Sodium and Potassium Balance

Question 1

Define osmolarity and osmole

Answer 1

Osmolarity = measure of the solute (particle) concentration in a solution (osmoles/liter)

1 Osmole = 1 mole of dissolved particles per liter (1 mole of NaCl = 2 moles of particles in solution)

Question 2

What does constant osmolarity of biological membranes implicate?

Answer 2

As we have a “constant osmolarity”, when the amount of salt changes the amount of water must change too leading to increase in volume or opposite (a reduction in salt will lead to a reduction in water and a reduction in volume).

Question 3

Describe plasma composition

Answer 3

Normal plasma osmolarity = 285-295 mosmol/L.

Sodium is 140mmol/L and hence predominant ion in ECF. As most prevalent, its the most important solute in the ECF.

Question 4

How does dietary sodium affect body weight?

Answer 4

The more sodium you eat, the more water you will retain and you weight will increase. If reduced, can observe a reduction in weight as water lost.

Question 5

How does sodium impact blood pressure?

Answer 5

Increased dietary sodium leads to higher total sodium. This will cause increased water intake and retention in order to maintain constant osmolarity. Therefore, increased ECF volume causing higher blood volume and pressure.

Question 6

How is sodium intake regulated?

Answer 6

Central and peripheral mechanisms regulate sodium intake. Central mechanisms depend on lateral parabroachial nucleus in the brainstem. In euvolaemia, inhibition of Na+ intake occurs through activity of serotonin and glutamate. In sodium deprived state, appetite for sodium increase through GABA and opioid neurons. Periphera; mechanism based on taste as taste receptors for salt exist. At low concentrations, is appetitive but at high concentrations is aversive - has bimodal taste.

Question 7

Where is sodium reabsorbed in the nephron?

Answer 7

67% of filtered sodium absorbed in proximal convoluted tubule along with water. Occurs through use of co- or counter transported ion facilitating reabsorbption of other molecules as well. 25% taken up in thick ascending limb of loop of Henle as part of counter current mechanisms, primarily through Na+/K+/Cl- triple transporter. 5% taken up in distal convoluted tubule through Na+/Cl- transporter. 3% taken up in collecting duct via Na+ channel ENAC. Less than 1% finally excreted.

Question 8

How is GFR calculated and what affects it?

Answer 8

GFR = renal plasma flow x 0.2
As 20% of renal plasma is filtered GFR, GFR is affected by renal plasma flow rate. RPF is proportional to blood pressure over a significant range of pressures but during times of elevated BP, like exercise, would get inappropriate amount of sodium and fluid loss so past 100mmHg, RPF doesn’t increase with BP.

Question 9

How does the macula densa function?

Answer 9

The distal convoluted tubule is separated from the glomerulus by a set of specialised cells, extraglomerular mesangial cells and juxtaglomerular cells. As more Na/Cl is delivered to the distal convoluted tubule, amount of sodium and chloride transported by cells of macula densa (via triple transporter). Above a threshold, start producing adenosine and ATP which activates receptors in the extraglomerular mesangial cells. This causes:
1. Reduction in renin production
2. Contraction of smooth muscle cells of afferent arteriole.
Leads to reduction in RPF and perfusion pressure.

Question 10

How does sympathetic stimulation reduce sodium excretion?

Answer 10

1. Reduction in perfusion pressure as promotes contraction of smooth muscle in afferent arteriole.
2. Increases uptake of sodium by cells in the proximal convoluted tubule, increasing activity of sodium proton exchanger in a mechanism that may rely on intra-renal renin-angiotensin system.
3. Activates production of renin by juxtaglomerular cells.
4. Reduction in the production of adenosine and a reduction in the inhibition of renin production by the juxtaglomerular cells.
5. Sympathetic activity overrides any effect of the extraglomerular cells on the smooth muscle of the afferent arteriole and we have an overall contraction of the smooth muscle and reduced GFR.

Question 11

What opposes the actions of sympathetic stimulation?

Answer 11

Opposed by the activity of atrial naturietic peptide which promotes dilation of the afferent arteriole inhibits renin release and reduces the uptake of sodium in the PCT, DCT and CT.

Question 12

Describe tubuloglomerular feedback mechanism

Answer 12

Increase in luminal sodium chloride results in a buildup of sodium, chloride and potassium in the macula densa cell as these are transported into the cell continually through the NKCC2 transporter. This increase in intracellular sodium chloride causes release of ATP from basolateral membrane via panexin channels. It is converted to AMP and then adenosine. This binds to an A1 receptor on extraglomerular mesangial cell causing activation of G-proteins. Gi inhibits adenylate cyclase while G0 causes release of calcium. Calcium enters adjacent extramesangial cells, smooth muscle cells and granular cells via gap junctions. Causes contraction of smooth muscle and inhibition of renin release.

Question 13

Summarise effect of sympathetic activity on blood pressure

Answer 13

Increased sympathetic activity leads to a reduction in GFR and reduced delivery of sodium and water to the nephron. Increased renin production which converts angiotensinogen into angiotensin I, then angiotensin II, in circulation. AII promotes renal NaCl reabsorption and water reabsorption + vasoconstriction to increase blood pressure. It also causes the release of aldosterone, helping reabsorption of sodium and thereby the reabsorption of water.

