4 - Volume And BP Control

Question 1

Why is [Na^+] regulation so important with regards to BP?

Answer 1

Na⁺ is the major osmotically active ion in the ECF; if there is a greater [Na⁺] in the ECF, there will be less water and hypotension will be a consequence. Na⁺ ingestion is not a constant (0.5 - 25g) - must be able to regulate concentrations depending on diet - Na⁺ balance is key.

Question 2

Where does the majority of salt get excreted?

Answer 2

In the urine; sweat and faeces also contribute to a far lesser degree.

Question 3

How does the body change ECF volume?

Answer 3

COULDN’T just add or remove water - will change plasma osmolarity - affecting electrolyte composition. Must add ISOTONIC solution - move osmoles first, then water will move (no active water pumps - cannot be the other way around).

Question 4

How much [Na⁺] is reabsorbed in the kidney and where?

Answer 4

PCT - 67% Descending Thin Limb LOH - 0% Ascending Thin and Thick Limb LOH - 15% DCT - ~5% CD - 3%

Question 5

How much [H₂O] is reabsorbed in the kidney and where?

Answer 5

PCT - 65% Descending Thin Limb LOH - 10-15% Ascending Thin and Thick Limb LOH - 0% DCT - 0% CD - 5-24% (water loading vs dehydration)

Question 6

What is Na⁺ reabsorption driven by?

Answer 6

The Na-K-ATPase (on the basolateral membrane). It is an active process.

Question 7

What is Cl^- reabsorption linked to? Why?

Answer 7

Na⁺ reabsorption - closely associated with activity of Na-K-ATPase. This maintains electro-neutrality. Can be transcelular (active) or paracellular (passive).

Question 8

Filtrate must be electroneutral. How is this ensured?

Answer 8

PCT reabsorption of cations and anions must be equal i.e. [Na⁺] = [Cl^- + HCO3^-]

Question 9

What [Cl^-] and [HCO3^-] is absorbed in the PCT?

Answer 9

~65% of Cl^-; 80-90% of HCO3^-

Question 10

In the different tubular segments, are the Na⁺ transporters on the apical membrane the same in each segment?

Answer 10

No, they vary. PCT: NHE, Na-Glucose symporter, Na-AA, Na-Pi LOH: NaKCC Early DCT: NaCl Late DCT & CD: ENaC

Question 11

In the different tubular segments, are the Na⁺ transporters on the basolateral membrane the same in each segment?

Answer 11

Yes, the Na-K-ATPase is present in all.

Question 12

What channels are found on the apical membrane of the PCT? What stimulation can affect their activity?

Answer 12

NHE - Na-H-exchanger.
Sympathetic stimulation activates NHE and basolateral Na-K-ATPase - increasing Na⁺ and (indirectly) H₂O reabsorption - increasing BP.

Question 13

In the PCT which molecules are preferentially absorbed?

Answer 13

Glucose, AAs, lactate (highest preference)

HCO3^-

Phosphate

Cl^- (lowest preference)

Question 14

How many sections is the PCT divided into?

Answer 14

3: S1, S2 and S3.

Question 15

In S1 of the PCT what channels are present on the apical and basolateral membranes respectively?

Answer 15

Apical: All mentioned… NHE, Na-glucose, Na-AAs, Na-Pi and aquaporin.

Basolateral: Na-K-ATPase; NaHCO₃^-

Question 16

What hormone affects activity of the Na-Pi channel?

Answer 16

Parathyroid hormone (PTH).

The greater the PTH the less the Pi excretion therefore the greater the Pi retention.

Question 17

As glucose, Na⁺ etc are reabsorbed what will happen to relative [Urea and Cl^-] as they go through S1 into S2-3?

Answer 17

They will increase creating a concentration gradient!

Question 18

In S2-3 of the PCT what channels are present on the apical and basolateral membranes?

