Renal Physiology. April, J. Mohan, PhD. Lecturer, Physiology Unit, Faculty of Medical Sciences, U.W.I., St Augustine.

Transcription

1 Renal Physiology April, 2011 J. Mohan, PhD. Lecturer, Physiology Unit, Faculty of Medical Sciences, U.W.I., St Augustine. Office : Room 105, Physiology Unit. References: Koeppen B.E. & Stanton B.A. (2010). Berne & Levy Physiology. 6th Edition. Mosby, Elsevier. Marieb, E. & Hoehn, K. (2010). Human Anatomy & Physiology. 8th Edition, Pearson, Benjamin Cummings. Stanfield, C.L. & Germann W.J. (2008). Principles of Human Physiology. 3rd Edition, Pearson, Benjamin Cummings. Hall, J.E. (2011). Guyton and Hall Textbook of Medical Physiology. 12th Edition, Elsevier, Saunders. April 04-07,

2 Physiology Objectives Objectives 1-5, PBL Booklet (See next page) Topics Body Fluid Compartments, Osmolarity, Osmolality & Tonicity and Membrane Transport Mechanisms. Review Ch. 1 : Principles of Cell Function Mechanisms of Membrane Transport, p 7-19 Ch. 2 : Homeostasis of Body Fluids Physiology Objectives Classify body fluid compartments with regard to their volume, relative percentages and percentage of body weight. Quantify the ionic components of the major body fluid compartments. Define osmolarity, osmolality and tonicity with respect to movement between intracellular and extracellular body fluid compartments. Review the various types of membrane transport (active transport, facilitated diffusion etc.) Explain the resultant effects on red blood cells which are added to hypotonic and hypertonic solutions. April 04-07,

3 Physiology Objectives cont d... Objectives 6-8, PBL Booklet Ch 32, Topic Functional Anatomy of the Kidneys, Physiology Objectives cont d... Review the gross and microscopic structure of the kidney and nephrons. Describe in detail the vascular arrangement of the kidneys. Give a detailed description of the structures encountered during the passage of the ultrafiltrate from the Bowman s capsule through the tubular segments into the renal pelvis. April 04-07,

4 Today s Topics Overview of ultrastructure of the Nephron, Renal Corpuscle, & Juxtaglomerular apparatus. Renal Clearance. Glomerular Filtration (GFR). Estimation of GFR- creatinine clearance. Clinical Importance. Composition of Ultrafiltrate. Determinants of Ultrafiltration. Dynamics of Ultrafiltration. Renal Blood Flow (RBF). Renal Autoregulation Mechanisms of Autoregulation Extrinsic Regulation of RBF & GFR (nerves & hormones). Functions of the Kidneys Regulatory 1. body fluid osmolality and volumes importance? 2. electrolyte balance importance? 3. acid-base balance importance? Excretory 1. metabolic products and foreign substances e.g. urea, uric acid, creatinine, Hb metabolism, hormone metabolites, drugs Endocrine 1. produce and secrete hormones e.g. renin, calcitriol, erythropoetin April 04-07,

5 Mechanisms of Urine Formation Urine formation and adjustment of blood composition involves three major processes Glomerular filtration Tubular reabsorption Secretion Figure 25.10; Marieb & Hoehn, 2010 Nephrons are the structural and functional units that form urine, consisting of: Renal Corpuscle Proximal Convoluted Tubule Loop of Henle Distal Convoluted Tubule Collecting Duct System The Nephron Figure 32.3, Koeppen & Stanton, 2010 April 04-07,

6 The Nephron Renal Corpuscle : Glomerulus a tuft of capillaries associated with a renal tubule Bowman s capsule blind, cup-shaped end of a renal tubule that completely surrounds the glomerulus The Nephron Unique cells in each nephron segment Figure 32.3; Koeppen & Stanton, 2010 April 04-07,

7 The Nephron All cells, (except intercalated cells), have in their apical plasma membrane a single nonmotile primary cilium that protrudes into the tubule fluid mechanosensors chemosensors initiate Ca2+-dependent signaling pathways, e.g. those that control kidney cell function, proliferation, differentiation, and apoptosis Types of Nephrons Cortical nephrons 85% of nephrons; located superficially in the cortex short LoH efferent arteriole peritubular capillaries nutrients delivers substances to the nephron for secretion path for return of reabsorbed H 20 & solutes to blood Figure 25.7; Marieb & Hoehn, 2010 April 04-07,

