CREDITS The Renin Angiotensin Aldosterone System

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CE Approaches to Cardiac and Renal Therapy, the sympathoadrenal system centrally and blast formation and collagen deposition 1 In. peripherally and by inhibition of vagal con response to decreased plasma volume Ang II. trol of the heart rate 5 Ang II also stimulates in conjunction with the sympathetic nervous. sodium resorption in the kidneys by acting on system promotes the release of vasopressin. the basolateral and luminal membranes of the from the posterior pituitary Vasopressin has. proximal tubule the medullary thick ascend weak vasoconstriction and inotropic effects. ing limb and the cortical collecting ducts on the heart and stimulates water resorption. Ang II has mitogenic properties stimulating through the aquaporin 2 water channels in. the release of cytokines and growth factors the renal collecting ducts 3 The final result is. The production of transforming growth factor systemic vasoconstriction and water retention. TGF platelet derived growth factor and One of the key effects of Ang II is the. nuclear factor leads to inflammation fibro regulation of aldosterone Ang II acts via AT1. Overview of the RAAS,QuickNotes,The RAAS affects,tissue throughout. E2 Compendium Continuing Education for Veterinarians January 2009 CompendiumVet com. Approaches to Cardiac and Renal Therapy CE,Box 1 little or no direct effect Dopamine has a. direct negative effect on aldosterone by inhib,Actions of Angiotensin II 1 3 5 7. iting adrenal response to exogenous Ang II,ANP is produced by atrial cardiac myocytes.
Angiotensin receptor 1 in response to left atrial enlargement and. Increases sodium resorption,tachycardia and it inhibits renin secretion and. Stimulates aldosterone release,blocks the action of Ang II on aldosterone. Stimulates vasopressin release,secretion 5,Promotes inflammation. Promotes fibrosis,Promotes myocyte hypertrophy Pathophysiology. Promotes vasoconstriction Cardiac Disease, Promotes glomerular capillary hypertension Heart failure is now recognized as a complex.
Inhibits vagal control syndrome that involves increased activity of. the adrenergic nervous system activation of, Angiotensin receptor II the RAAS overexpression of ANP and brain. Affects fetal organ development,natriuretic peptide BN P and increased. Promotes vasodilation,release of vasopressin endothelin 1 and. Inhibits proliferation,tumor necrosis factor 3 8 Reduced cardiac out. Inhibits inflammation,put and decreased blood pressure activate.
the adrenergic nervous system resulting in, receptors in the adrenal zona glomerulosa increased heart rate peripheral vasoconstric. to cause the release of aldosterone Sodium tion and increased myocardial contractility. depletion up regulates AT1 receptors for Ang These mechanisms increase blood flow to vital. II while excess sodium decreases the zona centers 3 8 However chronic activation of the. glomerulosa receptors 6 Ang II and aldoster adrenergic nervous system can lead to myo. one help regulate sodium and water balances cardial cell dysfunction and cell death periph. and maintain vascular pressure 3 eral vasoconstriction myocardial hypertrophy. In contrast to AT1 receptors AT2 recep and fibrosis tachycardia and arrhythmias. tors modulate organ development in the fetus Mechanoreceptors in the left ventricle. and possess vasodilatory and antiproliferative carotid sinus aortic arch and renal affer QuickNotes. effects on the vessel endothelium in select ent arterioles can sense arterial underfilling. organs The AT2 receptors appear to antago Decreased activation of these receptors due. Manipulation of the, nize the actions of the AT1 receptors 1 to reductions in systemic arterial pressure RAAS is the corner. stroke volume renal perfusion or peripheral stone of therapy for. Aldosterone vascular resistance leads to an increase in heart failure. Aldosterone has properties similar to those of sympathetic outflow from the central nervous. Ang II Box 2 It binds to receptors in the cor system activation of the RAAS and release. tical collecting duct of the nephron allowing of vasopressin 9 10 Renin release is stimulated. sodium and water resorption and potassium by 1 adrenergic stimulation decreased renal. secretion It also promotes sodium resorption perfusion and reduced sodium delivery to. in the salivary glands sweat glands and colon the renal tubules Renin release contributes. resulting in expansion of intravascular volume 5,Like Ang II aldosterone has mitogenic and Box 2. profibrotic properties directly increasing the,Actions of Aldosterone2 5 7. expression and production of TGF to cause,fibrosis and inflammation Both aldosterone.