Answer 18

Apical: NHE, Para/Transcellular Cl^-, aquaporin - bulk of H₂O uptake occurs here due to favourable gradient.

Basolateral: Na-K-ATPase

Question 19

What is the driving force of PCT reabsorption?

Answer 19

Osmotic gradient created by solute absorption - increased osmolarity in interstitial spaces; indreased hydrostatic force in intersticium; increased oncotic force in peritubular capillary (loss of 20% of renal blood flow to filtrate - still has PROTEINS and cells though).

N.b. remember reabsorption is isotonic.

Question 20

How is GFR autoregulated?

Answer 20

Myogenic action.

Tubuloglomerular feedback.

Question 21

Can Na⁺ reabsorption be regulated through another method (barring autoregulation of GFR)?

Answer 21

Glomerulotubular balance - essentially blunts changes in Na⁺ excretion as a response to changes in GFR (which happen despite autoregulation).

Question 22

What happens in the LOH (in simple terms)? Why does this happen?

Answer 22

The descending limb reabsorbs H₂O (25%) creating a gradient for the ascending limb to reabsorb solutes, e.g. Na⁺, (the Thick Ascending Limb is impermeable to water).

Question 23

How is Na⁺ normally reabsorbed in the thin ascending limb?

Answer 23

Passively (paracellular route), due to the gradient created by water reabsorption in the descending limb.

Question 24

What channels are found on the apical membrane of the loop of Henle? What hormone can affect its activity (specifically thick ascending limb)?

Answer 24

NKCC - Na-K-2Cl co-transporter
Anti-diuretic hormone (ADH or vasopressin) will stimulate the activity of the apical NaKCC transporter - increasing Na⁺ and (indirectly) H₂O reabsorption - increasing BP.

Question 25

If there is deficiency of ADH in the body, what condition can ensue?

Answer 25

Diabetes insipidus.

Question 26

What channels are found in the thick ascending limb? Passive/Active - consume energy?

Answer 26

There is the NaKCC but there is also ROMK.

In the nephron, this is the most energy-dependent region - thus it is more sensitive to hypoxa.

Question 27

What is the ascending limb also known as? Why?

Answer 27

The diluting segment - removes a lot of electrolytes, diluting it. It is hypo-osmotic.

Question 28

Is the early DCT permeable to water?

Answer 28

Not really.

Question 29

What channels are present in the early DCT?

Answer 29

Apical: NCC (electroneutral Na⁺and Cl^- co-transporter);
Ca²⁺channel

Basolateral: Na-K-ATPase; NCX

Question 30

Do any diuretics target transporters in the early DCT?

Answer 30

Yes - the Thiazide diuretics target NCC transporters - downregulating it, decreasing Na⁺ reabsorption … etc. therefore more urine, less ECF, lower BP.

Question 31

The DCT is a major site of Ca²⁺ reabsorption. What mechanism promotes this?

Answer 31

Release of PTH.

Question 32

Will fluid become more or less hypotonic in the early DCT?

Answer 32

More. ~5% of Na⁺ is reabsorbed. H₂O cannot follow however because it is relatively impermeable. Therefore filtrate becomes even more dilute.

Question 33

What channel is found on the apical membrane of the Late DCT & the CD? What hormone/drugs affect its activity?

Answer 33

ENaC - Epithelial Na⁺ Channel.

Aldosterone increases activity the ENaC on the principal cells of the CD and Na⁺ and (indirectly) H₂O reabsorption - increasing BP. (Also increases basolateral extrusion of Na⁺ via Na-K-ATPase).

Spironolactone blocks ENaC - increases Na⁺and H₂O reabsorption (mild diuresis) but reduces K+ excretion - need to watch out for hypokalaemia and arrythmias

Question 34

All tubules of the nephron have just one cell type. True or False?

Answer 34

False - the Late DCT and CD have two cell types (otherwise true):

Principal Cells: Reabsorption of Na⁺via ENaC

Type B Intercalated Cells: Active Reabsorption of Cl^-
(also involved with secretion of H⁺ or HCO₃^-)

Question 35

Outline a Principle Cell’s function.