8 Types of Nephrons Juxtamedullary nephrons: located at the cortexmedulla junction long LoH efferent arteriole series of vascular loops called the vasa recta functions of peritubular capillaries + involved in the production of concentrated urine Figure 25.7; Marieb & Hoehn, 2010 Ultrastructure of the Renal Corpuscle first step in urine formation : passive movement of a plasma ultrafiltrate from glomerular capillaries Bowman's space ultrafiltration : passive movement of an essentially protein-free fluid from the glomerular capillaries Bowman's space April 04-07,

9 Ultrastructure of the Renal Corpuscle the glomerulus : network of capillaries supplied by the afferent arteriole and drained by the efferent arteriole capillaries covered by epithelial cells called podocytes (visceral layer of Bowman's capsule) visceral cells face outward at the vascular pole to form the parietal layer of Bowman's capsule space between the visceral layer and the parietal layer - Bowman's space - lumen of the PCT Figure 32.5; Koeppen & Stanton, 2010 Ultrastructure of the Renal Corpuscle Figure 25.9; Marieb & Hoehn, 2010 April 04-07,

10 Filtration Membrane endothelial cells of glomerular capillaries are covered by a basement membrane that is surrounded by podocytes capillary endothelium, basement membrane & foot processes of podocytes form the filtration barrier/membrane Figure 25.9; Marieb & Hoehn, 2010 Endothelium fenestrated - contains 700 Å holes, where 1 Å = m freely permeable to H 2 0, small solutes (such as Na+, urea, & glucose) & most proteins not permeable to RBC, WBC or platelets Filtration Membrane endothelial cells express negatively charged glycoproteins on their surface retard filtration of large anionic proteins into Bowman's space Figure 25.9; Marieb & Hoehn, 2010 April 04-07,

11 Filtration Membrane Basement membrane porous matrix of negatively charged proteins, ( type IV collagen, laminin, proteoglycans agrin & perlecan, & fibronectin) important filtration barrier to plasma proteins charge-selective filter Figure 25.9; Marieb & Hoehn, 2010 Filtration Membrane Podocytes long finger-like processes that completely encircle the outer surface of the capillaries processes of the podocytes interdigitate to cover the basement membrane separated by apparent gaps called filtration slits Figure 25.9; Marieb & Hoehn, 2010 April 04-07,

12 Filtration Membrane Filtration Slits each filtration slit bridged by a thin diaphragm that contains pores Å filtration slit diaphragm composed of several proteins nephrin (NPHS1), NEPH-1, podocin (NPHS2), α- actinin 4 (ACTN4) & CD2-AP function primarily as a sizeselective filter Figure 32.7; Koeppen & Stanton, 2010 Ultrastructure of the Renal Corpuscle Mesangium mesangial cells & matrix mesangial cells possess many properties of smooth muscle cells surround the glomerular capillaries provide structural support for the glomerular capillaries secrete the extracellular matrix Figure 32.5; Koeppen & Stanton, 2010 April 04-07,

13 Ultrastructure of the Renal Corpuscle Mesangium cont d... exhibit phagocytic activity by removing macromolecules from the mesangium secrete prostaglandins & proinflammatory cytokines mesangial cells contract & are adjacent to glomerular capillaries may influence the GFR by regulating blood flow through the glomerular capillaries or by altering the capillary surface area mesangial cells located outside the glomerulus - extraglomerular mesangial cells Ultrastructure of the Juxtaglomerular Apparatus JGA Involved in: tubulo-glomerular feedback mechanism (autoregulation of RBF and GFR) Comprises : 1. macula densa 2. extraglomerular mesangial cells 3. granular cells of the afferent arteriole (renin) Figure 32.5; Koeppen & Stanton, 2010 April 04-07,

14 Ultrastructure of the Juxtaglomerular Apparatus macula densa morphologically distinct region of the thick ascending limb (dct?) passes through the angle formed by the afferent and efferent arterioles of the same nephron cells contact the extraglomerular mesangial cells & granular cells of the afferent arterioles Figure 32.5; Koeppen & Stanton, 2010 Ultrastructure of the Juxtaglomerular Apparatus Granular cells manufacture, store & release renin contain smooth muscle myofilaments Figure 32.5; Koeppen & Stanton, 2010 April 04-07,

