Midwestern University PHYSG 1501 Lecture 28 (PDF)
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Uploaded by AstoundingHyena3350
Midwestern University
2024
Johana Vallejo-Elias
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This document is a lecture handout for Midwestern University's PHYSG 1501 class, covering the control of extracellular fluid. It details the roles of various hormones in regulating fluid balance and presents different clinical examples.
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PHYSG 1501 - Lecture 28 Control of Extracellular Fluid Johana Vallejo-Elias, Ph.D. Professor Physiology Department College of Graduate Studies Office...
PHYSG 1501 - Lecture 28 Control of Extracellular Fluid Johana Vallejo-Elias, Ph.D. Professor Physiology Department College of Graduate Studies Office: Science Hall, 380-N pp. 293-296, Phone: 623-572-3313 Sherwood 311-315 E-mail: [email protected] pp. 535-547 © MWU 2024, J. Vallejo-Elias Learning Objectives Know the overall picture of ECF regulation in relation to the control of blood volume and plasma osmolarity. Describe the actions of the following hormones: aldosterone, angiotensin II, and renin (RAAS, renin-angiotensin-aldosterone system), atrial natriuretic peptide (ANP), and anti-diuretic hormone (ADH, vasopressin). Know where these hormones originate, be able to identify their targets and discuss their regulatory mechanisms. Understand the interplay between these hormones in maintaining ECF volume and osmolarity. Discuss the body’s response and explain the mechanisms of normal and abnormal water balance and acute sodium load (clinical examples). 2 © MWU 2024, J. Vallejo-Elias Overall Control of Extracellular Fluid (ECF) Regulation of extracellular fluid (ECF) volume and ECF osmolarity is accomplished by controlling sodium (Na+) and water. Na+ regulation responds primarily to changes in blood volume (driven mainly by changes in pressure): Renin-angiotensin-aldosterone system (RAAS) RAAS activity increases when blood pressure decreases Water regulation responds primarily to changes in osmolarity and secondarily to ECF volume (pressure): Antidiuretic hormone (ADH; Vasopressin) 3 © MWU 2024, J. Vallejo-Elias What hormones are involved in the regulation of sodium and water reabsorption? Renin - Angiotensin II - Aldosterone (RAAS) Anti-Diuretic Hormone Blood Pressure and (ADH; Vasopressin) Volume Blood Atrial Natriuretic Peptide (ANP) Pressure and Volume 4 © MWU 2024, J. Vallejo-Elias Blood Pressure and What is Aldosterone? Volume Origin: Steroid hormone from the adrenal cortex Targets: Binds to intracellular mineralocorticoid receptors (MR) in principal cells within the late distal tubule and collecting duct. Stimulates transcription resulting in up-regulation of apical ENaCs, apical K+ channels, Na+-K+ ATPase, mitochondrial metabolism, and H+-ATPase. Function: ↑ tubular Na+ reabsorption by the principal cells ↑ tubular K+ secretion by the principal cells 5 © MWU 2024, J. Vallejo-Elias What is the role of Aldosterone and how is regulated? Aldosterone stimulates Na+ reabsorption by the principal cells in the late distal tubule and collecting duct. Also stimulates K+ secretion. Na+ retention entails loss of K+. Aldosterone released is stimulated by increases in Angiotensin II and plasma K+ concentration. Only 2-3% of the filtered Na+ is under the control of aldosterone; this amounts to 30 g of NaCl/day. Rx: Aldosterone is antagonized by spironolactone, a weak diuretic (K+ sparing). 6 © MWU 2024, J. Vallejo-Elias Summary of Factors that alter Aldosterone secretion Increase Aldosterone Secretion Decrease Aldosterone Secretion ↑ Plasma K+ concentration ↓ Plasma K+ concentration ↑ Plasma angiotensin II concentration ↓ Plasma angiotensin II concentration ↑ Plasma ACTH concentration ↓ Plasma ACTH concentration 7 © MWU 2024, J. Vallejo-Elias Blood What is Angiotensin II (Ang II)? Pressure and Volume Origin: Produced from conversion of Angiotensin I into Angiotensin II by Angiotensin Converting Enzyme (ACE) in the lungs. Targets: Binds to Angiotensin II Type 1 receptors (AT1R) expressed in several tissues including the adrenal glands and vascular smooth muscle. It has other functions via AT2Rs. Primary functions: Powerful vasoconstrictor Stimulates aldosterone secretion 8 © MWU 2024, J. Vallejo-Elias What is the role of Angiotensin II Renin is released by (Ang II) in the regulation of the granular cells in the