physiology-1b-final-notes_removed.pdf

lOMoARcPSD|8900360 KIDNEY AND BODY FLUIDS Proximal tubule solutes PAH Used to measure effective renal plasma flow S1: PAH and inulin superimposed, only water absorption occurring here,  concentration Undergoes secretion from S2 segment of proximal tubule and conc rises much faster Inulin Concentr...

lOMoARcPSD|8900360 KIDNEY AND BODY FLUIDS Proximal tubule solutes PAH Used to measure effective renal plasma flow S1: PAH and inulin superimposed, only water absorption occurring here,  concentration Undergoes secretion from S2 segment of proximal tubule and conc rises much faster Inulin Concentration increase throughout the tubule Inulin is freely filtered but not reabsorbed or secreted (same amount remains) As conc is x3, it’s in 1/3 of the volume 2/3 of water is reabsorbed in the tubule Cl Increases in conc early on (S1 section not very permeable to Cl, not being reabsorbed) S2: forms a sufficient concentration gradient, starts being reabsorbed (conc doesn’t rise as it’s being absorbed in proportion to Na) Na+ Concentration stays the same throughout 2/3 of water is reabsorbed (see inulin) Thus reabsorbed 2/3 of sodium as well OSM Slight drop throughout Slightly more solute being reabsorbed than water overall HCO3Reabsorbed quite early Amino Concentration drops relative to plasma very acids quickly (solutes are rapidly reabsorbed) Glucose Concentration drops relative to plasma very quickly (solutes are rapidly reabsorbed) - Potential difference: - Comparing inside vs outside lumen In S1: lumen is –ve (reabsorbing Na, which is +ve along with neutral solute) o Taking +ve out of lumen, so becomes –ve Not very large PD (proximal tubule is leaky and can’t sustain big charge difference) +ve in S2 and S3 (Cl- has built up, reabsorbing more Cl than Na) Proximal tubule: 3 segments - S1: early proximal convolution tubule o Greater surface area, more mitochondria and can reabsorb more solutes o Rapid transcellular transport (across apical membrane into the cell and across the basolateral membrane) o Paracellular pathway is leakier (can’t develop step concentration gradients) - S2: remaining cortical proximal tubule o Secretion of organic anions and cations - S3: medullary / straight part of proximal tubule o Slow rates of transcellular reabsorption o Prarcellular pathways are tighter (higher concentration gradients) Segments of the loop of Henle Downloaded by Joseph Ha ([email protected]) lOMoARcPSD|8900360 Water Na & Cl Urea Transport Movemen t Ending osmolality Thin descending limb Very permeable (AQP1) Permeable permeable No active transport Water leaves the lumen (water permeable) Osmolality increases as its higher within the medulla than in tubule For cortical nephrons: increase to 600mosm/kg For juxtamedullary nephrons: increase to 1200mosm/kg Thin ascending limb Impermeable Very permeable Moderately permeable No active transport NaCl leaves passively down conc gradient (higher conc in lumen than medulla) and urea enters Volume stays the same, fluid more dilute since more NaCl leaving than urea entering Decrease to 500mosm/kg Thick ascending limb Impermeable Low permeability Active NaCl transport Reabsorption of HCO3NKCC2 cotransporter (Na, 2Cl, K reabsorbed) Lumen has overall positive PD Highly permeable paracellular pathway to electrolytes For cortical nephrons: decrease to 140mosm/kg For juxtamedullary nephrons: decrease to 200mosm/kg Distal convoluted tubule / connecting tubule - Connecting tubule is more sensitive to some hormones (both have similar functions) - Water impermeable - Low urea permeability - Active NaCl reabsorption o Sodium chloride co-transporter (electroneutral) o Low intracellular Na+ concentration, allowing sodium to be reabsorbed - Tight junctional complexes - Reabsorbs 8-10% of filtered sodium - Osmolality decreases to 100mosm/kg at the end of the tubule Collecting duct - Principal cells (75% in cortical, >90% in medullary and 100% in papillary) o Under light microscopy, they are light in appearance o Responsible for reabsorbing Na and increasing K secretion  In response to aldosterone o ADH allows the cells to reabsorb water - Intercalated cells (25% in cortical, <10% in medullary and none in papillary o Less of these cells as you move down the collecting duct o Under light microscopy, they are dark – lots of mitochondria and ribosomes o  subtype reabsorb K and secrete hydrogen ions o  subtype secrete HCO3- Water permeability: if ADH is not present, collecting tubule is water impermeable o If ADH present, permeable to water (AQP2) - Urea reabsorption o Cortical and medullary are impermeable, only papillary segment is permeable to urea o Stimulated by ADH - When ADH is present, water is reabsorbed and urea becomes more concentrated, at the papillary section urea is reabsorbed Cortical vs juxtamedullary nephrons Downloaded by Joseph Ha ([email protected]) lOMoARcPSD|8900360 - - Cortical nephrons ~ 75% (glomerulus is located in superficial / mid cortex) o Short loop of Henle (turns in between the inner and outer medulla – no thin ascending limb) Juxtamedullary nephrons ~25% (glomerulus is close to the medulla) o Long loop of Henle (thin descending, thin ascending and thick ascending) Urine formation 1. Forming an ultra-filtrate of plasma Small molecular weight fluids cross out of the glomerular capillary into Bowman’s space 2. Modification of the filtrate occurs once the fluid is in the tubule Tubular reabsorption – contents taken out of the tubule and into the peritubular capillary Secretion – plasma in peritubular capillaries has solute that gets secreted into the tubule 3. Urinary excretion if there are any fluids left Freely filtered substance at the glomerulus (e.g. inulin) - Blood travels in the afferent arteriole and substance is filtered across the glomerulus capillaries to get into the tubule - 80% of plasma becomes filtrate and continues in the efferent arteriole - 20% of the substance is in the tubule  all ends up in urine o Not reabsorbed or secreted throughout the nephron Freely filtered and undergoes partial reabsorption (e.g. vitamin C) - 20% filtered at glomerulus and into tubule o Some is reabsorbed  most is still in urine Freely filtered and totally reabsorbed (e.g. glucose) - All reabsorbed into the efferent arteriole - No substance in urine Freely filtered and totally secreted (e.g. PAH) - 80% in the efferent arteriole reaches the peritubular capillaries and is secreted back into the tubule - All substance is passed out in the urine  no substance left in blood leaving the kidney Changes in afferent/efferent arteriolar tone changes RBF Arteriolar tone – how vasoconstricted the vessel is Renal plasma flow (RPF) = RBF(100 – Hct%)/100 Flow (Q) = P/R (hydrostatic pressure between artery and vein / vascular resistance) - If perfusion pressure is constant: o Constriction of afferent / efferent arteriole   in RBF o Dilation of afferent / efferent arteriole   in RBF - Factors that influence RBF: angiotensin II, adrenaline, noradrenaline, ADH Renin angiotensin system Angiotensinogen (gamma globulin) is produced in liver Renin is proteolytic enzyme produced by the kidney - Splits angiotensinogen into Angiotensin I (not biologically active) - Angiotensin-converting enzyme splits Angiotensin I o Becomes Angiotensin II (biologically active)  Acts on receptors (AT1)  Causes vasoconstriction Downloaded by Joseph Ha ([email protected]) lOMoARcPSD|8900360 Glomerular filtration - As blood flows through the glomerulus, ultra-filtrate of plasma is formed o Ultra-filtrate doesn’t contain proteins or red blood cells - Filtration fraction o Not all the plasma that flows through glomerulus is filtered into Bowman’s space o Filtration fraction = GFR / RPF (16 – 20%) - Glomerular filtration rate (GFR) o Normal GFR in males = 125ml/min = 7.5L/hr = 180L/day o Determined using a substance freely filtered at the glomerulus and not reabsorbed or secreted along the remainder of the tubule (inulin – starch like polymer of fructose)  Amount filtered = GFR x plasma concentration (P)  Amount excreted = Urine concentration (U) x urine flow rate (V)  GFR = U x V/P of inulin = clearance of inulin Renal Plasma Flow (RPF) - The amount of a substance enters the kidney is equal to the amount of substance leaving the kidney (assuming no metabolising, make or storing occurs) - Determined using a substance freely filtered and is totally secreted, concentration in renal venous blood is 0 (para-amino hippuric acid PAH) o Entering = RPF x P, leaving = RPF x P + U x V o RPF = U x V/P of PAH = clearance of PAH Renal Clearance + calculations - Minimal volume of plasma that could have supplied the amount of the substance which was excreted in the urine per unit time o Clearance = U x V / P - Kidney trying to remove and excrete substances from the plasma - Measure of how successful is how much plasma was cleared per unit time - If clearance < GFR, substance undergoes net reabsorption Filtered load: rate of transfer of a substance across the glomerular filtration membrane - Filtered load = plasma concentration x GFR Excretion rate: amount of a substance excreted in the urine per unit time - Excreted = urinary concentration x urine flow rate If filtered < excreted, undergoes net secretion Mechanism of reabsorption (from tubule to blood) - Passive (moves down a concentration gradient and doesn’t need energy, e.g. water, urea) - Active (energy required, moving against a concentration gradient) o Primary – energy is expended to allow reabsorption (ATPase) o Secondary – if 2 or more substances is absorbed, one is moving down concentration gradient and is dragging the carrier along with it  Tubular maximum limited reabsorption: carrier involved with is saturated, definite