Advanced Pathophysiology Unit 7: Renal-Urologic Page 1 of 18

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1 Advanced Pathophysiology Unit 7: Renal-Urologic Page 1 of 18 Learning Objectives for this File: 1. Learn how the macula densa monitors physiologic state and its connection with renin production based on this monitoring in order to maintain GFR 2. Review the microscopic anatomy of the macula densa, glomerulus, afferent & efferent arterioles; location of JGA cells 3. Review what stimulates RAS activation 4. Review overall effects on the body of RAS activation 5. Review specific effects of Ang-II on the body (see also material from Unit 5) 6. Recognize how ADH & Aldosterone affect renal tubular function to result in salt and water retention (volume loading) 7. Learn about renal blood flow auto-regulation via different hormonal mechanisms 8. Learn about different hormonal affects on the body that cause either volume loading (salt and/or water retention) or diuresis. Where are the hormones made? How do they affect the kidney? Where in the nephron? 9. Review other hormones made by the kidney (EPO, PTH) 10. Understand the effects on the kidney of NSAID, ACEI, ARB drugs; high-protein diets; hyperglycemia; heavy metals.

2 Advanced Pathophysiology Unit 7: Renal-Urologic Page 2 of 18 RENAL PERFUSION & RENIN RELEASE & RAS ACTIVITY (SYSTEMIC BP CONTROL): The kidney controls BOTH systemic BP & its own internal blood flow (autoregulation). Juxtaglomerular complex (apparatus) cells (JGA cells): o juxta means next to o JGA cells are secretory renal endocrine cells cells in the walls of the afferent & efferent arterioles that abut (are right up next to) the macula densa in the ascending loop of Henle where it runs between the afferent & efferent arteriole of its own nephron as it climbs back up into the cortex from the medulla o JGA cells synthesize and store renin and release it based on input from the monitoring cells of the macula densa (monitoring cells) Macula densa monitoring: o Macula densa cells monitor the filtrate in the ascending loop of Henle for NaCl concentration (the macula densa is located in a plaque in the thick, ascending loop of Henle as it climbs out of the medulla back into the cortex right in between the afferent & efferent arterioles of its own nephron o Poor renal perfusion causes slow flow through the whole tubular system, increases time spent in the loop of Henle, and increases NaCl reabsorption lowering NaCl concentration in the filtrate this is an indirect measure of low renal perfusion o Low NaCl concentration in the filtrate causes the macula densa to stimulate the JGA cells to release renin & start the RAS volume loading, vasoconstriction and increased BP There is also a direct monitoring of incoming renal BP: o there are baroreceptors of the actual incoming pressure in the afferent arteriole (not the main stimulus to renin production) Actions of the macula densa: if low NaCl in filtrate, macula densa cells save the GFR o cause an decrease in the afferent sphincter arteriolar tone (allowing greater blood flow into the glomerulus more vasodilated) o they send signals to the JGA cells found in the walls of the afferent and efferent arterioles of the same nephron to release the enzyme renin to activate the RAS

3 Advanced Pathophysiology Unit 7: Renal-Urologic Page 3 of 18 OVERALL Results of activation of RAS activation increased CO & BP: increased NaCl reabsorption (salt loading) increased water reabsorption (overall volume loading) increased K secretion (excretion) & H+ secretion (excretion) peripheral vasoconstriction Autoregulation of renal vessels Efferent Arteriole Macula Densa Cells in Ascending thick Limb Loop of Henle Afferent Arteriole JGA cells in wall of afferent arteriole (make renin) Glomerulus where filtration occurs Filtrate leaves here into Bowman s Capsule and the proximal tubule

