Maintenance of Electrolyte and Fluid Balance A.A.J.Rajaratne
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Transcript of Maintenance of Electrolyte and Fluid Balance A.A.J.Rajaratne
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Maintenance of Electrolyte and Fluid
Balance
A.A.J.Rajaratne
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The loop of Henle:
In the loop of Henle about 20% of filtered Na+, Cl-, and K+ are reabsorbed.
Ca++, Mg++, and HCO3- are also
reabsorbed. About 17% of filtered water is
reabsorbed in Henle's loop. Water is reabsorbed from the
descending limb; the ascending limb is impermeable to water.
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The loop of Henle - contd:
1. Transport processes in thick ascending limb.
Na+ enters the TAL epithelial cells across the luminal membrane via the Na/K/2Cl transporter, which transports Cl- and K+ into the cell against their electrochemical potential gradients.
The energy of the Na+ gradient is used for this process.
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There is also a luminal Na/H exchanger, which exports H+ into the lumen and causes reabsorption of HCO3
-.K+, Cl-, and HCO3
- are transported across the basolateral membrane by other transport proteins.
The luminal fluid in the TAL is electrically positive to the extracellular fluid of the basolateral membrane.
This powers the reabsorption of Na+, K+, Ca++, and Mg++, partly via transcellular and partly via paracellular pathways.
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3 Na+
2 K+Na+
2Cl-
K+
Transport processes in the thick ascending limb
K+
H+
Na+
K+
Cl-
H2O+CO2H2CO3
H+ + HCO3 HCO3-
+
K+, Ca2+, Na+, Mg2+
C
A
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Significant absorption of solute occurs in the TAL, but water cannot follow due to the impermeability of the TAL to water.
Thus the osmolarity of TAL fluid falls below isotonicity, reaching less than 150 milliosmolar.
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The extrusion of Na+ and Cl- by the TAL contributes to an osmotic gradient in the medullary interstitium.
The osmotic pressure is highest near the renal papillae and lowest near the corticomedullary junction.
Since the descending limb is permeable to water (the ascending limb is not), water is reabsorbed from the descending limb as it descends through the osmotic gradient.
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The distal tubule and the collecting tubule
Reabsorb about 10% of filtered Na+ and Cl-
Secrete K+ and H+.
Reabsorb a variable amount of water.
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The first part of the distal tubule reabsorbs Na+, Cl-. and Ca2+.
Since this segment of the distal tubule is impermeable to water, the luminal fluid becomes still more dilute, approaching 100 mOsm.
The luminal membrane has electrogenic Na+ channels (blocked by amiloride and triamterine diuretics) and a coupled Na+/Cl- transporter (blocked by thiazide diuretics).
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3 Na+
2 K+
Cl-
H2O
Na+
Cl-
Na+
Thiazides
Amiloride
Transport mechanisms in Distal Tubule
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Last part of distal tubule and collecting tubule:
Contain two types of epithelial cells: 1. Principal cells 2. Intercalated cells
a. Principal cells in the last part of the distal tubule and in the cortical collecting tubule reabsorb Na+, Cl-, and water and usually secrete K+.
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3 Na+
2 K+
K+
Na+
K+
Transport processes in Principal Cells
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Intercalated cells Secrete H+ and reabsorb K+ and HCO3
-.
The H+ and HCO3- is derived from
CO2 produced by cellular metabolism. Carbonic anhydrase catalyzes formation of carbonic acid which dissociates into H+ and HCO3. H+ is extruded across the luminal membrane by an H+-ATPase. HCO3
- is absorbed into the blood across the basolateral membrane.
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2 K+
3 Na+
H+
HCO3-
Cl-
Transport mechanisms in the Intercalated cells
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Collecting ducts have two portions,1. Cortical portion2. Medullary portion
The water permeability is increased by antidiuretic hormone (ADH), also known as vasopressin. ADH from the posterior pituitary increases the permeability to H2O by causing the rapid insertion of aquaporin-2 water channels to the luminal surface of principal cells. When vasopressin is absent, the collecting duct epithelium is relatively impermeable to water.