romotes potassium homeostasis,and Ang II are involved in blood coagulation. Promotes platelet aggregation and activation, through increased platelet production plasmi Promotes vasoconstriction. nogen activator inhibitor type 1 PAI 1 activity Stimulates thirst. and aggregation and activation of platelets 2 7 Increases sodium resorption. Hypokalemia atrial natriuretic peptide Promotes fibrosis. ANP and dopamine all inhibit aldosterone Promotes vascular remodeling. release whereas plasma sodium levels have, CompendiumVet com January 2009 Compendium Continuing Education for Veterinarians E3. CE Approaches to Cardiac and Renal Therapy, to further sodium and water retention Renal Endothelin helps modulate vascular tone It. renin concentrations have been shown to be is produced by vascular endothelial cells in. elevated in cats with hypertrophic cardiomyo response to hypoxia stretch and the release. pathy 11 Ang II and aldosterone can directly of Ang II norepinephrine growth factors. affect the myocardium and vasculature lead cytokines and bradykinin It promotes vaso. ing to hypertrophy and fibrosis 3 8 constriction and increases myocardial con. In six major canine studies ACE inhibi tractility and aldosterone secretion eventually. tors e g enalapril benazepril were found to leading to hypertrophy of the vascular smooth. reduce morbidity and mortality in dogs with muscle and myocardium 3 In the setting of. dilated cardiomyopathy and mitral valve dis congestive heart failure the plasma norepi. ease 8 However there are concerns regarding nephrine concentration is inversely correlated. the effects of long term ACE inhibitor use on with survival 9. renal function It has been demonstrated that Levels of tumor necrosis factor are. dogs with severe compensatory mitral valve increased in congestive heart failure caus. disease receiving enalapril for 2 years had no ing left ventricular dilation and remodeling. statistical difference in serum urea nitrogen Cachexia in dogs with heart failure correlates. and creatinine levels from those in healthy with high levels of tumor necrosis factor. dogs suggesting that long term enalapril use Supplementation with fish oils has been eval. does not adversely affect renal function 12 ACE uated in dogs to help counteract the effects. inhibitors do reduce Ang II and aldosterone of this factor and other cytokines Dogs that. production but non ACE mediated pathways received this supplementation appeared to. can enable continued aldosterone production have improved cachexia scores compared. during long term ACE inhibitor therapy i e with those in a placebo group 8. aldosterone escape This can cause persistent, sodium retention potassium loss myocardial Renal Disease.
fibrosis and diuretic resistance The use of As with cardiac disease the RAAS has an inte. aldosterone antagonists e g spironolactone gral role in the progression of renal disease. QuickNotes in addition to ACE inhibitors may further Chronic renal disease in dogs and cats begins. reduce morbidity and mortality 8 with nephron injury that results in hyperfil. ACE inhibitors are, Vasopressin is activated through stimula tration glomerular capillary hypertension. not contraindicated tion of the sympathetic nervous system Ang glomerulosclerosis and interstitial fibrosis 7 13. in azotemic patients II release and reduced plasma volume sensed Activation of the RAAS helps protect renal. by stretch receptors in the atria and large function in the early stages but prolonged. veins Vasopressin activation leads to vaso renal ischemia and direct insult from Ang II. constriction and water retention via the renal and aldosterone eventually exacerbate renal. collecting ducts 3 8 Elevated vasopressin levels injury through several mechanisms 1 Ang II. have been detected in patients with congestive increases the production of TGF a fibro. heart failure Arterial underfilling and activa genic cytokine that stimulates the production. tion of carotid baroreceptors may be the cause of extracellular matrix contraction of smooth. of this paradoxical vasopressin release Use of muscle and proli feration of glomer ular. the vasopressin receptor blocker conivaptan mesangial cells the major cells involved in. to offset this effect is being studied in people the development of glomerulosclerosis Ang II. and dogs 8 also increases the production of PAI 1 thereby. Natriuretic peptides have a role in counterbal deactivating renal proteases and allowing fur. ancing the effects of the RAAS and the sympa ther accumulation of the extracellular matrix 13. thetic nervous system ANP release is triggered Ang II activates inflammatory cells by direct. by atrial distention causing arteriole dilation chemotaxis and the release of proinflamma. increasing renal excretion of sodium and water tory mediators and mononuclear cells to the. exerting an antihypertrophic effect on myo interstitium and glomeruli Increased glom. cytes and degrading Ang II bradykinin and erular capillary pressure extracellular matrix. endothelin 8 BNP which is primarily released accumulation and aldosterone stimulation all. from the left ventricle in response to increased contribute to glomerulosclerosis and intersti. filling pressures exerts similar effects 8 tial fibrosis 13. E4 Compendium Continuing Education for Veterinarians January 2009 CompendiumVet com. Approaches to Cardiac and Renal Therapy CE, Ang II promotes renal efferent arteriolar table 1 Drugs for Direct Manipulation of the. vasoconstriction in an effort to increase the,glomerular filtration rate However this vaso. Renin Angiotensin Aldosterone System1 2 18 20 24, constriction also leads to glomerular capil Class Generic Names a Mechanism of Action. lary hypertension an increase in glomerular, Renin inhibitors Aliskiren Interfere with the first rate.