15 Innervation of the Kidneys renal nerves regulate RBF, GFR & salt & water reabsorption by the nephron sympathetic nerve fibers; no parasympathetic adrenergic fibers release norepinephrine & dopamine adrenergic fibers lie adjacent to the smooth muscle cells of the major branches of the renal artery & the afferent & efferent arterioles also, sympathetic nerves innervate the renin-producing granular cells of the afferent arterioles renin secretion nerve fibers also to PCT, LoH, DCT & collecting duct; Na+ reabsorption by these nephron segments Today s Topics Overview of ultrastructure of the Nephron, Renal Corpuscle, & Juxtaglomerular apparatus. Renal Clearance. Glomerular Filtration (GFR). Estimation of GFR- creatinine clearance. Clinical Importance. Composition of Ultrafiltrate. Determinants of Ultrafiltration. Dynamics of Ultrafiltration. Renal Blood Flow (RBF). Renal Autoregulation Mechanisms of Autoregulation Extrinsic Regulation of RBF & GFR (nerves & hormones). April 04-07,

16 Assessment of Renal Function The coordinated actions of the nephron's various segments determine the amount of a substance that appears in urine Depends on 3 processes : (1) glomerular filtration (2) reabsorption of the substance from tubular fluid back into blood (3) (in some cases) secretion of the substance from blood into tubule fluid Renal Clearance Renal clearance : theoretical basis for measurement of GFR & RBF based on the Fick principle (i.e., mass balance or conservation of mass) i.e. the amt substance entering organ= amt leaving organ, assuming no synthesis /degradation of substance by organ the renal artery is the single input source to the kidney, whereas the renal vein & ureter are the two output routes Figure 32.12; Koeppen & Stanton, 2010 April 04-07,

17 Renal Clearance P a x & P v x = concentrations of substance x in the renal artery & renal vein plasma, respectively RPFa & RPFv = renal plasma flow rates in the artery & vein, respectively U x = concentration of substance x in urine V (dot) = urine flow rate Figure 32.12; Koeppen & Stanton, 2010 Renal Clearance For any substance that is neither synthesized nor metabolized, the amount that enters the kidneys is = the amount that leaves the kidneys in urine + the amount that leaves the kidneys in renal venous blood allows measurement of the amount of substance x excreted in urine vs the amount returned to the systemic circulation in renal venous blood Figure 32.12; Koeppen & Stanton, 2010 April 04-07,

18 Renal Clearance C x = U x X V P x ml/min represents a volume of plasma from which all of substance x has been removed and excreted into urine per unit time i.e. rate of removal of substance x from plasma by kidneys Note : ratio of the amount of x excreted in urine to the amount of x in plasma Renal Clearance C x = U x X V Pa x ml/min E.g. if Ux = 100 mg/ml; V= 1 ml/min Then excretion rate of x = 100 mg/ml x 1 ml/min = 100 mg/min If Px = 1 mg.ml, then Cx = 100 mg/min 1 mg/ml = 100 ml/min April 04-07,

19 Today s Topics Overview of ultrastructure of the Nephron, Renal Corpuscle, & Juxtaglomerular apparatus. Renal Clearance. Glomerular Filtration (GFR). Estimation of GFR- creatinine clearance. Clinical Importance. Composition of Ultrafiltrate. Determinants of Ultrafiltration. Dynamics of Ultrafiltration. Renal Blood Flow (RBF). Renal Autoregulation Mechanisms of Autoregulation Extrinsic Regulation of RBF & GFR (nerves & hormones). Mechanisms of Urine Formation Urine formation and adjustment of blood composition involves three major processes Glomerular filtration Tubular reabsorption Secretion Figure 25.10; Marieb & Hoehn, 2010 April 04-07,