juxtaglomerular sodium and water reabsorption? apparatus (JGA). Angiotensin II has several other effects that favor salt retention and elevation of arterial blood pressure: Powerful vasoconstrictor Stimulates release of aldosterone Stimulates Na+-H+- exchange (NHE) in the proximal nephron. ADH Stimulates thirst (dipsogen) Promotes ADH release from pituitary 9 © MWU 2024, J. Vallejo-Elias Summary of Angiotensin II Effects Target Hormone Actions Major Effects Proximal tubule ↑ Na+-H+ exchange activity ↑Na+ and H2O reabsorption ↑ ENaC and Na+-K+-ATPase in principal cells (late distal tubule and collecting duct) Adrenal cortex ↑ Aldosterone secretion ↑ Na+ reabsorption H2O follows in the presence of ADH Hypothalamus ↑ H2O permeability in principal cells ↑ ADH secretion from (ADH is made in the (late distal tubule and collecting duct) posterior pituitary hypothalamus ) ↑ H2O reabsorption ALL actions of angiotensin II favors Na+ retention (conserve salt and water) and elevation of arterial blood pressure. 10 © MWU 2024, J. Vallejo-Elias Blood Pressure and What is Renin? Volume Origin: Enzyme produced by the granular cells in the juxtaglomerular apparatus (JGA) within the kidney. Targets: Catalyzes the conversion of angiotensinogen (renin substrate) to Angiotensin I, a decapeptide. Angiotensin I has little biologic activity, other than to serve as a precursor to Angiotensin II. Function: Regulates Angiotensin II production 11 © MWU 2024, J. Vallejo-Elias Review: What is the Juxtaglomerular Apparatus (JGA)? Refer to Lecture 23, Page 17 The JGA is a region where the distal convoluted tubule (DCT) returns to the “parent” or same nephron glomerulus. Specialized macula densa cells within the DCT are in contact with the afferent and efferent arterioles forming the JGA. Sense blood flow and sodium delivery The JGA regulates RPF, GFR, and Renin release from granular cells. 12 © MWU 2024, J. Vallejo-Elias From: J Clin Invest DOI: 10.1172/JCI22929 How is the released of Renin regulated at the juxtaglomerular apparatus (JGA) ? Intrarenal baroreceptors: granular cells of JGA respond to pressure (stretch) in afferent arterioles; release of renin is inversely related to pressure in afferent arterioles. (e.g., ↓ BP → ↑ renin secretion) Macula densa: senses flow to distal tubule (GFR); renin release is inversely related to GFR. (e.g., in response to a ↓ NaCl → ↑ renin secretion) Renal sympathetic nerves (RSN): end near granular cells; stimulation of RSN increases renin release via stimulation of β receptors. (e.g., ↓ BP below normal → stimulates baroreceptor reflex → ↑ RSN activity → ↑ renin secretion) 13 © MWU 2024, J. Vallejo-Elias Summary of Factors That Alter Renin Release From Granular Cells Factors Promoting Renin Release Factors Inhibiting Renin Release ↓ Arterial blood pressure (via ↑ Arterial blood pressure intrarenal baroreceptors) ↓ Sympathetic activity to granular cells ↑ Sympathetic activity to granular ↑ NaCl delivery to the macula densa cells (β-adrenergic stimulation, input to RSN from vascular baroreceptors) *Atrial natriuretic peptide (ANP) ↓ NaCl delivery to the macula densa * Atrial natriuretic peptide (ANP), released from the atria of the heart, directly inhibits renin release by granular cells (see slides 16-18). 14 © MWU 2024, J. Vallejo-Elias Renal Component of the Integrated Response to Hemorrhage Refer to Lecture 12, page 8 HEMORRAGE MACULA INTRARENAL DENSA BARORECEPTORS ADH SYMPATHETIC INPUT GRANULAR CELLS ↑ RENIN SECRETION ↑ RAAS 15 © MWU 2024, J. Vallejo-Elias Blood Pressure and What is Atrial Natriuretic Peptide (ANP)? Volume Origin: Atrial natriuretic peptide (ANP, ANF) is released from the atria of the heart. Stimulants: ↑ pressures (e.g., ↑NaCl, ↑ ECF volume, ↑ arterial BP) Targets: Renal JGA (increases GFR, inhibits renin) Adrenal cortex (reduces Aldosterone) Vascular smooth muscle (vasodilation) Hypothalamus (reduces ADH) 16 © MWU 2024, J. Vallejo-Elias What is the role of Atrial Natriuretic Peptide (ANP)? Increases GFR and the filtered load of NaCl: ADH Posterior Pituitary Dilates the afferent arteriole and constricts the efferent arteriole. Decreases NaCl reabsorption by the collecting duct at several steps. Directly inhibits secretion of renin and aldosterone Directly inhibits Na+ reabsorption by medullary collecting duct (natriuresis). 