Sodium Flashcards
How does water move and its relation to sodium?
- Water will move from an area of low osmolality to an area of high osmolality
- As sodium moves, water will move
What is the location of the Kidneys?
- Located between the 11th thoracic and 3rd lumbar vertebrae in the retroperitoneum on either side of vertebral column
- The right kidney is lower than the left kidney
What are parts of the kidneys?
- Renal Capsule
- Renal Pelvis
- Ureter
- Renal Vein
- Renal Artery
- Renal Medulla
- Renal Cortex
What is the gross anatomy of the kidneys?
- Dimensions: 13 x 6 x 4 cm
- Weight: ~150 g each
- Cardiac output: Receives 20 – 25% of which 90% supplies the renal cortex
What are parts of the nephron?
Functional unit of kidney and contains approx 1 million
- Renal Artery and Vein
- Glomerular Capsule/Bowmans Capsule
- Proximal Convoluted Tubule
- Loop of Henle: Thin descending loop, Thin ascending loop, Thick Ascending loop
- Distal Convoluted Tubule
- Collecting Duct
How does sodium reabsorption take place?
- <1% filtered Na+ is excreted in the urine
- Therefore, >99% filtered Na+ must be reabsorbed via a process of tubular reabsorptiom which involves PROTEIN CARRIERS and ION-SPECIFIC CHANNELS
How does Sodium reabsorption take place in the Proximal Convuluted Tubule?
There is secondary active transport in PCT. Energy from basolateral through Na+-K+-ATPase. This creates favourable inward gradient for Na+
- Na+-H+ ANTIPORTERS: Most Na+ reabsorbed in exchange for H+. It also allows reabsorption of HCO3-
- Na+-SOLUTE CO-TRANSPORTERS: Allows simultaneous reabsorption of various organic & inorganic solutes
How does the Loop of Henle absorb Sodium?
Basolateral membrane
- Secondary active transport due to energy from basolateral Na+-K+-ATPase. This creates favourable inward gradient for Na+
- Cl- leaves cell via channel which creates favourable inward gradient for Cl-.
Apical membrane
- NKCC2 CO-TRANSPORTER: Na+ reabsorbed with K+ & 2x Cl-. Potassium is recycled back via ROMK1
- Mg2+ & Ca2+ REABSORPTION: K+ movement drives reabsorption of Mg2+ & Ca2+
How does the Counter-Current System work?
- Descending limb is permeable to H2O and some NaCl
- The Ascending limb is impermeable to H2O and able to transport NaCl into the interstitium via NKCC2
- This helps create a gradient within the medulla that gets more concentrated as the loop enlongates.
How does efficiency of the counter current system change?
- Efficiency depedns on the length of the loop of Henle
- JUXTAMEDULLARY NEPHRONS are more important for this process as they are longer
- Cortical nephrons make little contribution due to them being shorter in length
How does the DCT reabsorb Sodium?
Basolateral
- Secondary active transport through energy from basolateral Na+-K+-ATPase. This creates favourable inward gradient for Na+
- Cl- leaves cell via channel which creates favourable inward gradient for Cl-
Apical
- Na+ reabsorbed with Cl-
How does the Collecting Duct reabsorb Sodium?
- In CD, luminal concentration of Na+ can be lower than intracellular Na+ so can’t set up concentration gradient!!
APICAL SODIUM CHANNEL
- Na+ channel is electrogenic. Electronegativity allows Na+ entry into the cell. K+ is secreted simultaneously to balance charge
- Intracellular electronegativity generated by Na+-K+-ATPase
- Controlled by ALDOSTERONE
Which conditions are diuretic prescribed?
- Hypertension
- Heart failure
- Liver cirrhosis
- Nephrotic syndrome
What is the effect of Diuretics?
- Cause NEGATIVE FLUID BALANCE
- Decreases renal NaCl reabsorption and increases urinary losses of Na+ and therefore H2O
What are the main classes of Diuretics?
- Loop Diuretics
- Thiazide Diuretics
- Potassium-sparing
What is the action of Loop Diuretics?
Promote excretion of 20-25% filtered Na+ at max dose
- TARGET: Thick ascending limb of the Loop of Henle
- INHIBIT: NKCC2
- ACTION: Compete with Cl- for binding sites on NKCC2
What is the action of Thiazide Diuretics?
Promote excretion of 3-5% filtered Na+ at max dose (Less potent than Loop Diuretics)
- TARGET: Distal convoluted tubule
- INHIBIT: NaCl cotransporter
- ACTION: Compete with Cl- for binding sites on NaCl cotransporter
What are Potassium Sparing Diuretics?
Promote excretion of 1-2% filtered Na+ at max dose. Avoid renal K+ wasting
- TARGET: Principle cells of collecting duct
- INHIBIT: ENaC
- ACTION: Decrease the number of open Na+ channels inhibiting the channel directly (amiloride) or competitively inhibiting aldosterone binding to MR (spironolactone, eplenerone)
What is the Renin-Angiotensin Alsoterone system?