4 Advanced Pathophysiology Unit 7: Renal-Urologic Page 4 of 18 RENIN-ANGIOTENSIN-SYSTEM (RAS) is also called by some people RENIN- ANGIOTENSIN-ALDOSTERONE-ADH-KININ SYSTEM (RAAAKS): Long term & very powerful control Efferent Arteriole An endocrine system controlled by the kidney that affects the cardiovascular system Also involves activation of the fibrinolytic system Thus, the kidney talks to the heart RENIN-ANGIOTENSIN SYSTEM (RAS): overall volume & salt loading (increases blood volume) & peripheral vascular resistance (vasoconstriction) BP elevation & CO. What stimulates the enzyme renin release from the JGA cells: 1) the vascular receptor in the afferent renal arteriole (respond to hypovolemia & sympathetic activity) direct method of monitoring renal perfusion 2) the macula densa cells of the thick limb of the ascending loop of Henle, located in between the afferent and efferent arteriole of that nephron s glomerulus (respond to low NaCl concentration) 3) stimulation from endogenous substances (electrolytes, A-II, female hormones, adrenal steroids, ADH, PGs, calcium via T-channels) to also cause renin release 4) sympathetic nervous system activity, with release of catecholamines and stimulation of the beta-1 renal receptor to release renin enzyme. Endocrine results of renin release: 1) formation of the hormone angiotensin-i from an inactive zymogen called angiotensinogen 2) this is converted to angiotensin-ii (A-II) by angiotensin coverting enzyme (ACE) mostly in the lung 3) A-II causes release of other hormones antidiuretic hormone (ADH) & aldosterone as well as having its own direct effects on the body. Effects of hormones: increased blood volume & BP. 1) Aldosterone: sodium & water retention, potassium & H+ excretion (via secretion). 2) ADH: free water retention (increased reabsorption). 3) Angiotensin-II (A-II): peripheral vasoconstriction, increased afterload, increased preload, positive inotropy, positive chronotropy, changes in renal blood flow that enhance filtration, trophic cardiac effects (remodeling of the left ventricle, or cardiomegaly) and fibroblast mitotic effects (stimulation of vascular endothelium to accelerate atheroma formation). Value of the system: Overall, a system to maintain our BP & CO, to protect the kidney & vital organs in case of hemorrhage, dehydration. Problems with the system: chronic increases in this systems activity lead to ventricular remodeling (cardiomegaly), atherosclerotic heart disease, and hypertension. Feedback Inhibition in the RAS to maintain homeostasis: renin release is inhibited by its own effects won t be released with increased perfusional glomerular pressure (afferent arteriole), high A-II levels or increased NaCl concentration at the macula densa

5 Advanced Pathophysiology Unit 7: Renal-Urologic Page 5 of 18 RAS (RAAAKS) (Renin Angiotensin Aldosterone ADH Kinin Pathway): long term & very powerful control. Really a part of the endocrine system. Also involves the fibrinolytic system. RENIN-ANGIOTENSIN ENZYMES ACE'S OTHER JOB Angiotensinogen Inflammatory Bradykinins (made in liver, inactive) & inflammatory cytokines are ALSO VASODILATING KININS tpa or Renin Enzyme Angiotensin-I ACE and non-ace enzymes in tissues (e.g. Chymase) Angiotensin-II AT1 Receptor (Bad Guy) vasoconstriction, endothelial mitotic effects (atherosclerosis), cardiac remodeling (LVH), reno-vascular effects, release of ADH & aldosterone (salt & water loading, increase blood volume) Kinins are degraded and inactive (reduced vasodilatation, increased vasoconstriction); ACEI drugs may improve vasodilatation by preventing degradation, but may also cause cough & angioedema AT2 Receptor (Good Guy) vasodilatation (opposite effects from AT1 receptor)

6 Advanced Pathophysiology Unit 7: Renal-Urologic Page 6 of 18 A prettier picture and more COMPLETE: The Renin-Angiotensin-Aldosterone System Cascade Tissue: Heart, Brain, Kidney, Arteries Angiotensinogen Systemic: Liver ACE-Independent Pathway renin ACE-Dependent Pathway TPA Cathepsin G Tonin Chymase CAGE Angiotensin I Angiotensin II ACE Bradykinin Substance P Enkephalins Other Peptides A n g i o t e n s i n R e c e p t o r s Inactive Fragments AT 1 AT 2 TPA=tissue plasminogen activator; CAGE=chymostatin-sensitive angiotensin II-generating enzyme. Adapted from Schmieder RE. Am J Hypertens. 2005;18: Destruction of Ang-II: destroyed by circulating enzymes called angiotensinases