Answer 35

Contain ENaC - assist in Na⁺ reabsorption.

This produces a negative luminal charge.. (remember Na⁺will be moving from lumen –> tubule cell –> ECF)

Cl^- will follow due to the electrochemical gradient (via PARACELLULAR route)

This negative luminal charge will also increase K⁺secretion.

There is variable H₂O uptake through aquaporin depending on the action of ADH!

Question 36

What is Barter’s syndrome?

Answer 36

A genetic disease, where the thick ascending limb of the loop of Henle cannot reabsorb salts leading to hypokalaemia, hypotension and metabolic alkalosis.

Question 37

Do changes in the composition of the peritubular capillaries affect Na+ reabsorption in the PCT?

Answer 37

Yes - changes in osmotic and hydrostatic pressure in the peritubular capillaries will do this.

If reduced they promote Na⁺ (and water) reabsorption and vice-versa.

Question 38

In summary: …

Answer 38

Question 39

What are a couple of equations relating to blood pressure?

Answer 39

Pressure = Flow x Resistance...
BP = CO x TPR

CO = HR x SV… Therefore

BP = HR x SV x TPR

Question 40

How is BP regulated in the short-term?

Answer 40

Baroceptor Reflex

Question 41

What is the baroceptor reflex mediated by?

Answer 41

Stretch-receptors in the aortic arch and the carotid sinus. These receptors, or more precisely - nerve endings - stretch in response to high arterial pressure.

Question 42

Why does the baroreceptor reflex not work in the long term?

Answer 42

The threshold for baroreceptor firing resets.

It is very effective in the short-term however, producing a rapid response to manage acute changes in BP.

Question 43

How is BP regulated in the long-term?

Answer 43

4 Mechanisms that control [Na⁺] and therefore ECF - plasma is part of the ECF so it will control plasma as well.:

RAAS System
Sympathetic Nervous System
Antidiuretic Hormone (ADH)
Atrial Natriuretic Peptide (ANP)

Question 44

Outline how the RAAS works.

Answer 44

Angiotensinogen –renin–> Angiotensin 1 –ACE–> Angiotensin 2 - has many effects…

Question 45

What are some of the effects that angiotensin 2 has on the body?

Answer 45

Stimulate Na<sup>+</sup> reabsorption at kidney (via NHE in the PCT)
Release aldosterone (which will help Na<sup>+</sup> reabsorption).
Vasoconstriction - afferent and efferent arteriole (nephron).

Question 46

Where does renin come from?

Answer 46

The Juxtaglomerular Apparatus - granular cells of the afferent arteriole, macula densa cells and surrounding mesangial cells.

Question 47

What regulates the release of renin?

Answer 47

3 factors influence renin’s release:

Reduced NaCl in DCT (macula densa cells detect).

Reduced perfusion pressure from renal artery (baroreceptors in the afferent arteriole detect this).

Sympathetic stimulation to JGA increases release of renin.

Question 48

How does the Renin-Angiotensin-Aldosterone System serve to regulate BP?

Answer 48

Through an increased production of angiotensin 2, there will be greater vasoconstriction, Na⁺ reabsorption, aldosterone release - this will lead to increases in BP (through increased ECV and TPR).

Question 49

How is angiotensin 2 regulated by the body?

Answer 49

It isn’t. It’s production can only be influenced by drugs - ACE-inhibitors.

Question 50

What effect will ACE-inhibitors have on BP?

Answer 50

Less angiotensin 2 - less Na⁺reabsorption (less aldosterone also contributing to this) and LESS vasoconstriction - relative vasodilatation

BP will fall.

Used to treat hypertension and also in heart failure and in certain situations after a heart attack.

Question 51

What is heart failure?