permeability and excessive protein filtration limiting step in the synthesis. Proteinuria may also be worsened through of Ang I from angiotensinogen. R A AS disr uption of nephrin expression, Nephrin is a transmembrane protein located ACE inhibitors Benazeprilb Inhibit the conversion of Ang I. in the slit diaphragm of the glomerular pod into Ang II. ocyte that limits protein loss by maintaining, slit diaphragm integrity Protein in the urine is Enalaprilb c. also toxic to the tubules resulting in additional Imidapril. tubulointerstitial inflammation and scarring 7 Lisinopril. Manipulation of the RAAS is becoming the, mainstay of therapy for some forms of renal Ramipril. disease The American College of Veterinary, Internal Medicine ACVIM published a con Angiotensin receptor Candesartan Block the binding of Ang II to. antagonists AT1 receptors, sensus statement in 2004 regarding the man Irbesartan.
agement of canine and feline proteinuria Losartan,which is both a marker of glomerular damage. and a cause of progression in renal failure 14 In Valsartan. dogs with marked proteinuria ACE inhibitors,Aldosterone Spironolactoneb Block the binding of. may have renoprotective effects and reduce aldosterone to principal cells. antagonists, the magnitude of proteinuria14 15 because they of the renal collecting ducts. decrease efferent glomerular arteriolar resis a,Not all available drugs are listed. tance They also decrease the formation of Ang b, These drugs are routinely used in veterinary medicine.
II and aldosterone potentiate the vasodilatory cThis drug is available in a veterinary approved form. effects of bradykinin and lower glomerular,transcapillary hydrostatic pressure Treatment. with enalapril may counteract proteinuria and Researchers have found that human patients. delay the onset or progression of azotemia in whose serum creatinine levels increase but sta. dogs with idiopathic glomerulonephritis 14 15 bilize within 2 months have the greatest long. The ACVIM consensus statement recommends term delay in progression of renal failure 1 18. that patients with persistent renal proteinuria A study of dogs with experimentally induced. be treated with an ACE inhibitor an appro renal failure evaluated the pharmacokinetics. priate high quality protein diet and omega 3 of enalapril and benazepril The metabolites. fatty acid supplementation 14 of benazepril were eliminated in both bile and. ACE inhibitors have been evaluated in dogs urine whereas the metabolites of enalapril. and cats with renal failure 13 16 17 One study in were eliminated in urine Thus dogs with. cats with experimentally induced renal failure renal disease can clear benazepril from the. found that those treated with benazepril had system but those treated with enalapril may. either no change or an increase in whole kid need lower doses 19 The optimal dose of ACE. ney glomerular filtration rate compared with inhibitors in patients with renal disease is still. The Renin Angiotensin Aldosterone System Approaches to Cardiac and Renal Therapy T he renin angiotensin aldosterone system RAAS plays a significant role in preserving hemodynamic stability in response to the loss of blood volume salt and water 1 2 It is primarily associated with the kidneys but its activity also affects the brain heart blood vessels and adrenal glands 3 These

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