Physiology of osmo- and volume regulation, LOs #78 & #79 Gyöngyi Karcsúné Kis, MSc, PhD 2 nd March 2018 Characteristic Osmoregulation Volume regulation What is being sensed Plasma osmolality Effective circulating volume Sensors Effectors What is affected Hypothalamic osmoreceptors ADH Thirst Water excretion Water intake (via thirst) Share efferents, synergist reactions! Carotid sinus Afferent arteriole Atria Renin-angiotensinaldosterone system Sympathetic nervous system Natriuretic peptides (ANP, urodilatin) Pressure natriuresis Urinary sodium excretion 1
Fluid contents Intracellular fluid accounts for about 67%. Extracellular fluid accounts for the rest. There are different types of extracellular fluid: Interstitial fluid (26%) Blood plasma (7%) Cerebrospinal fluid in the brain (approximately 1%) Homeostasis Plasma osmotic concentration (number of particles contained in 1 liter of water) Clinical labs: glucose, urea and Na + are measured Normal: 280-29 mosm/kg water Glucose & urea < 10 mosmol/kg water sodium is the primary determinant of osmolality Sodium balance is the critical determinant of fluid compartment size (extracellular volume) Osmol(ality) gap Water balance alteration manifests in plasma osmolality change measured as plasma sodium concentration change (reflects ratio of solute and water) 2
#Osmoregulation to maintain water balance; to compensate for water loss, avoid excess water gain, and maintain the proper osmotic concentration (osmolarity) of the body fluids 55-60 %, new-born: 75 %, elderly: 45 % Involves multiple body-to-brain signalling mechanisms reporting the status of total body fluids and of the distribution of fluids in the body a brain neural network (the visceral neuraxis) which receives and integrates body fluidrelated input reflex (autonomic and endocrine) and behavioural (thirst- and sodium appetite-related behaviours) mechanisms that are controlled and activated by the visceral neuraxis Fluid balance fast H 2 O change (NaCl-balance regulation is due to volume regulation) Fluid balance Water intake 2.2-3.5 l/day excretion 2.2-3.5 l/day food: 1l, drink: 1-2 l evaporation: 0.8-1 l, sweating: 0.2 l, (individuals!) faeces: 0.2 l, urine: 0.5 (min.)-2 l Regulation through urine content and concentration (ADH) + thirst (drink) Key role: hypothalamus Stimulus: plasma osmolarity and volume 3
Osmoreceptors 1. ET, EET,NO Kidney macula densa cells ET Osmoreceptors 2. Anterior hypothalamus (circumventricular organs that lack BBB; OVLT and SFO, MnPO ) osmosensory transduction Role of cell volume: ion channels underlying osmoreception (?) their activity appears to be inhibited by membrane stretch, reduces cation conductance, relaxation (shrinkage) depolarization Kidney International 2012 82, 1051-1053DOI: (10.1038/ki.2012.271) 4
Potential role of TRPVs Properties (as a putative transduction channel of osmoreceptor neurons): activated by cell shrinkage directly mechanosensitive ion permeability characteristic of a non-selective cation channel be inhibited by pharmacological inhibitors Why TRPV? hypertonicity-induced responses of osmoreceptors can be blocked by ruthenium red, a broad-spectrum antagonist of TRPV channels TRPV1,TRPV2 and TRPV4 are osmosensitive channels δn-trpv1: transfected cells response hypertonicity and heating Sharif-Naeiniet al., 2008 Kidney International 2012 82, 1051-1053DOI: (10.1038/ki.2012.271) ADH release Osmolarity Volume AVP gene products Point mutationshereditary hypothalamic diabetes insipidus AP Depolarization Ca 2+ exocytosis 5
ADH acting mechanisms Nedd4, long-term effect Sauter et al., 2006 Cheng et al., J Mol Endocr, 2009 A) Water reabsorption - ADH 6
B) Urea recycling Increased medullary blood flow Medullary blood flow is <10% of total renal blood flow (RBF) washout of the cortico-medullary osmotic gradient impaired urinary concentrating ability sustained decrease ischaemia, tissue (papillary) necrosis, scarring and chronic kidney injury Compensatory mechanisms: governed upstream by renal arterial pressure DVR pericytes? (Kennedy-Lydon et al., 2013) 7