20 GFR Glomerular Filtration Rate (GFR) the sum of the filtration rates of all functioning nephrons index of kidney function quantity of glomerular filtrate formed each minute in all nephrons of both kidneys in normal adult male : ml/min in normal adult female : ml/min So, in 24 hours or 1 day, as much as 180 L of plasma is filtered by the glomeruli can be estimated using creatinine clearance test Estimation of GFR Creatinine byproduct of skeletal muscle creatine metabolism freely filtered across the glomerulus into Bowman's space not reabsorbed, secreted, or metabolized by the cells of the nephron April 04-07,

21 Estimation of GFR the amount of creatinine excreted in urine per minute = the amount of creatinine filtered at the glomerulus each minute where : P Cr = [plasma] creatinine U Cr = [urine] creatinine V = urine flow Figure 32.13; Koeppen & Stanton, 2010 Estimation of GFR From equation : GFR = U Cr X V P Cr where : P Cr = [plasma] creatinine U Cr = [urine] creatinine V = urine flow Figure 32.13; Koeppen & Stanton, 2010 April 04-07,

22 Estimation of GFR NB: this equation is the same form as that for clearance So, clearance of creatinine provides a means for determining the GFR Figure 32.13; Koeppen & Stanton, 2010 Estimation of GFR Creatinine is not the only substance that can be used to measure GFR Any substance that meets the following criteria can serve as an appropriate marker for the measurement of GFR The substance must: 1. Be freely filtered across the glomerulus into Bowman's space 2. Not be reabsorbed or secreted by the nephron 3. Not be metabolized or produced by the kidney 4. Not alter the GFR e.g. Inulin - fructose polymer- its clearance measures GFR April 04-07,

23 Filtration Fraction not all of the plasma coming into the kidneys is filtered approximately 10% of plasma that enters the kidneys in the renal artery does not pass through the glomerulus the portion of filtered plasma = filtration fraction Filtration Fraction = GFR RPF ~ Glomerular Filtration Rate Clinical Importance of GFR : measuring GFR is important when kidney disease is suspected : GFR may be the first & only clinical sign of kidney disease knowledge of the patient's GFR is essential in evaluating the severity and course of kidney disease GFR kidney disease is progressing GFR recuperation a 50% loss of functioning nephrons reduces the GFR only by about 25%; the decline in GFR is not 50% because the remaining nephrons compensate April 04-07,

24 Glomerular Filtration Rate Because measurements of GFR are cumbersome, kidney function is usually assessed in the clinical setting by measuring P Cr, which is inversely related to GFR BUT changes in P Cr are small : GFR from ml/min (~ 20%) is accompanied by an increase in P Cr from 1.0 to 1.2 mg/dl Figure 32.14; Koeppen & Stanton, 2010 Composition of Glomerular Filtrate first step in the formation of urine is ultrafiltration of plasma by the glomerulus the plasma ultrafiltrate = glomerular filtrate no cellular elements (i.e., RBC, WBC & platelets) no proteins [salts & organic molecules], e.g. glucose and amino acids, is similar to plasma Starling forces drive ultrafiltration across the glomerular capillaries and changes in these forces alter the GFR April 04-07,

25 Determinants of Ultrafiltrate Composition the glomerular filtration barrier determines the composition of the plasma ultrafiltrate it restricts the filtration of molecules on the basis of both size & electrical charge neutral molecules with a radius < 20 Å are filtered freely molecules > 42 Å are not filtered molecules between Å are filtered to various degrees, depending on their electrical charge e.g. cations Eg: serum albumin : an anionic protein molecular radius of 35.5 Å, (i.e. < 42 Å) BUT is filtered poorly (because of negative charges on it) Determinants of Ultrafiltrate Composition Clinical importance of the negative charges on the filtration barrier in restricting the filtration of plasma proteins : removal of the negative charges from the filtration barrier proteins filtered solely on the basis of their size at sizes between Å, filtration of polyanionic proteins > the filtration in the normal state E.g. glomerular diseases the negative charges on the filtration barrier are reduced because of immunological damage and inflammation filtration of proteins proteins appear in urine (proteinuria) April 04-07,

26 Determinants of Ultrafiltrate Composition Figure 32.16; Koeppen & Stanton, 2010 Dynamics of Ultrafiltration Ultrafiltration occurs because the Starling forces (i.e., hydrostatic and oncotic pressure) drive fluid from the lumen of glomerular capillaries, across the filtration barrier Bowman's space Figure 32.17; Koeppen & Stanton, 2010 April 04-07,

