Control of ECF Control of ECF osmolality and osmolality and

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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

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

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

Osmolar concentration of plasma:

290 mosm/L - 142 mEq/L [Na+]

Tonicity – Osmolality of a solution in relation to plasma - isotonic, hypertonic, hypotonic

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)

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

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

Sensors:

1. Extrarenal baroreceptors

Carotid sinuses

Arteries

Great veins

Atria

2. Renal juxtaglomerular apparatus

Efferents:

1. Renal sympathetic nerves

2. Macula densa renin angiotensin II aldosterone

Control of GFR:

1. Angiotensin II efferent arteriolar constriction PGC

2. Renal sympathetic nerves Na+ adrenergic receptors Constriction of afferent and efferent arterioles PGC

Osmoreceptor -Osmoreceptor -ADH mechanismsADH mechanisms

Renal handling of NaCl and water:

NaCl & H2O are freely filterable at the glomerulus.

There is extensive tubular reabsorption but notubular secretion.

Na+ reabsorption is driven by the basolateral Na+/K+-ATPase and is responsible for the major energy expenditure in kidney.

a. Na+ entry per se by SFD

Na+

GlNa+

HNa+

Cl

b. Na+ co-transported with glucose or organic acids

c. Na+ counter-transported with intracellular H+

d. Na+ co-transported with Cl-

e. Na+ following Cl- diffusion through tight junctions

Mechanisms of Sodium Reabsorption:

Proximal Tubule:The PT is highly permeable to water.

Reabsorbs ~ 65% of filtered sodium (active transport) and water plus organic nutrients etc.

Water reabsorption is passive, along osmotic gradients and keeps pace with solute.

Therefore, the [Na+] remains virtually constant through the PT, whereas the mass of Na+ is reduced by 65%.

Movement of water is facilitated by the presence of water channels - aquaporin 1, in the apical membranes of proximal tubule epithelial cells

Late in the PT, some Na+ is also reabsorbed by simple diffusion and solvent drag.

Cl- initially lags behind and the concentration gradient is established by water reabsorption.

Accordingly, in the middle and late PT, Cl- is the major anion coupled with Na+.

Solute

Na+

Solute transport in PCT

3 Na+

2 K+

S

At the end of the PT:

1. Luminal osmolality is isotonic

2. The concentration of Cl- is higher

3. The concentration of HCO3- is lower

Loop of Henle:Reabsorbs a further 25% of the filtered NaCl plus

15% of filtered water.

The descending limb does not reabsorb NaCl.The entire ascending limb of loop of Henle does.

a. thin ALH reabsorption of of NaCl

b. thick ALH co-transport of Cl- & Na+ (carrier transports Na+, K+, 2Cl-)

3 Na+

2 K+Na+

2Cl-

K+

Transport processes in the thick ascending limb

K+

H+

Na+ H2O+CO2H2CO3

H+ + HCO3 HCO3-

+C

A

The ALH, unlike the PT, reabsorbs more solute than water, therefore delivers hypotonic urine to the distal tubule.

The decrease [Na+] is greater than the decrease in osmolality due to the addition of urea to lumen in the ALH.

Drugs that inhibit transport of Cl- in the ALH therefore also inhibit Na+ reabsorption producing diuresis.

Distal Tubule & Collecting Duct:NaCl reabsorption continues along the DT & CT so that the final urine contains ~ 1% of the filtered mass.

H2O permeability of the early DT is extremely low and not subject to physiological control.

Accordingly almost no water is reabsorbed in the early distal segment.

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 EDT presents the LDT 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+.

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.

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.

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.

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.

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.

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.

Aquaporin-2

H2O

3 Na+

2 K+

ADH

Adenyl cyclasecAMP

Effect of ADH on collecting tubule cells

Summary:

osmolality

Stimulation of osmoreceptors in anterior hypothalamusSupraoptic &

paraventricular Nuclei

Posterior pituitary ADH

permeability of LDT, CCD, MCD to H2O

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

Thirst mechanism

Thirst (conscious desire for water):

Under hypothalamic osmoreceptor control

Water intake is regulated by- increased plasma osmolality- decreased ECF volume- psychological factors

Stimulus:

Intracellular dehydration due to increased osmolar concentration of ECF

Excessive K+ loss Low intracellular K+ in osmoreceptors

Mechanism is activated by

The arterial baroreceptor reflex BP

The volume receptors- low pressure receptors in atria; CVP

Angiotensin II

Increased Na+ in CSF

Hyp

Hypertonicity

Osmoreceptors

Hypovolaemia

BaroreceptorsAngiotensin II

Thirst

Thirst center:

Subfornical organ

Organum vasculosum of the lamina terminalis

Other factors regulating water intake:

Psycho-social

Dryness of pharyngeal mucous membrane

? Gastrointestinal pharyngeal metering

Renin-angiotensin Renin-angiotensin –aldosterone –aldosterone

systemsystem

Renin:

Produced by

Juxtaglomerular cells – located in media of afferent arterioles

Lacis cells – junction between afferent and efferent arterioles

Factors affecting renin secretion:

Stimulatory

Increased sympathetic activity via renal nerves

Increased circulating catecholamines

Prostaglandins

Inhibitory

Increased Na+ and Cl- reabsorption in macula densa

Angiotensin II

Vasopressin

Renin

Angiotensinogen Angiotensin I

Angiotensin-converting enzyme

Angiotensin I Angiotensin II

Adrenal cortex Aldosterone

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

Brain - increases water intake (AP, SSFO, OVLT)

Actions of aldosterone:

Increased reabsorption of Na+ from urine, sweat, saliva and GIT – ECF volume expansion

Kidney P cells – increased amounts of Na+ are exchanged for K+ and H+

Salt appetiteSalt appetite

ECF Na+

Blood volume

Hypothalamic centers

Salt appetite

Potassium Potassium excretionexcretion

Renal handling of K+:

800 mEq/day enter the filtrate

100 mEq/day is secreted

PCT – reabsorption

DCT and CD – both reabsorption and secretion

Secretion is mainly by the Principal cells

3 Na+

2 K+

Na+

K+

Aldosterone

ENaC Nucleus

ENaC = epithelial sodium channels

Control by P 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

The End