7 Advanced Pathophysiology Unit 7: Renal-Urologic Page 7 of 18 ANGIOTENSIN-II hormone (Ang-II): our most powerful endogenous vasoconstrictor increases preload and afterload via return of blood to circulation from venous capacitance vessels, as well as increasing peripheral resistance increases blood volume via hormonal effects on the kidney (ADH increases free water reabsorption, Aldosterone increases Na and water reabsorption) direct effects on the heart direct effects on the blood vessel cells Formation: Angiotensinogen (alpha-2-globulin) is a glycoprotein made by the liver and is an inactive zymogen in the blood. Renin enzyme cleaves this to form: angiotensin-i (A-I). A-I circulates through the body, and is further lysed by angiotensin converting enzyme (ACE), mostly in the lung, forming angiotensin-ii (A-II), an octapeptide. A-II exerts its activity via effects on its receptors AT-1 and AT-2 Other effects of ACE the Kinin & thrombolytic systems: Degrades inflammatory and vasodilating mediators called bradykinins. Since the vasodilators are degraded by ACE, its activity contributes to MORE vasoconstriction (by getting rid of natural vasodilators). High levels of ACE and circulating A-II interact with the fibrinolytic system o increasing tissue levels of PAI-1 (plasminogen activator inhibitor type 1) o causing a pro-thrombotic (procoagulative) state. Thus this system may activate clot-forming mechanisms o contributing to cardiovascular disease from another mechanism other than purely increased blood pressure and volume loading or mitotic effects on the heart. Ang II and Cardiovascular Risk Atherosclerosis MI and Stroke Ventricular Remodeling Ventricular Dilatation Heart Failure Endothelial Dysfunction Oxidative Stress Ang II End Stage CVD Hypertension Vascular Damage Adapted from Dzau V. J Hypertens Suppl. 2005;23:S9 S17.

8 Advanced Pathophysiology Unit 7: Renal-Urologic Page 8 of 18 How does Angiotensin-II work? Receptors! It is really a type of stressor hormone Overall AT1 activation causes vasopressor & blood volume increase and other changes that lead to CARDIOVASCULAR DISEASE Ang-II effects from the AT-1 receptor effects: Peripheral vasoconstriction & vasopressor response: o smooth-muscle arteriolar contraction in peripheral blood vessels (systemic vascular tone). Hyperglycemia: o hepatic gluconeogenesis & glycogenolysis. Volume loading: o through the thirst response and renal effects on GFR. Maintains GFR = multiple mechanisms: o vasoconstricts the efferent arteriole, increasing glomerular hydrostatic pressure that maintains GFR. ADH release: o from hypothalamus/posterior pituitary. o Results in retention of free water Aldosterone release: o from adrenal cortex. o Results in sodium and water retention, excretion of acid and potassium Catecholamine release: o system-wide vasopressor. Cardiac myocyte trophic effects: o left ventricular remodeling, LVH as well as positive chronotropy & inotropy. Blood vessel proliferative (trophic) effects: o proliferative changes and possible promotion of atherogenesis. o These effects are sometimes called mitotic effects of the vascular endothelium = proliferation of endothelial fibroblasts fostering atheroma development. o Thus, blockade of this system is beneficial in managing HF due to LVH and may slow atherosclerosis progression. Fibrinolytic-blood clotting system: o High levels of ACE and circulating A-II interact with the fibrinolytic system, increasing tissue levels of PAI-1 (plasminogen activator inhibitor type 1) causing a prothrombotic (procoagulative) state. o Thus this system may activate clot-forming mechanisms, contributing to cardiovascular disease from another mechanism other than purely increased blood pressure and volume loading or mitotic effects on the heart. Not just the "bad guy" AT1 receptor effects also produce renal vasodilators: o prostaglandins (epoprostenol) and Nitric Oxide (NO) are produced with AT1 activation so there is a balance of vasoconstriction and vasodilatation o Drug blockade such as ACE inhibition (ACEI drugs) or AT1-receptor blockade (ARB drugs) blocks these effects & may cause acute renal failure in persons with renal hypoperfusion (renal artery stenosis, solitary kidney) or hypovolemia, reduced renal blood flow due to renal loss of autoregulation ability (see more below)