- Renin released which cleaves angiotensinogen to angiotensin 1
- Angiotensin is converted to angiotensin 2 by the Angiotensin converting enzyme (ACE)
- Angiotensin 2 leads to proudction of Aldosterone which leads to sodium and water rentention.
- This leads to systemic volume expansion
Where is Renin secreted from?
- Synthesized and secreted by juxtaglomerular cells which are part of juxtaglomerular apparatus (JGA
- They are specialised smooth muscle cells that are sensitive to arteriolar stretch ie. sense changes in ECF volume
- Sodium is the main determinant of Renin Secretion
Where is ACE mainly found and which proteins does it act on?
Dipeptidyl carboxypeptidase highly concentrated in the lungs. It acts to cleave dipeptides from a range of substrates:
- Angiotensin I
- Bradykinin
- Substance P
- Enkephalins
Describe the Angiotensinogen metabolism
Angiotensinogen
- 60 kDa, α2-globulin
- Produced by the liver
- Normally present in the plasma at a concentration of 1 mmol/L
Angiotensin 1
- Formed from the cleavage of a decapeptide from angiotensinogen which is catalysed by RENIN
- INACTIVE
Angiotensin 2
- Formed from the cleavage of a dipeptide from angiotensin I
- Catalysed by ACE
- ACTIVE
What are the main effects of Angiotensin 2?
SYSTEMIC VASOCONSTRICTION
- Increases blood pressure
Na+ AND H2O RETENTION
How does Angiotensin 2 increase Na+ and H2O retention?
- Stimulates ALDOSTERONE release
- Stimulates ADH release (H2O retention)
- Increases tubular reabsorption of Na+ & H2O
What is Aldosterone?
- Steroid hormone produced by the zona glomerulosa cells in the Adrenal Glands that acts as a mineralcorticoid
- Aldosterone freely diffuses into CD cells and binds to mineralocorticoid receptor (MR)
What is the effect of Aldosterone?
- Increase in number of open Na+ channels so increased Na+ reabsorption & hence H2O reabsorption
- Increased Na+ transport out of cell via Na+-K+-ATPase so Intracellular K+ increases
- Increased K+ secretion as a result
How can the RAAS mechanism be altered for therapy?
ACE Inhibitors (e.g. captopril, lisinopril, ramipril)
- Produce vasodilation by inhibiting production angiotensin II
- Block breakdown of bradykinin therefore increased levels contribute to vasodilator action of ACE-I
Angiotensin II receptor blockers (e.g. candesartan, losartan)
- Receptor antagonists, dilate arteries and veins reducing arterial pressure and load on heart
- Promote renal excretion Na and H2O
Aldosterone receptor blockers (e.g. spironolactone, eplerenone)
- Antagonise actions of aldosterone in DCT resulting in excretion of Na and H2O
What is structure of ADH?
- Nonapeptide
- MW = 1084 Da
- Rapidly metabolized by Liver and Kidney
- t1/2 = 15 – 20 mins
What is the role of ADH?
Decrease the amount of urine produced by increased reabsoprtion of H2O
How is ADH synthesised and secreted?
Synthesized by HYPOTHALAMUS
- Supraoptic nuclei (SON)
- Paraventricular nuclei (PVN)
Secreted by:
- POSTERIOR pituitary
What is action of ADH?
- Binds to ADH receptor (V2) in the kidneys
- This increases the aquaporin channels inserted into the apical membrane of the collecting duct
- This increases the amount of water reabsorption
Where are ADH receptors located?
- V1(v1a): Located in smooth muscle of mesenteric artery. It causes vasoconstriction
- V2: Located in Kidney. It leads to anti-diuresis
- V3(v1b): Located in Pituitary Gland. It leads to release of ACTH
What are ‘other’ causes of ADH secretion?
- Nausea
- Pain
- Surgery
- Pregnancy
- Angiotensin II
- Low Cortisol
How is ADH secretion controlled?
- Increased Extracellular fluid osmolality: increase in plasma osmolality stimulates ADH release & thirst
- Decreased Extracellular fluid volume: decrease in plasma volume (without a change in osmolality) stimulates ADH release
- Others
How does increased ECF osmolality cause ADH release?
- Increase ECF osmolality
- ALL cells in the body become dehydrated and ALL cells in the body shrink including hypothalamic osmoreceptors
- Loss of H2O from hypothalamic osmoreceptors leads to activation of “stretch-inactivated cation channels”
- There is depolarization of the cell
- This leads to stimulation of ADH secretion and synthesis
How does decrease in ECF volume cause ADH release?
- Detect decrease ECF volume
- Massive increase in ADH secretion
- Maximum urine concentration achieved