Question 14

What are the functions of aldosterone?

Answer 14

Increased Sodium reabsorption
(controls reabsorption of 35g Na/day)
Increased Potassium secretion
Increased hydrogen ion secretion

Aldosterone increase in K+ secretion is a consequence of the increased sodium reabsorption. The change in voltage promotes an indirect stimulation of proton secretion but there are also direct effects of aldosterone on the secretion of protons via alterations in the expression of anion exchanges as H+-ATPases

Question 15

What occurs when aldosterone is in excess?

Answer 15

An excess of aldosterone can lead to hypokalaemic alkalosis as controls potassium and H+ secretion.

Question 16

How does aldosterone produce these effects?

Answer 16

Aldosterone is a steroid hormone so crosses cell membrane where it binds to the mineralocorticoid receptor. In the absence of aldosterone this receptor is a monomer bound to HSP90 and kept in the cytoplasm. On binding the steroid, the MR loses its association with HSP90 and dimerises. It then translocates into the nucleus where it binds to DNA in the promoter region of target genes and stimulates their expression.

Question 17

What genes does aldosterone activate in the collecting duct?

Answer 17

Important target genes include the ENaC (epithelial sodium channel) the sodium potassium ATPase and sets of regulatory proteins. This co-ordinates an increase in the number of sodium transporters and their activity thereby increasing sodium reabsorption.

Question 18

What are symptoms of hypoaldosteronism?

Answer 18

Dizziness
Low blood pressure
Salt craving
Palpitations

Question 19

What are symptoms of hyperaldosteronism?

Answer 19

High blood pressure
Muscle weakness
Polyuria
Thirst

Question 20

What is Liddle’s syndrome?

Answer 20

An inherited disease of high blood pressure in which there are mutations to the aldosterone activated sodium channel that increase overall ENaC activity causing increased sodium retention and hypertension. There are a number of mutations but main one alters re-internalisation and degradation of the channel and others change the opening time of the channel increasing the likelihood of it being open.

Question 21

Where are baroreceptors found?

Answer 21

On low pressure side, found in atria, right ventricle and in the pulmonary vasculature. On the high pressure side, there are receptors in the carotid sinus, aortic arch and in the juxtaglomerular apparatus.

Question 22

How are changes in blood pressure detected on the low pressure side?

Answer 22

In the case of low pressure, reduced baroreceptor firing and this signal is transmitted to the brainstem via afferent fibres, increasing sympathetic activity and ANP release. If high pressure detected, atrial stretch detected and ANP + BNP released.

Question 23

How are changes in blood pressure detected on the high pressure side?

Answer 23

Low pressure results in reduced baroreceptor firing which is transmitted to brainstem via afferent fibres, increasing sympathetic activity and ADH release. JGA cells release more renin.

Question 24

What is ANP and what are its actions?

Answer 24

Small peptide made in the atria (also make BNP). Released in response to atrial stretch (i.e. high blood pressure).

• Vasodilation of renal (and other systemic) blood vessels
• Inhibition of Sodium reabsorption in proximal tubule and in the collecting ducts
• Inhibits release of renin and aldosterone
• Reduces blood pressure

Question 25

What happens if there is a volume expansion?

Answer 25

Leads to reduced sympathetic activity, afferent arteriolar dilation and increased GFR (throwing away more water and sodium). Sodium uptake in the PCT, renin- angiotensin and aldosterone levels reduced so less sodium reuptake in the PCT, DCT and CT. With reduced sodium reabsorption, there is reduced water reabsorption so increased excretion of both. ANP release compliments these effects suppressing renin, increasing GFR and inhibiting sodium reuptake in the CT. It will also suppress the release of ADH. Combined these responses cause a reduction in volume

Question 26

What happens if there is a volume contraction?

Answer 26

If the volume is reduced, the opposite occurs with increased sympathetic activity, renin/angiotensin aldosterone production and increased AVP expression. These increase sodium reuptake, water retention and prevent further loss of volume.

Question 27

What determines water reabsorption?

Answer 27

Osmotic gradient. If the osmolarity of the fluid in the tubule is the same as that in the interstitium there will be no net movement of water onto the interstitium. So if you reduce the osmolarity of the interstitium you will reduce water reabsorption similarly if you increase the osmolarity of the tubular fluid you will reduce the difference between the tubular fluid and interstitium and so reduce water reabsorption.

Question 28

What is an effect of increased sodium excretion?

Answer 28

Na+ levels determine the ECF volume. Reducing ECF volume reduces BP. Reducing Na+ reabsorption reduces total Na+ levels, ECF volume and BP. Therefore, increasing sodium excretion has become a major method to reduce blood pressure through the use of diuretics.

Question 29

How do ACE inhibitors exert their effect?

Answer 29

Reduce angiotensin 2 formation resulting in vasodilation and increased vascular volume. Decrease in peripheral resistance decreases blood pressure. Direct renal effects include a decrease in Na+ reuptake in PCT and increased sodium in distal nephron. Adrenal effect is reduced aldosterone plus same effects as listed above. This leads to decreased water reabsorption and overall drop in blood pressure due to decrease in volume.