27 Dynamics of Ultrafiltration GFR is proportional to the sum of the Starling forces that exist across the capillaries [(PGC - PBS) σ (πgc - πbs)] multiplied by the ultrafiltration coefficient (Kf) GFR = Kf [(P GC - P BS) σ (π GC - π BS)] GFR = Kf x Net Filtration Pressure (NFP) Kf = the product of the intrinsic permeability of the glomerular capillary and the glomerular surface area available for filtration σ = reflection coefficient for proteins across the glomerular capillary = 1 Dynamics of Ultrafiltration the rate of glomerular filtration is > in glomerular capillaries than in systemic capillaries, mainly because Kf is approximately 100 times > in glomerular capillaries Also, P GC is approximately twice as great as the hydrostatic pressure in systemic capillaries April 04-07,

28 Dynamics of Ultrafiltration GFR can be altered by changing Kf or by changing any of the Starling forces ( NFP) In normal individuals, the GFR is regulated by alterations in P GC that are mediated mainly by changes in afferent or efferent arteriolar resistance P GC is affected in 3 ways: 1. Changes in afferent arteriolar resistance : resistance increases P GC & GFR (See D) resistance decreases P GC & GFR (See A) Dynamics of Ultrafiltration 2. Changes in efferent arteriolar resistance : resistance decreases P GC & GFR (See C) resistance increases P GC & GFR (See B) 3. Changes in renal arteriolar pressure : pressure transiently increases P GC GFR pressure transiently decreases P GC GFR Figure 32.21; Koeppen & Stanton, 2010 April 04-07,

29 Today s Topics Overview of ultrastructure of the Nephron, Renal Corpuscle, & Juxtaglomerular apparatus. Renal Clearance. Glomerular Filtration (GFR). Estimation of GFR- creatinine clearance. Clinical Importance. Composition of Ultrafiltrate. Determinants of Ultrafiltration. Dynamics of Ultrafiltration. Renal Blood Flow (RBF). Renal Autoregulation Mechanisms of Autoregulation Extrinsic Regulation of RBF & GFR (nerves & hormones). Renal Blood Flow Blood flow through the kidneys serves several important functions : 1. Indirectly determines the GFR 2. Modifies the rate of solute & H 2 0 reabsorption by the PCT 3. Participates in the concentration and dilution of urine 4. Delivers O 2, nutrients, and hormones to the cells of the nephron and returns CO 2 and reabsorbed fluid and solutes to the general circulation 5. Delivers substrates for excretion in urine April 04-07,

30 Renal Blood Flow Blood flow through any organ may be represented by : Q = P R where : Q = blood flow P = mean arterial pressure minus venous pressure for that organ R = resistance to flow through that organ Renal Blood Flow Renal Blood Flow (RBF) is equal to the pressure difference between the renal artery and the renal vein divided by renal vascular resistance: RBF = Aortic pressure renal venous pressure Renal vascular resistance April 04-07,

31 Renal Blood Flow arterial pressure RBF = Aortic pressure Renal venous pressure Renal vascular resistance afferent arteriole efferent arteriole interlobular artery RBF remains relatively constant ABP = mm Hg GFR is also regulated over the same range of ABP the phenomenon whereby RBF and GFR are maintained relatively constant = autoregulation achieved by in vascular resistance (afferent arterioles) Renal Blood Flow Figure 32.18; Koeppen & Stanton, 2010 April 04-07,

32 Autoregulation of RBF & GFR Two mechanisms : 1. Responds to changes in arterial pressure 2. Responds to changes in [NaCl] in tubular fluid Autoregulation of RBF & GFR Pressure mechanism : Myogenic Mechanism intrinsic property of vascular smooth muscle: the tendency to contract when stretched when arterial pressure rises and the renal afferent arteriole is stretched, the smooth muscle contracts Because the increase in resistance of the arteriole offsets the increase in pressure, RBF & therefore GFR remain constant (See equation for Renal Blood Flow) April 04-07,