9 Advanced Pathophysiology Unit 7: Renal-Urologic Page 9 of 18 Ang-II effects from the AT2 receptor: the AT2 receptor is like a cardiovascular "good guy" & helps maintain vasodilatation & opposes many effects of the AT1 receptor. Improved renal perfusion at the glomerulus (vasodilates the large preglomerular vessels improving glomerular perfusion Antiproliferative effect on blood vessel tissues (less atherogenesis) Stimulates apoptosis (dropping off of old cells, allowing for regression of pathological proliferation in blood vessels) Ang-II in health & disease: Normal circumstances: o Normally, A-II effects are physiologic and mostly on the afferent arteriole o causing reduced GFR (less diuresis volume loading). During low perfusion states: o during reduced perfusion (from renal artery hypotension), the main effect is on efferent arteriole o maintaining glomerular hydrostatic pressure to maintain (increase) GFR. o Thus, this is another reason that drug blockade of this system may cause acute renal failure in persons with renal hypoperfusion (renal artery stenosis, solitary kidney, dehydration, sepsis, hypovolemia). o Can t use these drugs in renal patients without careful monitoring HORMONAL EFFECTS OF ANG-II: When the RAS is activated, it promotes volume retention, loss of potassium, gain of sodium If the RAS is blocked (due to drugs), it promotes diuresis, hyperkalemia, hyponatremia Aldosterone is released due to Ang-II: Overall effects: volume increase, loss of K, gain of Na. o Fluid retention o Hypokalemia, hypernatremia A sterol hormone synthesized & released by the adrenal cortex in response to A-II, potassium, & ACTH (corticotropin). Activity: o on the kidney to promote Na retention, K excretion, and water retention. Antidiuretic Hormone (ADH) is released due to Ang-II: A peptide hormone synthesized by the hypothalamus, stored & released from the posterior pituitary. Overall effects: o increases overall body water (volume). Activity: o increases permeability of distal nephron o enhances "free" water reabsorption back into the body o also activates CNS thirst response.

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11 Advanced Pathophysiology Unit 7: Renal-Urologic Page 11 of 18 AUTOREGULATION OF RENAL BLOOD FLOW: Even with large variations in systemic BP ( systolic) feedback mechanisms maintain glomerular filtration rate (GFR) & renal blood flow so that homeostasis is maintained. Sensory macula densa cells in the kidney monitor the situation and autoregulate renal blood flow RAS activation: o cause renin release to increase activity of the renin-angiotensin-aldosterone-adhkinin system (RAS) (JGA cells) synthesis of Ang-II and effects on AT1 and AT2 receptors on renal blood vessels Autacoid production: o Autacoids locally released and locally acting vasoactive substances ("local hormones") that affect renal blood flow & GFR 1) Endothelin is locally released by damaged endothelial cells (for hemostasis) a. a vasoconstrictor b. may play a role in the reduced renal blood flow and reduced GFR of toxemia of pregnancy, acute renal failure, chronic uremia. 2) Endothelial derived relaxing factor (EDRF), actually nitric oxide (NO) is locally produced by vascular endothelial cells a. vasodilator -- preferential local vasodilatation of the renal afferent & efferent arterioles b. affects renal blood flow, GFR & reabsorption rates. 3) Prostaglandins a. effect on the kidney normally causes vasodilatation of the afferent arteriole, and improve glomerular blood flow, maintaining GFR. b. Epoprostenol (prostacyclin, PGI2) c. Made by medullary interstitial cells in the renal medulla (not associated with the glomerular apparatus) using the arachidonic acid pathway and COX-2 activity d. Clinical correlate: Long-term use of NSAID drugs that inhibit prostaglandin synthesis may reduce GFR due to reduced afferent flow to the glomerulus & may cause chronic renal failure (CRF) Especially damaging if combined with RAS blockade (ACEI, ARB, DRI) drugs that block the synthesis or effects of Angiotensin-II at the glomerulus REMEMBER: o the kidney needs BOTH the RAS system AND the production of local autacoids to autoregulate renal blood flow o blocking one or both systems long-term can cause nephropathy Remember the ACE system: normally ACE enzyme has two jobs. Job 1: converts A-I to A-II (more active) Job 2: in the lung, and elsewhere, degrades vasodilating kinins o RAS blockade may cause less degradation of vasodilating kinins o Thus, more kinins are present to enhance vasodilatation (other reason these drugs lower BP) these are the non-renin effects of RAS blocade (peripheral vasodilatation)

