and renal and extrarenal carcinomas (ovary, pancreas, lung) Secondary aldosteronism Severe renin-dependent hypertension (accelerating hypertension common) Hypokalemia ; sodium retention limited by pressure natriuresis Renovascular hypertension Atheromatous (main) Fibromuscular (main or branch) Renal emboli/segmental infarcts Renal artery aneurysms Renal artery dissection/injury Subcapsular hematoma Hypersecretion of renin due to segmental, unilateral, or bilateral renal ischemia Secondary aldosteronism Hypertension (usually renin-dependent, accelerating hypertension common); progressive renal dysfunction possible Sodium retention (depending on extent of renal compromise); hypokalemia may be masked by decreased distal delivery of sodium

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Hypertensive Disorders RAAS Dysregulation Clinical Manifestations Malignant hypertension and other renal small vessel disease (e.g., polyarteritis , scleroderma, hemolytic uremic syndrome, lupus) Hypersecretion of renin due to generalized renal ischemia Secondary aldosteronism Severe renin-dependent hypertension Renal dysfunction Microangiopathic hemolytic anemia Hypertensive encephalopathy Sodium retention and hypokalemia variable (as above) Pheochromocytoma and other catecholamine-secreting tumors Hypersecretion of renin due to catecholamine excess Renal ischemia due to extrinsic renal compression and/or neurofibromatosis involving the renal artery (occasionally) Secondary aldosteronism Sustained or paroxysmal hypertension (accelerating hypertension common) Other typical manifestations of catecholamine excess Hypokalemia ; sodium retention often limited by pressure Natriuresis

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Hypertensive Disorders RAAS Dysregulation Clinical Manifestations Essential hypertension HR (~15%)—PRA mildly elevated, cause uncertain (sympathetic drive?, hypovolemia ?) NR (~60%)—PRA within “normal” range, but may be inappropriate in setting of hypertension LR (~25%)—PRA low due to several possible mechanisms (sodium/volume excess?, nephrosclerosis?, appropriate response?) Hypertension usually responds well to RAAS blockade Increased susceptibility to heart attack or stroke? Hypertension often responds to RAAS blockade Hypertension responds best to diuretics, calcium channel- or alpha1-blockers Tissue RAAS may not be similarly suppressed (e.g., kidney) Primary aldosteronism and other MC excess Primary hypersecretion of aldosterone or other MC hormone by adrenal neoplasms; or very rare genetic syndromes resulting in MC hormone dysregulation Secondary suppression of renin and Ang II Hypertension (may be severe at times) Hypokalemia and hypomagnesemia Sodium and volume expansion, without edema (limited by “mineralocorticoid escape”) Reversible atrophy of contralateral adrenal cortex (due to suppressed Ang II)

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Role of ACE INHIBITORS over RAAS

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Angiotensinogen Angiotensin I Angiotensin II Vasoconstriction Increased peripheral vascular resistance Increased blood pressure Aldosterone secretion Increased sodium and water retention Kininogen Bradykinin Inactive Increased prostaglandin synthesis Vasodilation Decreased peripheral vascular resistance Decreased blood pressure Renin Kalikrein Converting Enzyme 2 2 1 1 X

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ACEIs competitively block the action of ACE and thus the conversion of AT I to AT II, thereby reducing circulating and local levels of AT II. ACEIs also decrease aldosterone and vasopressin secretion and sympathetic nerve activity. Short-term ACEI therapy is associated with a decrease in AT II and aldosterone and an increase in renin release and AT I . However , long term ACE inhibition may associated with a return of AT II and aldosterone toward baseline levels (“ ACE escape ”)—perhaps, through proposed activation of the so-called alternate pathways.

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On the other hand, because ACEIs are all competitive inhibitors of the enzyme, it is possible that increased levels of AT I (provoked by the compensatory increase in PRA due to loss of negative feedback inhibition) can tend to partially overcome the blockade. This would be especially likely in high-renin or volume-depleted patients with a particularly robust reactive rise in PRA.

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In general, short-term, pharmacodynamic responses to decreases in AT II through inhibition of ACE include dose dependent reductions in cardiac preload and afterload, with lowering of systolic and diastolic blood pressure, but, in normotensive and hypertensive patients without cardiac dysfunction, little or no change in cardiac output or capillary wedge pressure. Unlike direct-acting arterial vasodilators, ACEI-induced reductions in total peripheral vascular resistance occur without a significant change in heart rate. ACEIs also decrease renal vascular resistance, increase renal blood flow , and promote sodium and water excretion.

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Mainly through cellular effects in the kidney and through alterations in glomerular hemodynamics , ACEIs also may prevent the progression of microalbuminuria to proteinuria, reduce proteinuria in patients with established glomerular disease, and prevent or delay the progression of renal insufficiency to end-stage renal disease .

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Because ACE is identical to kininase II, ACEIs may also lead to elevation of bradykinin levels in some tissues (but unlikely in the circulation); this effect is potentially associated with increased bradykinin -dependent release of NO and vasoactive prostaglandins, including prostacyclin and prostaglandin E2. These actions may potentially contribute to the vasodilatory , antithrombotic, antiatherogenic , and antiproliferative effects of ACEI, although the importance of this pathway is debated.

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In 40% to 60% of patients with mild-to-moderate hypertension, ACEI monotherapy produces a satisfactory reduction in blood pressure. In this population, ACEIs contribute to reversal of cardiac hypertrophy and remodelling , and do so with significantly greater efficacy than beta blockers . In patients with CHF, ACEIs relieve pulmonary congestion by a balanced reduction in cardiac preload and afterload .

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ACEIs have also been shown to improve endothelial dysfunction in patients with heart failure, as well as in patients with CAD and type 2 DM. In early landmark trials in patients with CHF (such as CONSENSUS and SOLVD), ACEIs were shown not only to markedly improve symptoms and functional status, but also to dramatically reduce mortality . In subsequent studies in patients who have suffered a myocardial infarction (MI), such as SAVE, AIRE, and TRACE, ACEI therapy has been shown to prevent or retard ventricular remodeling and progression to CHF, and thereby to reduce overall mortality and prolong survival.

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Furthermore , results of the HOPE trial and other smaller studies indicate – broad cardiovascular benefits of ACEI therapy in “high-risk” patients (including both hypertensive and normotensive individuals ), and these benefits are independent of their blood pressure-lowering effect.

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Several large-scale studies of various ACEIs have shown a reduction in incidence of new-onset diabetes in association with ACEI therapy. For example, this has been shown with captopril in patients with hypertension (CAPP), with ramipril in patients at high risk for cardiovascular disease (HOPE), with enalapril in patients with left ventricular dysfunction (SOLVD), and with trandolapril in patients with stable coronary disease (PEACE). The mechanism of this benefit has not been determined.

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Side effects :- ACEI therapy is generally well tolerated by most patients. Most frequent side effect is dry cough , which has been attributed to accumulation of substance P (which is normally degraded by kininase II). More serious side effects include angioedema (which is potentiated by decreased catabolism of kinins) and fetal abnormalities and mortality. Other “ physiologic ” consequences of ACE inhibition may include hypotension, deterioration of renal function, and hyperkalemia. Lastly , toxic effects, associated mainly with captopril , include abnormal (metallic or salty) taste, rash, neutropenia, hepatic toxicity, and proteinuria (membranous nephropathy).

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