fixed transport rate which cannot be exceeded e.g. glucose, phosphate  Active gradient-time limited mechanisms: limited by the gradient which can be established across the walls within the interval of time the fluid is in contact with the epithelium e.g. sodium Reabsorption of sodium Transcellular pathway: requires energy expenditure - Sodium potassium ATPase pump on the basolateral membrane, 3 Na out, 2 K in - Intracellular Na conc is low  cross apical membrane, down its concentration gradient Paracellular pathway: doesn’t require energy Downloaded by Joseph Ha ([email protected]) lOMoARcPSD|8900360 - Na moves between cells (reabsorption and back leak occur) Regulation of water balance Thirst and drinking: regulated by specific area in the hypothalamus  cerebral cortex -  plasma osmolality (very sensitive effect) -  blood volume (not as sensitive) - Renin Angiotensin system is a potent dipsogen, angiotensin II stimulates thirst - Dryness of mouth and throat Kidneys excrete excess water as dilute urine: - Taking solute out of the tubule and leaves water behind  function from thin ascending limb of Loop of Henle onwards o Thin aLH, thick aLH and distal convoluted tubule are always water impermeable o If no ADH present, collecting duct also water impermeable Kidneys retain water by producing concentrated urine: - Taking water out of the lumen of the tubule in excess of solute o Need to have high medullary osmolality and ADH present - Medullary interstitial osmolality rises progressively from the outer to inner medulla - When collecting ducts are permeable to water (ADH present), water flows out down osmotic gradient until lumenal osmolality = medullary interstitial osmolality Antidiuretic Hormone (ADH) - Causes a decrease in urine flow rate and vasoconstriction of blood vessels - Produced by nerve cells which have their cell bodies in the supraoptic and paraventricular nuclei of the hypothalamus - Axons terminate in the posterior lobe of the pituitary gland (cleavage occurs) - ADH released into the blood when an action potential travels down the nerve o Stimulated by stressful situations (surgery, anaesthesia, nausea) and Angiotensin II o Inhibited by ANP and drugs including alcohol and narcotic antagonists Osmotic control of ADH - Osmoreceptors located in the lamina terminalis near the hypothalamus o If rise in plasma osmolality is detected, osmoreceptors shrink, action potentials move down the nerves and stimulates release of ADH o If plasma osmolality falls, cells swell and ADH release inhibited (levels undetected) Haemodynamic control of ADH - If blood volume or blood pressure falls, detected by low and high pressure baroreceptors o Increase in ADH Actions of ADH Kidney: controls the permeability of the apical membrane of the principal cells of the collecting duct to water - ADH interacts with V2 receptor on the basolateral membrane - Phosphorylation occurs and Aquaporin-2 channels move to the lumen o Apical membrane is now permeable to water - If no ADH present, AQP-2 channels are withdrawn by endocytosis Cardiovascular: potent vasoconstrictor and increase arterial pressure - Vascular receptor is V1A - Stimulates vagus and slows the heart rate Sodium Balance Sodium intake: ~100 – 400 mmol Na / day average -  Na intake   plasma osmolality  thirst (water intake)  ADH release (retention)   extracellular volume (increase in subjects weight) Downloaded by Joseph Ha ([email protected]) lOMoARcPSD|8900360 Sodium output - Sweat – negligible at rest, but while exercising in hot environments, lose a lot of Na - Urine ~ 100 – 400 mmol/day depending on Extracellular fluid volume Increase the amount of sodium in the diet Plasma sodium levels No change Hormonal control of sodium excretion Urinary sodium excretion Increase Excretion is decreased by: Plasma renin activity Decrease - Renin angiotensin aldosterone system Plasma aldosterone levels Decrease o Increases levels of aldosterone Plasma ADH levels No change o Directly stimulates proximal tubule Plasma ANP levels Increase sodium reabsorption  Both basolateral and lumenal membrane through AT1 transporter o Renal vasoconstriction – decrease medullary blood flow, osmotic gradient enhanced and passive Na reabsorption in the thin ascending loop is enhanced - Aldosterone – steroid hormone produced in zone glomerulosa of the adrenal cortex o Increases Na reabsorption in association with K and H secretion o Acts on the principal cells of the collecting duct and distal convoluted tubule  Across the basolateral membrane and acts on MR receptor, moves into the nucleus and affects the genome  New proteins are made and cause production o epithelial sodium channel (enhances sodium reabsorption, stimulated NaK ATPase)  Increases apical membrane permeability to potassium o Controls reabsorption of 2% of filtered sodium Downloaded by Joseph Ha ([email protected])