12 Advanced Pathophysiology Unit 7: Renal-Urologic Page 12 of 18 SUMMARY HORMONAL CONTROL OF TUBULAR REABSORPTION: Ang-II, ADH, Aldosterone, ANP (ANF) Where are they made? How do they affect the nephron? What are their overall effects? ANGIOTENSIN-II (Ang-II): volume contraction. made normally & in extra amounts when there is hypotension, or EFFECTS in the KIDNEY: increased aldosterone production (FEEDBACK TO ADRENAL CORTEX) that in turn will affect tubular processes increased ADH secretion (FEEDBACK TO CNS) that in turn will affect tubular processes constricts afferent & efferent arterioles slows flow & reduces hydrostatic pressure in peritubular capillary, enhancing reabsorption stimulates Na-K pump in the PCT (enhancing Na reabsorption with osmotic water retention) stimulates Na-H exchange pump in proximal tubules (enhancing acid excretion & Na/water retention). All together, results in Na & water retention, acid excretion. In low perfusion states combats hypotension with its associated acidosis (e.g. cardiogenic shock). o During low perfusion states, there is preferential constriction of the efferent arteriole, providing some protection of GFR & renal blood flow. o This is what MOST clinicians will say that A-II does to the renal blood flow!!! ALDOSTERONE: adrenal cortical mineralocorticoid hormone. Synthesis: o Sterol hormone, synthesized by zona glomerulosa cells of adrenal cortex. o Mineralocorticocid Release: o stimulated by presence of hyperkalema or through action of A-II on the adrenal cortex. Action: o on principal cells of cortical collecting tubule to increase Na+ reabsorption & K+ secretion. Stimulates Na-K & Na-H pumps here. o The largest effect is on Potassium (K) secretion (enhanced) and some acid secretion (enhanced). Clinical correlates: o Addison's disease: lowered production of aldosterone -- Na wasting (hyponatremia) & K accumulation (hyperkalemia), acidosis. o Cushing's disease: overproduction of aldosterone -- Na & water retention (edema), K wasting (hypokalemia), alkalosis (loss of acid).

13 Advanced Pathophysiology Unit 7: Renal-Urologic Page 13 of 18 Anti-Diuretic Hormone (ADH): increased water reabsorption and thus prevents diuresis (thus it is anti diuretic) Synthesis: peptide hormone, by hypothalamus (CNS). Storage: in posterior pituitary. Release: under influence of angiotensin-ii, hypovolemia. Actions: o Increases permeability of distal nephron to free water, increasing urinary concentration and conserving fluid. o Basis of urinary concentrating ability, as long as there is an intact loop of Henle to provide the electrolyte gradient in the renal medulla o Activates CNS thirst response ATRIAL NATRIURETIC FACTOR (PEPTIDE)(ANF, ANP): Natriuretic peptides: Natriuretic peptides (NPs) vasodilate and cause natriuresis/diuresis o Secreted from heart, kidneys, blood vessels & CNS in heart failure (HF) Release stimulated by: o Cardiac atrial distension, angiotensin-ii, endothelin, sympathetic stimulation (betareceptor) o Thus released in hypervolemic states Examples of types of NPs: o Atrial natriuretic peptide (ANP) o Brain-type natriuretic peptide (BNP) (made by heart as well as brain) Effects of NPs: OVERALL increases urinary excretion & reduction of vascular volume o Increase glomerular filtration rate (GFR) to cause natriuresis (sodium excretion) and diuresis (water excretion) o decreases Na and water reabsorption by effects on permeability at the collecting ducts o NO effect on potassium o Decrease renin release blocking the RAS and further increasing natriuresis and diuresis, also increasing vasodilatation and lowering TPR o Overall effects: Lowers blood volume and intravascular pressures Reduces cardiac output Degradation of NPs: o degraded by enzyme neprilysin (NEP)(a neutral endopeptidase enzyme) o this enzyme also degrades vasodilating bradykinins OUT OF ALL THESE HORMONES AND SYSTEMS, THE ONLY ONE THAT CAUSES DIURESIS...EVERYTHING ELSE PROMOTES ELEVATED BLOOD VOLUME, ELEVATED BP, ELEVATED CO.