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Control of ECF Control of ECF osmolality and osmolality and
volumevolume
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MAIN DIFFERENCES BETWEEN ICF AND ECF
• More Na+ in ECF
• More K+ in ICF
• More Cl- in ECF
• More PO4, HCO3, and Pr- in ICF
These differences are maintained by transport processes in the cell membrane
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Na+ K+
Total intracellular 9.0 89.6
Total extracellular 91.0 10.4
Plasma 11.2 0.4
Interstitial fluid 29.0 1.0
Connective tissue 11.7 0.4
Bone 36.5 7.6
Transcellular 2.6 1.0
Distribution of Na+ and K+ in the body
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ECF volume
20% of body weight
14 L (in a 70 kg man)
3.5 L plasma; 10.5 L interstitial fluid
Measured by using inulin, mannitol or sucrose
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Osmolar concentration of plasma:
290 mosm/L - 142 mEq/L
0.9% saline is isotonic
270 mosm/L is contributed by Na+, Cl- and HCO3
-
Plasma proteins contribute less than 2 mosm/L (28 mm Hg oncotic pressure)
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Ranges of salt and water intake and excretion:
a. Salt intake from 50 mg to 25 g/day
b. Water excretion from 400 ml to 25 l/day
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Total body sodium is relatively constant.
Freely filtered
Reabsorbed but not secreted
Therefore,
Na+ excretion = Na+ filtered – Na+ reabsorbed
= (GFR X PNa) - Na+ reabsorbed
PNa is relatively constant
Therefore control is exerted by
GFR
Na+ reabsorption
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Sensors:
1. Extrarenal baroreceptorsCarotid sinusesArteriesGreat veinsAtria
2. Renal juxtaglomerular apparatus
Efferents:1. Renal sympathetic nerves2. Macula densa renin
angiotensin II aldosterone
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Control of GFR:
1.Angiotensin II efferent arteriolar constriction PGC
2.Renal sympathetic nerves Na+ adrenergic receptors Constriction of afferent and efferent arterioles PGC
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Osmoreceptor -Osmoreceptor -ADH mechanismsADH mechanisms
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Renal handling of NaCl and water:
NaCl & H2O are freely filterable at the glomerulus.
There is extensive tubular reabsorption but no tubular secretion.
Na+ reabsorption is driven by the basolateral Na+/K+-ATPase and is responsible for the major energy expenditure in kidney.
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H2O permeability of the late DT:Water permeability of distal tubule
and initial collecting tubule, is also extremely low.
However under the influence of ADH it becomes highly water permeable.
Further removal of solute in the EARLY DT presents the LATE DT with markedly hypotonic urine containing even less Na+
Removal of Na+ continues in the LDT and collecting system, so that the final urine may contain virtually no Na+.
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Anti-diuretic hormone:
ADH (antidiuretic hormone), vasopressin or arginine vasopressin (AVP) is the major regulator of urine osmolality and urine volume.
ADH is a nonapeptide produced by neurons in the supraoptic and paraventricular nuclei of the hypothalamus.
The axon terminals of these neurons reside in the posterior pituitary.
ADH is stored in these axon terminals.
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When ADH is released from the posterior pituitary it causes the kidney to produce urine that is high in osmolality and low in volume.
In the absence of ADH the kidney tends to produce a large volume of urine with low osmolality.
Total solute excretion is relatively constant over a wide range of urine flow rates and osmolalities.
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Control of ADH release:
1. Increased osmolality of ECF is a powerful stimulus for ADH release: a 1% change in osmolality induces significant increase in ADH release.Hypothalamic supra-optic and paraventricular nuclei respond to increased osmolality of ECF by producing ADH.As a result of this high sensitivity, responses to increased osmolality occur rapidly.
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Control of ADH release:
2. Volume: In a volume-depleted individual, the release of ADH is more sensitive to increased osmolality.
In a volume-expanded state, ADH release is less sensitive to increases in osmolality.