Osmotic vs. free water clearance To assess renal H 2 O handling C H2 O= solute free Total urine V=water (C osm )solute-containing isosmotic with plasma + C H2 O C H2 O= V-C osm C osm =U*V/P V > C osm C H2 O positive V = C osm C H2 O zero V < C osm C H2 O negative (! concentrated urine) Coffe & alcohol ADH release via decreased Ca 2+ conductivity of neurosecretory cells 8
THIRST (craving for fluid) Osmoreceptors Lateral hypothalamus Efferent pathways Brain stem Spinal cord Drinking SUMMARY DEPRIVE OF H 2 O Plasma osmolarity Osmoreceptors in hypothalamus Thirst ADH secretion - posterior pituitary Water drinking H 2 O permeability of principal cells (late distal tubule and collecting duct) H 2 O reabsorption Urine osmolarity and urine volume PLASMA OSMOLARITY TOWARD NORMAL 9
#Volume regulation Hypovolemic thirst Main purpose: maintain ECF volume EC volume proportional to NaCl content Plasma volume decreases >10 % volume regulation is dominant Sodium consumption Daily uptake Daily excretion Filtration: 150 l/day; 140 mmol/l Na + 21 000 mmol/day Excreted: 1 to 50 mmol/day isoosmotic hypervolaemia: NaCl intake results in plasma volume increase because of the rapid compensatory mechanism of osmoregulation 10
Volume sensors Baroreceptors: High pressure BRs: Sinus caroticus n. glossopharyngeus Aortic arch n. vagus Low pressure BRs Atria (veins & aa. pulmonares) BRs Diffuse baroreceptors circumscribed baroreceptors distributionof the baro-receptors De Castro, 1926 (Cajal s disciple) baroreceptor fine terminals 11
The arterial baroreflex sympathoinhibitory pathway Benarroch, Neurology, 2008 Effector - GFR Effective filtration pressure GFR Na + excretion Plasma volume (minor importance) 12
Effector - RAAS 13
Effector - RAAS Angiotensins 14
Aldosteron Aldosterone-induced Na + retention & K + excretion Antagonists: spironolactone, eplerenone 15
Atrial natriuretic peptide ANP & co-workers Atrial natriuretic peptide, also known as ANP alternative form in kidney: urodilatin Brain natriuretic peptide, also known as BNP C-type natriuretic peptide, also known as CNP Atrial natriuretic peptide Potter et al., Handb ExpPharmacol., 2009 Structure of the human natriuretic peptides. 16
Receptors for natriuretic peptides half-life of ANP in humans is approximately 2 min; elimination: neutral endopeptidase (neprilysin, NEP), binding to the natriuretic peptide clearance receptor (NPR-C) receptor-mediated internalization and degradation Massimo Volpe et al. Clin. Sci. 2016;130:57-77 Actions of NPs Increased GFR by inducing vasodilatation of afferent arterioles and vasoconstriction of efferent arterioles Kidney Induction of natriuresis by inhibiting Na +, H + exchanger in the proximal tubule, Na +, Cl cotransporter in the distal tubule and Na + channels in the collecting duct Induction of diuresis due to inhibition of AVP-induced acquaporin-2 incorporation into collecting ducts' apical membrane Cardiac Haemodynamic Endocrine Reduction in preload leading to fall in cardiac output Inhibition of cardiac remodelling Vasorelaxation Elevating capillary hydraulic conductivity Decreased cardiac preload and afterload Suppression of the following: - Renin Ang aldosterone axis - Sympathetic outflow - AVP - Endothelin 17
Escape phenomenon Na + intake Na + excretion + E.C. volume increase Aldosterone temporary decrease in Na + excretion (Na + escapes) E.C. still high 2 processes: Pressure natriuresis Decreased proximal sodium resorption primary hyperaldosteronism does not cause oedema Prostaglandins (PGE 2, PGI 2 ) in kidney Feed back Blood vessel dilatation Inhibition of TAL NaCl reabsorption Inhibition of ADH effect in collecting duct Urea-exit Water reabsorption Vasa recta blood flow Medullary gradient Kidney dilutes 18
Overvie w Overview 19
Osmo- and volumeregulation > 10 % in volumevolume reulation is dominant 20