33 Autoregulation of RBF & GFR [NaCl]-dependent mechanism : Tubuloglomerular Feedback [NaCl] in tubular fluid is sensed by the macula densa of the JGA & converted into a signal that affect afferent arteriolar resistance GFR Autoregulation of RBF & GFR formation & release of ATP & ADO vasoconstriction of afferent arteriole GFR to normal levels GFR [NaCl] NaCl enters the macula densa cells ATP & ADO production & release vasodilation of the afferent arteriole GFR Figure 32.19; Koeppen & Stanton, 2010 April 04-07,

34 Autoregulation of RBF & GFR Figure 32.20; Koeppen & Stanton, 2010 Autoregulation of RBF & GFR GFR [NaCl] in tubule fluid at the macula densa uptake of NaCl across the apical cell membrane of macula densa cells via the 1Na+-1K+-2Cl- (NKCC2) symporter [ATP] & [adenosine] (ADO) ATP binds to P2X receptors & ADO binds to adenosine A1 receptors in the plasma membrane of smooth muscle cells in afferent arteriole intracellular [Ca2+] vasoconstriction of the afferent GFR ATP & ADO also renin release by granular cells in the afferent arteriole via intracellular [Ca2+] in vascular smooth muscle (VSM) cells April 04-07,

35 Autoregulation of RBF & GFR GFR [NaCl] in tubule fluid uptake of NaCl into macula densa cells release of ATP & ADO intracellular [Ca2+] GFR release of ATP & ADO release of renin by granular cells Also, entry of NaCl into macula densa cells production of PGE2 renin secretion by granular cells NB: although ADO is a vasodilator in most other vascular beds, it constricts the afferent arteriole in the kidney Importance of Autoregulation many activities can change arterial blood pressure, so, we need mechanisms that maintain RBF & GFR relatively constant despite changes in arterial pressure if RBF & GFR or suddenly in proportion to changes in blood pressure urinary excretion of fluid and solute would also change suddenly; if no corresponding intake fluid & electrolyte imbalance autoregulation of RBF & GFR : provides an effective means for uncoupling renal function from arterial pressure ensures that fluid and solute excretion remain constant April 04-07,

36 Autoregulation of RBF & GFR 3 points concerning autoregulation should be noted : 1. Autoregulation is absent when arterial pressure is < 90 mm Hg 2. Autoregulation is not perfect; RBF & GFR do change slightly as arterial blood pressure varies 3. Despite autoregulation, RBF & GFR can be changed by certain hormones and by changes in sympathetic nerve activity Regulation of RBF & GFR Table 32-1; Koeppen & Stanton, 2010 April 04-07,

37 Can you predict the effect of these changes in afferent & efferent arterioles on P GC, GFR & RBF? Figure 32.21; Koeppen & Stanton, 2010 Regulation of RBF & GFR Constriction of the afferent arteriole (A) decreases PGC because less of the arterial pressure is transmitted to the glomerulus, thereby reducing GFR Constriction of the efferent arteriole (B) elevates PGC and thus increases GFR Dilation of the efferent arteriole (C) decreases PGC and thus decreases GFR Dilation of the afferent arteriole (D) increases PGC because more of the arterial pressure is transmitted to the glomerulus, thereby increasing GFR Figure 32.21; Koeppen & Stanton, 2010 April 04-07,

38 Sympathetic Nerves Regulation of RBF & GFR Dehydration or strong emotional stimuli, such as fear and pain sympathetic activity afferent & efferent arterioles innervated by sympathetic neurons sympathetic nerves release NE & dopamine circulating E secreted by adrenal medulla NE & E vasoconstriction by binding to α1-adrenoceptors mainly on afferent arterioles GFR & RBF Renalase from kidneys facilitates degradation of catecholamines Regulation of RBF & GFR Angiotensin II Ag II is produced systemically and locally within the kidneys constricts the afferent & efferent arterioles and decreases RBF & GFR efferent arteriole more sensitive to Ag II than afferent arteriole, so low [Ag II] constriction of efferent arteriole GFR & RBF high [Ag II] constriction of afferent & efferent arteriole GFR & RBF April 04-07,