3. Decreased blood pressure or blood volume also enhance ADH release, but not with such high sensitivity: 5 to 10% changes are required to alter ADH secretion.
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Effects of ADH on the kidney:
ADH increases the water permeability of the epithelial cells of late distal tubules and the collecting tubules
May also increase NaCl absorption in the thick ascending limb of the loop of Henle.
ADH also increases the urea permeability of the inner medullary collecting tubules.
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Action of ADH:
Binds to receptors in the basolateral membrane, causing increased cAMP.
This results in rapid insertion of aquaporin-2 protein channels into the luminal membrane of principal cells.
The water channel proteins are present in preformed intracellular vesicles, so this up regulation of water permeability can occur quickly.
The water channels can be rapidly re-internalized when ADH is no longer present.
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Aquaporin-2
H2O
3 Na+
2 K+
ADH
Adenyl cyclasecAMP
Effect of ADH on collecting tubule cells
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Summary:
osmolality
Stimulation of osmoreceptors in anterior hypothalamus
Supraoptic & paraventricular Nuclei
Posterior pituitary ADH
permeability of LDT, CCD, MCD to H2O
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Summary of handling of Na+ by the kidney
Glomerular filtrate
26 000 mEq/Day
PCT 65% Active transport
Thick ascending loop
27% Active transport
LDCT 8% Aldosterone
Cortical collecting duct
Aldosterone
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Thirst (conscious desire for water):
Under hypothalamic osmoreceptor control
Water intake is regulated by- increased plasma
osmolality- decreased ECF volume- psychological factors
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Stimulus:
Intracellular dehydration due to increased osmolar concentration of ECF
Excessive K+ loss Low intracellular K+ in osmoreceptors
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Mechanism is activated by
The arterial baroreceptor reflex BP
The volume receptors - low pressure receptors in atria; CVP
Angiotensin II
Increased Na+ in CSF
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Hyp
Hypertonicity
Osmoreceptors
Hypovolaemia
BaroreceptorsAngiotensin II
Thirst
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Other factors regulating water intake:
Psycho-social
Dryness of pharyngeal mucous membrane
? Gastrointestinal pharyngeal metering
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Renin-angiotensin Renin-angiotensin –aldosterone –aldosterone
systemsystem
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Renin:
Produced by
Juxtaglomerular cells – located in media of afferent arterioles
Lacis cells – junction between afferent and efferent arterioles
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Factors affecting renin secretion:Stimulatory
Increased sympathetic activity via renal nervesIncreased circulating catecholaminesProstaglandins
InhibitoryIncreased Na+ and Cl- reabsorption in macula densaAngiotensin IIVasopressin
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Renin
Angiotensinogen Angiotensin I
Angiotensin-converting enzyme
Angiotensin I Angiotensin II
Adrenal cortex Aldosterone
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Actions of angiotensin II
Arteriolar vasoconstriction and rise in SBP and DBP
On adrenal cortex to produce aldosterone
Facilitates release of noradrenaline
Contraction of mesangeal cells - GFR
Brain - sensitivity of baroreflex
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Actions of aldosterone:
Increased reabsorption of Na+ from urine, sweat, saliva and GIT – ECF volume expansion
Kidney Principal cells – increased amounts of Na+ are exchanged for K+ and H+
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Salt appetiteSalt appetite
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ECF Na+
Blood volume
Hypothalamic centers
Salt appetite
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Potassium Potassium excretionexcretion
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Renal handling of K+:
800 mEq/day enter the filtrate
100 mEq/day is secreted
PCT – reabsorption
DCT and CD – both reabsorption and secretion
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Secretion is mainly by the Principal cells
3 Na+
2 K+
Na+
K+
Aldosterone
ENaC
Nucleus
ENaC = epithelial sodium channels
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Control by Principal cells
1. Na:K pump
2. Electrical gradient from blood to lumen
3. Permeability of luminal cell membrane to K+
Stimulation Inhibition
ECF K+ Acidosis
Aldosterone
Urine flow rate
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How the kidney How the kidney makes makes
concentrated and concentrated and dilute urinedilute urine
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There is a gradient in osmolality in the medullary interstitium.