17 © MWU 2024, J. Vallejo-Elias Summary of Atrial Natriuretic Protein (ANP) Regulation Factors Promoting Release Targets Effects ↑ NaCl (Na+ retention) JG apparatus of the ↓ Renin secretion kidney ↑ ECF volume (expansion of the ↓ Aldosterone ECF volume) Adrenal cortex secretion ↑ Arterial blood pressure Posterior pituitary ↓ ADH (vasopressin) secretion ALL factors promote atrial natriuretic peptide (ANP) secretion from the atrial myocardium by inducing stretch. Since the stimulus for ANP release is increased plasma volume/ arterial stretch, the effect of ANP is to (1) increase GFR, (2) inhibit Na+ reabsorption, and (3) inhibit ADH secretion to allow more water to be excreted (diuresis). These actions results in increased urine output to decrease blood volume and blood pressure. Thus, ANP promotes natriuresis and accompanying diuresis. 18 © MWU 2024, J. Vallejo-Elias Blood What is Antidiuretic Pressure and Volume Hormone (ADH) or Vasopressin? Origin: Released from the posterior pituitary when plasma osmolality increases or plasma volume decreases. or ADH Targets: Binds to V1 and V2 receptors Signaling via V2 receptors in the kidney primarily increases water permeability of the principal cells of the late distal tubule and collecting duct via insertion of aquaporins (AQP2) into apical membranes (see next slide). Function: Most important hormone regulating water balance. ADH has a small effect on NaCl excretion. Also called vasopressin for its powerful vasoconstricting properties via V1 receptors. 19 © MWU 2024, J. Vallejo-Elias Regulation of Water Reabsorption by ADH Refer to Lecture 27, pages 3-6 Insertion of AQP2 channels 20 © MWU 2024, J. Vallejo-Elias How is Antidiuretic Hormone (ADH) regulated? Changes in blood osmolarity (tonicity): Hypothalamic osmoreceptors are very sensitive to small changes in [plasma]osm (1%). Changes in blood volume: Hypovolemia stimulates ADH secretion (5-10% change in volume via arterial and left atrial baroreceptors). This represents an adaptive response to hemorrhage In the kidney, ADH: ↑ permeability of the CD to water ↑ Na+-K+-2Cl- cotransporter in the LOH (↑ cortico-medullary gradient) ↑ permeability of inner medullary CD to urea 21 © MWU 2024, J. Vallejo-Elias Summary of Antidiuretic Hormone (ADH)/ Vasopressin Regulation Increase ADH Secretion Decrease ADH Secretion ↑ Plasma osmolarity ↓ Plasma osmolarity ↓ ECF volume ↑ ECF volume ↑ Plasma angiotensin II ↑ Plasma atrial natriuretic peptide (ANP) Hemorrhage Drugs: Drugs: Nicotine Alcohol The major action of ADH on kidneys is to increase H2O permeability by incorporation of aquaporins in the late distal tubule and collecting duct. H2O is reabsorbed from the late distal tubule and collecting ducts until the osmolarity of tubular fluid equals that of the surrounding interstitial fluid. The urine will have a maximum osmotic concentration as that in the medullary interstitial fluid (final urine concentration equals that at the tip or bend of the loop of Henle). 22 © MWU 2024, J. Vallejo-Elias Normally, Volume and Concentration are Adjusted Simultaneously by RAAS and ADH…. Plasma volume Plasma osmolality Sympathetic Brain ADH Activity Thirst Renal Water Renin Conservation Secretion Drinking Water Plasma Ang II Osmolality Renal Sodium Aldosterone Plasma volume Conservation 23 © MWU 2024, J. Vallejo-Elias Guyton and Hall. 2006. Textbook of Medical Physiology. 11th ed. Fig. 28-1, page 349. Elsevier Saunders. Sometimes Solutes and Water May Be Adjusted Separately… Water diuresis after ingesting 1 liter of water. Note the excretion of a large volume of dilute urine. However, the total amount of solute excretion remains relatively constant. 24 © MWU 2024, J. Vallejo-Elias Clinical Example: Dehydration Hyperosmotic Volume Contraction Plasma Water deprivation/ sweating Osmolarity Clinical presentation: Plasma Thirst ADH High plasma osmolality Decrease urine output Amber-color urine Diuresis (high osmolality) 25 © MWU 2024, J. Vallejo-Elias Clinical Example: Acute Water Load Hypoosmotic Volume Expansion Excess Plasma Free Water Osmolarity Plasma ADH Diuresis 26 © MWU 2024, J. Vallejo-Elias Clinical Examples:Diabetes Insipidus Hyperosmotic Volume Contraction ADH very low or ineffective Neurogenic (Central Diabetes Insipidus): Plasma ADH is low due to hypothalamic-pituitary injury Will respond to exogenous ADH agonists (e.g., desmopressin) Nephrogenic (Nephrogenic Diabetes Insipidus): Kidney is unable to respond to ADH Causes: defect in V2 receptor or elsewhere, atrogenic (e.g., lithium toxicity, hypercalcemia) Clinical