14 Advanced Pathophysiology Unit 7: Renal-Urologic Page 14 of 18 ANOTHER HORMONE MADE BY THE KIDNEY ERYTHROPOIETIN (EPO): Normally synthesized by the renal interstitial cortex cells. Kidney monitors blood oxygen and makes EPO in response to hypoxemia Renal disease can cause anemia due to failure of kidney to synthesize and release this hormone that would stimulate bone marrow to make RBC. AND LASTLY, REMEMBER A HORMONE made elsewhere with effects ON THE KIDNEY PARATHYROID HORMONE (parathormone, PTH): effects on calcium, phosphate & magnesium because of its effects on the kidney Synthesis, release: made & released by the parathyroid gland in response to low calcium levels. Effects: o Increases calcium reabsorption in late distal tubules, collecting tubules, & collecting ducts. o Inhibits phosphate reabsorption (causes excretion) at proximal tubule, o stimulates magnesium reabsorption in loop of Henle. Clinical correlate: o Continuous action required, or eventually renal filtration would deplete body Calcium & Magnesium stores and be overloaded with phosphate. o Thus, renal failure patients are low in calcium, overloaded with phosphate

15 Advanced Pathophysiology Unit 7: Renal-Urologic Page 15 of 18 SYSTEMIC BLOOD PRESSURE EFFECTS ON URINE FORMATION: Decreased BP & the NEUROGENIC response via the sympathetic nervous system: in crisis or hypotensive situations sympathetic nervous system activation To maintain vascular volume, water is conserved and urine formation is reduced. May cause complication of renal failure. Sympathetic responses include: o Pressor response can vasoconstrict the renal vasculature via beta-1 stimulation of renal vessels, reducing GFR & reducing Na/water excretion. o Renin enzyme release creates hormone response of RAS angiotensin: the macula densa sees lower NaCl concentration due to reduced GFR & increased Na/Cl reabsorption & tries to protect the GFR. Renin release also from direct beta-1 stimulation eventual A-II formation Thus, A-II can be thought of as a crisis hormone Increased BP causes DIRECT Pressure Effects: Increases in arterial pressure lead to small increase in urine formation: Increased GFR & increased renal blood flow together cause a pressure diuresis & pressure natriuresis o mostly seen with acute increases in BP. o In the healthy kidney autoregulation should prevent a large change. RESPONSE TO REDUCED ARTERIAL PRESSURE TO GLOMERULUS ADAPTIVE CHANGES RESTORE FILTRATION PRESSURE IN BOWMAN S CAPSULE Arterial Pressure Glomerular Hydrostatic Pressure: decreased filtration GFR Macula Densa NaCl Angiotensin II Production from Renin release Efferent Arteriolar Resistance (increases Filtration Pressure) Afferent Arteriolar Resistance (increases incoming blood flow)