Cortico-medullary junction 300 mOsM.
Renal papilla 1200 mOsM in presence of ADH.
About half of this is due to NaCl and the other half to urea.
The vasa recta function as countercurrent exchangers, so that the blood flow does not wash out the gradients of NaCl and urea.
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Effect of ADH:
In the presence of ADH, the collecting tubule is highly permeable to water.
As fluid in the collecting tubule descends through the medullary gradient, water is extracted, producing a low volume of urine that is high in osmolality (up to 1200 mOsM).
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In the absence of ADH a large volume of dilute urine leaving the DCT (about 100 mOsM).
In the absence of ADH, the collecting tubule is highly impermeable to water. The dilute fluid does not lose water as it descends through the medullary interstitium.
Thus, volume does not decrease, nor does solute concentration increase, and a high volume of dilute urine is produced.
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The Medullary Countercurrent System:
The maximal concentration of urine produced ~ 1200-1400 mosmol/l.
Urea, sulphate, phosphate and other waste ~ 600 mosmol/day obligatory water loss ~ (600 mosmol/day)/(1300 mosmol/l) ~ 0.46 l/day.
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The countercurrent multiplier effect of the loop of Henle relies on the following:
1. ALH is not homogeneous, structurally or functionally
a. very thin from the bend until the outer medulla where the thick limb begins.
b. remains very impermeable to water over the entire length.
c. thick ALH actively transports NaCl. Relatively permeable to NaCl
Maximum transluminal gradient ~ 200 mosmol/l
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Countercurrent multiplier effect relies on :
2. DLH (late PCT not included) a. does not actively transport Na + or Cl -
b. is highly permeable to water over its entire length
c. is relatively impermeable to ions
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Countercurrent multiplier in loop of Henle
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At each horizontal level, the medullary interstitium is concentrated by transport of solute from ALH.
As the DLH is freely water permeable, water passively leaves the tubule concentrating the luminal contents.
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These two processes proceed at each horizontal level so that the final concentration of solute deep in the medullary interstitium is ~ 1200-1400 mosmol/l.
The gradient at each horizontal level across the ALH remains at only 200 mosmol/l.
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Role of the vasa recta:
Form a countercurrent exchange system, having descending and ascending branches running in close proximity to the loop and each other.
Countercurrent exchange in the vasa recta prevents washout of too much NaCl and urea.
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Role of the vasa recta:
As blood descends in the vasa recta, NaCl and urea enter the blood.
As blood rises in the ascending limbs of the vasa recta, NaCl and urea diffuse out of the blood and back into the interstitium and the osmolality decreases to about 350 mOsM.
Thus blood perfuses the medulla (flow is low), but relatively small amounts of NaCl and urea are removed from the medulla by the blood.
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1. In the PT ~ 65% of filtered NaCl and water are reabsorbed but the urine remains iso-osmotic.
2. In the loop, water is reabsorbed from the DLH but a greater amount of NaCl is removed from the ALH, so that hypo-osmotic fluid enters the DT.
3. The early DT is always impermeable to water, therefore further dilutes the urine. This, with the ALH are referred to as "diluting segments”.
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4. from the late DT, plasma ADH determines water permeability of the tubule.
i. low [ADH] Little water reabsorbed, therefore these segments production of large volume of dilute urine.
ii. high [ADH] By the end of the cortical CT's
the urine is again iso-osmotic, and is further concentrated through the medulla to 1400 mosmol/l (containing ~ no NaCl)
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5. Although NaCl in the medullary interstitium is essential for the concentrating ability of the kidney, the final urine may contain virtually none, the excreted solute being urea, creatinine, urate, K+, etc.
6. The excretion of large quantities of Na+ is always accompanied by the excretion of large amounts of water.
7.However, the excretion of large amounts of water does not necessitate the excretion of Na+, decreased [ADH]pl not significantly altering Na+ transport.
