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19/04/2013 Pathophysiology: Regulation of Water Intake and Excretion, Ghent 03/2013 Université de Montréal Groupe des Protéines Membranaires; Service de néphrologie, Hôpital du SacréCœur de Montréal Daniel G. Bichet, M.D. Outline: Regulation of water intake and excretion • Cellular dehydration to perceive thirst and release arginine-vasopressin (AVP), the antidiuretic hormone • Volume regulation including Angiotensin II osmoregulatory gain • Unregulated AVP release by tumors or infections • Concentration and dilution of the urine 1 19/04/2013 Increased blood-oxygen-level-dependent (BOLD) signal under conditions in which thirst was stimulated in a healthy human by infusion of hypertonic saline anterior cingulate cortex (ACC; left-hand arrow) and in the area of the lamina terminalis (right-hand arrow) Mammals are Osmoregulators: They have Evolved Mechanisms that Maintain Extracellular fluid Osmolality near a Stable Value • sagittal section of midline of ventral brain around the 3rd ventricle in mice • subfornical organ (SFO) • median preoptic nucleus (MnPO) • lamina terminalis (OVLT) Cellular dehydration ,that is, cell shrinking, is required for thirst and Vasopressin release 2 19/04/2013 Deconstruction of a neural circuits for thirst and vasopressin secretion…Osmoregulatory circuits in the mammalian brain and the periphery ACC, anterior cingulate cortex NTS, nucleus tractus solitarius INS,insula PBN, parabrachial nucleus Charles Bourque, Nature Reviews, Neuroscience,July, 2008 Anterior Cingulate Cortex: involved in rational decision making Virginia Hughes; Stress: The roots of resilience Nature 490, 165-167, 11 october 2012 3 19/04/2013 The act of drinking by the thirsty person is pleasurable, Chapter 35 Thirst MICHAEL J. MCKINLEYT Mammals Strive to Maintain a constant Osmolality, yet Values Fluctuate around a Set Point: • 40 minutes of strenuous exercise in the heat , or 24 hours of water deprivation, causes plasma osmolality to rise by more than 10 mosmol kg–1. • In a dehydrated individual, drinking the equivalent of two large glasses of water (~850 ml) lowers osmolality by approximately 6 mosmol kg–1 within 30 minutes . • Ingestion of 13 g of salt increases plasma osmolality by approximately 5 mosmol kg–1 within 30 minutes . 4 19/04/2013 Cationic channels inactivated by stretch, TRPVs (Transient Receptor Potential Vanilloid channels), are the osmoreceptors of the anterior hypothalamus : thirst and magnocellular neurons. Hyperosmotic stimuli depolarize these cells via the activation of nonselective cation channels (NSCCs) Hypoosmolality causes hyperpolarization by inhibiting NSCCs Osmosensation in vasopressin neurons: Prager-Khoutorsky M, Bourque CW.Trends Neurosci. 2010 Feb;33(2):76-83. Angiotensin II is inducing an osmoregulatory gain. This helps restoration of volume and blood pressure maintenance. 5 19/04/2013 Set-points and slopes of vasopressin secretion are changed by effective arterial blood volume perceptions a r a r osmolality Arterial and venous blood volume perception 6 19/04/2013 Determinants of Vasopressin Secretion B 5 1000 Increase in Plasma Arginine-Vasopressin (pg/mL) Plasma Arginine-Vasopressin (pg/mL) A 4 100 3 10 2 1 Detection Limit 120 125 130 1 0 135 140 Plasma Sodium (mEq/L) 145 10 20 30 40 50 60 % Fall in Mean Arterial Blood Pressure Hypertonicity sensing requires cell shrinking A, Time course of normalized volume changes (nVol, relative to baseline) observed in three isolated mouse OVLT neurons exposed to a 60 min hyperosmotic stimulus (+40 mosmol/kg; excess mannitol) B, Steady-state values of nVol observed in different isolated OVLT neurons exposed to various external osmolalities (n = 19). Sorana Ciura1, Wolfgang Liedtke2, and Charles W. Bourque1The Journal of Neuroscience, 12 October 2011, 31(41): 14669-14676; 7 19/04/2013 Hepatic Osmoreceptors Require TRPV4 for Normal Function The Molecular and Cellular Identity of Peripheral Osmoreceptors:Lechner S.G. et al.Neuron: 69; 332-344, 2011. Defective Osmoregulation of Trpv1-/and Trpv4-/- mice. Neuron: 69; 332-344, 2011. 8 19/04/2013 Taste receptors in the mouth, more than just the basic five but no taste for water Michael Eisenstein ; More than meets the mouth, Nature, 468, 23/30 dec 2010, Trivedi B.P.;The finer points of taste, Nature 21 june 2012 Model of urine concentration 9 19/04/2013 Separation of salt and water in the thick ascending loop of Henle 10 19/04/2013 Vasopressin makes the cortical and medullary collecting ducts permeable to water Bichet DG.Clin J Am Soc Nephrol. 2012 May;7(5):700-3 Molar mass of urea CO(NH2)2 = 60g/mol Molecular weight calculation ; 12.0107 + 15.9994 + (14.0067 + 1.00794x2)2 60g of urea = 1000 mmol 30g of urea = 500 mmol “Medicinal urea” 30 g × 1 month will be less than $1.00: urea 10, NaHCO3 2g Citric Acid 1.5g, sucrose 200 mg 11 19/04/2013 60g of urea=1000 mmol: forcing water excretion , however, bitter taste and necessity to absorb with additional fluid Daily Intake (Solute + Water) Urinary Osmolality (mOsm/kg) Urine Volume (Liter/day) Water Balance (Liter/day) Normal 500 mmol of solute + 2 liters of water 250 2 liters 0 SIADH 500 mmol of solute + 2 liters of water 500 1 liter (500/500) +1 2. 500 mmol of solute + 500 mmol of urea + 2 liters of water 500 2 liters (1000/500) 0 Editorial,What Is the Role of Vaptans in Routine Clinical Nephrology? Daniel G. Bichet Clin J Am Soc Nephrol 7: 700–703, 2012. What did we learn? • Thirst and cellular dehydration • Vasopressin secretion and cellular dehydration • TRPV1 channels centrally and TRPV4 in the periphery mediating the effects of cellular dehydration • Diluting segment of the nephron: thick ascending loop of Henle • Action of vasopressin on principal cells of the collecting duct. 12