16 Advanced Pathophysiology Unit 7: Renal-Urologic Page 16 of 18 SOME CLINICAL CORRELATES: Heavy metal poisoning: e.g. mercury poisons the proximal tubules, preventing Na reabsorption. Due to high NaCl level in filtrate, macula densa reduces renin release, and eventually volume depletion results as well as renal failure due to perfusion failure (volume contraction hypotension & no GFR). Dietary effects on physiologic release of renin: renin is released with high protein meal (amino acids) and/or a high glucose load If renin released elevated BP via stimulation of RAS Could occur with: o hyperglycemia, e.g. uncontrolled DM or very sugary diet o High-protein diets can they cause renal harm in the long term?? Neuro-endocrine correlate: sympathetic nervous system activation causes renin release (renal Beta-1 receptor) cortisol also released with sympathetic activation. NSAID drugs: Effect on renal health: o Longterm use of NSAID drugs that inhibit prostaglandin synthesis may reduce GFR due to reduced afferent flow to the glomerulus o may cause chronic renal failure (CRF) o ESPECIALLY if taken with ACEI or ARB drugs Effect on salt/water balance: o NSAIDs (and aspirin doses over 160 mg/day) interfere with renal sodium excretion o Result is increased sodium and water loading that increases overall blood volume o This increases blood pressure and is associated with mortality risk

17 Advanced Pathophysiology Unit 7: Renal-Urologic Page 17 of 18 RAS blockade with drugs: ACEIs (ACE inhibitors): o Enzyme inhibitors of ACE and prevent the conversion of Ang-I to Ang-II o since ACE degrades bradykinin in the lungs, blocking this enzyme allows buildup of inflammatory mediators (bradykinins) causing a side effect of cough and edema o since ACE degrades bradykinin in the lungs and elsewhere, blocking this enzyme (ACEI drugs) allows buildup of the bradykinins which are ALSO VASODILATORS (drop the BP) so bradykinin is a potentially beneficial effect of ACEI therapy ARBs (Ang-II Receptor Blockers): o Selectively block the AT1 receptor multiple drugs on the marker (all generic names end in -sartan (e.g. valsartan) o Block the EFFECTS of Ang-II o No effect on bradykinin, so less risk of cough & edema (but still can occur) DRI (Direct Renin Inhibitors): o Enzyme inhibitor drug that blocks renin enzyme o Block the system at the beginning point All these RAS blockade drugs: o Used in management of hypertension, heart failure o they may result in critical loss of renal perfusion in cases of renal artery stenosis or hypovolemia, since angiotensin II increases efferent arteriolar sphincter tone & maintains glomerular HP (for GFR) during low-flow states. o Not for use in solitary kidney, dehydration

18 Advanced Pathophysiology Unit 7: Renal-Urologic Page 18 of 18 HAVE YOU LEARNED ALL YOU NEED TO KNOW? MORE on the NATRIURETIC PEPTIDES a counter-regulatory system to the RAS Natriuretic Peptides (NPs): Natriuretic peptides (NPs) vasodilate and cause natriuresis/diuresis o Secreted from heart, kidneys, blood vessels & CNS in heart failure (HF) o Release also stimulated by atrial distension, angiotensin-ii, endothelin, sympathetic stimulation (beta-receptor) o Thus released in hypervolemic states Examples of types of NPs: o Atrial natriuretic peptide (ANP) o Brain-type natriuretic peptide (BNP) (made by heart as well as brain) Effects of NPs: o Increase glomerular filtration rate (GFR) to cause natriuresis (sodium excretion) and diuresis (water excretion) o NO effect on potassium o Decrease renin release blocking the RAS and further increasing natriuresis and diuresis, also increasing vasodilatation and lowering TPR o decreases Na and water reabsorption by effects on permeability at the collecting ducts o Overall effects: Lowers blood volume and intravascular pressures Reduces cardiac output Degradation of NPs: o Degraded by an enzyme called neprilysin o Also called NEP (because neprilysin is a neutral endopeptidase enzyme) Pharmacologic correlates: ANP is available as a drug for heart failure therapy, nesitiride (Natrecor) Angiotensin receptor neprilysin inhibitor (ARNI) drugs o Neprilysin inhibitor drug that prevents the action of neprilysin enzyme (thus, enzyme inhibitors) and thus prevent the degradation of natriuretic peptides o Given together with ARB to minimize angioedema side effect risk