Answer 51

HF: where the blood supplied by the heart cannot match the demand from the body - DESPITE an adequate filling pressure.

Most commonly divided into RHF, LHF and Biventricular HF (or Congestive HF).

Can also be divided into Systolic (‘pump failure’) and Diastolic (failure of relaxation) HF.

Question 52

What is Starling’s Law of the Heart?

Answer 52

Filling pressure determines the stretching of the myocardium and therefore the force of myocardial contraction. In HF this no longer applies.

Question 53

What is the aetiology of HF?

Answer 53

Primary cause is Coronary Heart Disease (aka Ischaemic Heart Disease) - which can also develop into an acute emergency, a myocardial infarction.

There are 4 Classes ranging from I - no symptoms to IV possible symptoms at rest

Question 54

What are the differences between left and right HF?

Answer 54

LHF: tachycardia, cardiomegaly, ‘gallop rhythm’ (extra heart sounds)

RHF: raised JVP, hepatomegaly, ascites (relates to areas distending because of fluid accumulation in areas drained by systemic veins) - more often 2^oto LHF! Otherwise due to chronic lung disease, PE etc.

Both have symptoms of fatigue, exertional dyspnoea, orthopnea.

Question 55

Why are ACE-inhibitors given in cases of HF?
What other drugs are given?

Answer 55

They will decrease arterial pressure, preload and afterload on the heart - reducing stress on it.

ß-blockers, Ca²⁺channel blockers, Digoxin (cardiac glycosides), Organic nitrates,

Question 56

What are the two types of angiotensin receptors and their functions?

Answer 56

AT1 & AT2 - main action is mediated via AT1 - both are GPCRs. They are found in the arterioles (vasoconstriction), kidneys (Na⁺reabsorption), adrenal cortex (release aldosterone), hypothalamus (increases thirst sensation through ADH release), SNS (release NA)

Question 57

Why are ACE-inhibitors given in certain situations after MIs? What other medications are given?

Answer 57

Similarly to HF, to reduce the stress (afterload) to the heart.

ß-blockers (reduce force of contraction - not given with acute heart failure), Aspirin/Clopidogrel/IV Heparin (antiplatelet/fibrinolysis therapy)

Question 58

Why is a persistent dry cough a frequent side effect of taking ACE-inhibitors?

Answer 58

ACE also breaks down bradykin (a vasodilator) into peptide fragments - increasing vasoconstriction even more.

ACE-inhibitors inhibit the action of ACE. Therefore less bradykinin will be broken down. This accumulation of bradykin leads to the persistent dry cough.

Question 59

How does the sympathetic nervous system help regulate BP?

Answer 59

Increased stimulation leads to..:

Decrease renal perfusion rate (more goes to liver, muscles etc) - decreases GFR - decreasing Na⁺ excretion.

Activates RAAS through increased secretion of renin

Increases Na+ reabsorption in PCT via apical NHE and basolateral Na-K-ATPase.

Question 60

How does ADH regulate BP?

Answer 60

Its role is to form concentrated urine. This is through water and Na⁺ retention as well as controlling plasma osmolarity. It acts on the thick ascending limb, stimulating NaKCC channels.

Question 61

What stimulates ADH release?

Answer 61

Severe hypovolaemia or increases in plasma osmolarity.

Question 62

How do atrial naturetic peptides (ANP) regulate BP?

Answer 62

Promotes Na⁺ excretion. It is released by atrial myocytes, where it is synthesised and stored, in response to stretch. These stretch receptors are low pressure volume sensors and are found in the atria.

Question 63

What inhibits the release of ANP?

Answer 63

Low ECV because reduced filling of the heart will mean the atria is stretched less.

Question 64

How does ANP affect Na⁺reabsorption, the body in general and BP?

Answer 64

It vasodilates the afferent arteriole - increasing blood flow and therefore GFR. This inhibits Na⁺ reabsorption along the nephron. This will decrease Effective Circulating Volume and BP will decrease.