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H2O + NaCl
H2O
H2O
H2O
H2O
H2O
H2O + NaCl
H2O + NaCl
H2O + NaCl
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H2O
H2O
H2O
H2O
H2O+NaCl
H2O+NaCl
NaClNaCl
NaCl
NaCl
NaCl
NaCl
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ADH also needed to concentrate urine: how does it work?•Antidiuretic Hormone (ADH)/Arginine Vasopressin (AVP)
•Increases permeability of collecting ducts to H2O by inserting H2O channels (Aquaporins).
•Helps to make small amount of concentrated urine.
•Reabsorption of H2O increase urea conc. in tubule, increasing its recycling effect.•ADH allows rapid, graded control of urine conc. – v. sensitive.•ADH released in response to plasma osmolality and ECF volume – osmoreceptors and baroreceptors.
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ADH (aka AVP)
Increased plasma osmolality stimulates osmoreceptors in the hypothalamus that trigger the release of ADH, which inhibits water excretion.
Increased osmolality stimulates a second group of osmoreceptors that trigger thirst, which promotes water intake.
Other factors also trigger ADH release e.g. decreased effective circulating volume, decreased BP, pregnancy, pain, morphine, nausea, congestive heart failure (CHF) (due to reduced ECV).
CHF may cause such retention of H2O = hyponatremia.
Hyperaldosteronism = hypernatremia. Due to chronic volume expansion, where osmoreceptors become less sensitive to ADH, reducing ADH inappropriately.
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Renin-angiotensin-aldosterone axis
Principal factor controlling Ang II levels is renin release.
Decreased circulating volume stimulates renin release via: Decreased BP
(symp effects on JGA).
Decreased [NaCl] at macula densa (“NaCl sensor”)
Decreased renal perfusion pressure (“renal” baroreceptor)
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Angiotensin II – important actions
Stimulation of aldosterone release from adrenal cortex.
Vasoconstriction of renal and other systemic vessels.
Enhanced tubuloglomerular feedback – makes macula densa more sensitive.
Enhance Na-H exchanger and Na channel function to promote Na reabsorption.
Renal hypertrophy. Stimulates thirst and ADH release by acting
upon hypothalamus.
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Aldosterone
Aldosterone stimulates Na+ reabsorption and K+ excretion by the renal tubule.
Aldosterone exerts indirect negative feedback on RAAS by increasing ECV and by lowering plasma [K+].
Really important in conserving Na+ and water, but also really good at preventing massive swings in K+ levels.
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Atrial Natriuretic Peptide (ANP)
ANP promotes natriuresis (loss of sodium). Atrial myocytes synthesise, store and release
ANP in response to stretch (low P volume sensor).
Major effect is renal vasodilatation. Increased blood flow = increased GFR.
Thus, more Na+ reaches macula densa. More Na+ excreted. May inhibit actions of renin, and generally
opposes effects of angiotensin II.
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Feedback systems involved in osmolality control
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Comparison of systems controlling effective circulating volume and osmolality
What is sensed?
Effective Circulating Volume Plasma Osmolality
SensorsCarotid sinus, aortic arch, renal
afferent arteriole, atriaHypothalamic
osmoreceptors
Efferent Pathways
RAAS, Symp NS, ADH, ANP ADH Thirst
EffectorShort term: heart, blood vessels
Long term: KidneyKidney
Brain: drinking
behaviour
What is affected?
Short term: Blood pressure
Long term: Na+ excretion
Renal water
excretionWater intake
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Control of effective circulating volume
Feedback control of effective circulating volume.
A low effective circulating volume triggers 4 parallel effector pathways that act on the kidney.
Either changes haemodynamics or changes Na+ transport by renal tubule cells.
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ECF volume receptors
“Central” vascular sensors Low pressure (very important)
Cardiac atria Pulmonary vasculature
High pressure (less important) Carotid sinus Aortic arch Juxtaglomerular apparatus (renal afferent
arteriole)Sensors in the CNS (less important) Sensors in the liver (less important)N.B. Regulation of ECF volume = Regulation of body
Na+. Thus, regulation of Na+ also dependent upon baroreceptors.