presentation: High plasma osmolality Low urine osmolality Polyuria (large volume of dilute urine), Polydipsia (excessive thirst from hypertonic plasma) 27 © MWU 2024, J. Vallejo-Elias Clinical Example: SIADH Syndrome of Inappropriate High ADH Plasma Diuresis ADH Plasma Osmolarity Clinical presentation: Decrease urine output with high osmolarity High ECF Volume (High BP) Low plasma osmolality 28 © MWU 2024, J. Vallejo-Elias Clinical Example: Hyperosmotic Volume Expansion: Na+ Load Posm Plasma Plasma Diuresis Osmolarity ADH 29 © MWU 2024, J. Vallejo-Elias https://www.researchgate.net/figure/Effects-of-antihypertensive-drugs-on-the-renin-angiotensin-aldosterone-system-Pointed_fig1_351556793 Drugs that Target RAAS Angiotensin converting enzyme (ACE) inhibitors are drugs that inhibit the generation of angiotensin II (e.g., Captopril, Benazepril, Ramipril). Angiotensin II receptor blockers (ARBs) are drugs that antagonize the AT1R (e.g., Losartan, Candesartan, Irbesartan) Directly inhibits Na+ reabsorption Decrease aldosterone secretion Aldosterone antagonists ARBs) are drugs that antagonize the aldosterone receptor. (e.g., Spironolactone, Eplerenone) Beta-blockers are drugs that reduce renin release (e.g., Propanolol, Atenolol) Diuretics are known as water pills (e.g., Thiazide diuretics, loop diuretics like Furosemide) 30 © MWU 2024, J. Vallejo-Elias The Biology of Vasopressin Biomedicines 2021, 9(1), 89 31 © MWU 2024, J. Vallejo-Elias Summary of Hormones That Regulate Tubular Na+ and Water Reabsorption Cellular Hormone Site of Action Mechanisms Effects Angiotensin II Proximal tubule Luminal (apical) Na+ -H+ exchanger ↑ Na+ and H2O reabsorption, ↑ K+ secretion in proximal tubule Hypothalamus ↑ ADH release ↑ H2O reabsorption in the principal cells of the late distal tubule and collecting duct Aldosterone Late distal tubule and collecting ↑ insertion of luminal epithelial Na+ ↑ Na+ reabsorption and ↑ K+ secretion duct (Principal cells) channels (ENaC) and basolateral (H2O reabsorption follows Na+ Na+-K+-ATPase. reabsorption in the presence of ADH) Antidiuretic hormone (ADH) Late distal tubule and collecting Water channels ↑ H2O reabsorption in late distal tubule duct (Principal cells) (AQP-2) and collecting duct Atrial natriuretic peptide (ANP) Late distal tubule and collecting ↓ Renin secretion ↓ Na+ reabsorption and K+ secretion in duct (Principal cells) ↓ Angiotensin II secretion late distal tubule and collecting duct ↓ Aldosterone secretion Hypothalamus ↓ ADH secretion ↓ H2O reabsorption in late distal tubule and collecting duct 32 © MWU 2024, J. Vallejo-Elias Summary Blood volume is regulated hormonally by the renin-angiotensin-aldosterone system (RAAS). Aldosterone regulates renal Na+ reabsorption. Plasma osmolarity, in contrast, is regulated by the antidiuretic hormone (ADH). ADH is also released in response to low-volume states. Aldosterone stimulates sodium reabsorption by collecting ducts. Sodium reabsorption is accompanied by K+ secretion. In principal cells of collecting ducts, aldosterone upregulates activity of apical ENaC proteins, apical K+ channels, Na+-K+-ATPase activity, and H+-ATPase activity. Aldosterone release from the adrenal cortex is controlled by plasma angiotensin II (AT II) concentrations. AT II is a powerful pressor, and it stimulates the NHE Na+/H+ antiport and the medullary thirst centers in addition to aldosterone release. Angiotensin II is formed from angiotensin I by angiotensin converting enzymes in the lung. Angiotensin I is formed from angiotensinogen by the enzyme renin. Renin is released from granular cells located in the afferent arterioles. Renin release is regulated by three inputs. First, low pressures in the afferent arterioles stimulate renin release. Second, low flows through nephrons as detected by macula densa will also stimulate renin release. Finally, sympathetic stimulation of receptors on granular cells will cause release of renin. The atrial natriuretic peptide (ANP) is released from atria in high blood pressure states. It acts in opposition to the RAAS in several ways. ANP increases GFR and decreases sodium reabsorption by the nephron. The antidiuretic hormone (ADH) enhances water reabsorption by principal cells. ADH is released from the posterior pituitary in response to hyperosmolarity or decreases in blood volume (> 5%). RAAS and the ADH hormonal control systems can work together or separately to maintain ECF volume.