39 Regulation of RBF & GFR blood vol ABP Figure 32.22; Koeppen & Stanton, 2010 Regulation of RBF & GFR Prostaglandins (PGs) : clinical importance PGs do not play a major role in regulating RBF in healthy, resting people However, during pathophysiological conditions e.g. hemorrhage, there is production of PGs (PGI2, PGE1 & PGE2) by kidneys ; PGs RBF without changing GFR PGs RBF by dampening the vasoconstrictor effects of sympathetic nerves & Ag II prevents severe & potentially harmful vasoconstriction & renal ischemia dehydration & stress (e.g., surgery, anesthesia), Ag II, & sympathetic nerves synthesis of PGs April 04-07,

40 Regulation of RBF & GFR Prostaglandins (PGs) : clinical importance non-steroidal anti-inflammatory drugs (NSAIDs), e.g. aspirin & ibuprofen synthesis of PGs administration of NSAIDs during renal ischemia and hemorrhagic shock is contraindicated because by blocking the production of prostaglandins, they decrease RBF & increase renal ischemia PGs play an increasingly important role in maintaining RBF & GFR as individuals age, so NSAIDs can significantly RBF & GFR in the elderly Nitric Oxide Regulation of RBF & GFR NO : an endothelium-derived relaxing factor (EDRF) important vasodilator under basal conditions counteracts vasoconstriction produced by Ag II & catecholamines blood flow increases greater shear force on endothelial cells in the arterioles production of NO ACh, histamine, bradykinin, & ATP facilitate release of NO from endothelial cells NO dilation of the afferent and efferent arterioles in the kidneys NO total peripheral resistance (TPR) NO TPR April 04-07,

41 Regulation of RBF & GFR Endothelin potent vasoconstrictor secreted by endothelial cells of the renal vessels, mesangial cells, and distal tubular cells in response to Ag II, bradykinin, epinephrine, and endothelial shear stress profound vasoconstriction of the afferent & efferent arterioles decreases GFR & RBF production of endothelin in a number of glomerular disease states (e.g., renal disease associated with diabetes mellitus) Regulation of RBF & GFR Bradykinin vasodilator that acts by stimulating the release of NO & PGs increases GFR & RBF kallikrein = proteolytic enzyme produced in the kidneys cleaves circulating kininogen to bradykinin Adenosine (ADO) produced within the kidneys vasoconstriction of the afferent arteriole GFR & RBF (see tubuloglomerular feedback) April 04-07,

42 Regulation of RBF & GFR Natriuretic Peptides secretion of ANP by cardiac atria & BNP by cardiac ventricle when ECF ANP & BNP dilate afferent arteriole & constrict efferent arteriole ANP & BNP produce a modest increase in GFR with little change in RBF Regulation of RBF & GFR Adenosine Triphosphate cells release ATP into the renal interstitial fluid ATP has dual effects on GFR & RBF under some conditions, ATP constricts the afferent arteriole, reduces RBF & GFR (tubuloglomerular feedback) ATP also may NO production & GFR & RBF Glucocorticoids therapeutic doses of glucocorticoids GFR & RBF April 04-07,

43 Regulation of RBF & GFR Histamine local release of histamine modulates RBF during the resting state and during inflammation and injury resistance of afferent and efferent arterioles RBF without elevating GFR Dopamine produced by PT RBF & renin secretion Regulation of RBF & GFR Figure 32.23; Koeppen & Stanton, 2010 NB : role of Angiotensin-converting enzyme (ACE) located on the surface of endothelial cells lining the afferent arteriole & glomerular capillaries converts Ag I to Ag II GFR & RBF Ag II also produced locally in granular cells in the afferent arteriole & PT cells April 04-07,

44 Regulation of RBF & GFR Clinical Importance of ACE ACE degrades & thereby inactivates bradykinin converts Ag I to Ag II ACE Ag II levels & bradykinin levels Drugs : ACE inhibitors (e.g., enalapril, captopril), Ag II levels & bradykinin levels systemic vascular resistance BP Ag II levels & bradykinin levels renal vascular resistance GFR & RBF therefore used to systemic blood pressure in hypertensive patients Regulation of RBF & GFR Clinical Importance of AgII receptor antagonists Ag II receptor antagonists (e.g., losartan) are also used to treat high blood pressure block the binding of Ag II to the Ag II receptor (AT1) block the vasoconstrictor effects of angiotensin II on the afferent arteriole; GFR & RBF Ag II receptor antagonists do not inhibit kinin metabolism (e.g., bradykinin) as do ACE inhibitors April 04-07,