24-02-23 - The long-term control of blood pressure. Oedema, dehydration. Flashcards
Learning outcomes
- Describe how the kidneys integrate salt and water balance in terms of regulating extracellular fluid volume and extracellular fluid osmolality.
- Define what the effective circulating volume is and how it is sensed.
- Describe how the renin-angiotensin-aldosterone system (RAAS) responds to a drop in the effective circulating volume.
- Give a brief overview of how the 3 additional pathways: renal sympathetic nerve activity, AVP and ANP act to correct a low effective circulating volume.
- Demonstrate an understanding of clinical conditions where an increase in effective circulating volume gives rise to increased arterial blood pressure e.g. primary hyperaldosteronism or Liddle syndrome.
- Describe how diuretics lower blood pressure by targeting the effective circulating volume.
What is the formula for blood pressure?
What are parts of the short term and long-term control of blood pressure?
What regulated blood pressure and local tissue flow?
What does it also involve?
- Formula for blood pressure:
- BP = CO X TPR
- Cardiac output (CO = SV X HR) and total peripheral resistance (TPR) are part of short-term control of blood pressure
- Effective circulating volume (ECV) is part of the long-term control of blood pressure
- Complex interactions of neurohormonal and local control systems that regulate BP and local tissue flow
- It also involves additional systems that regulate circulatory volume in relation to vascular capacitance
What % of total body water is ICF and ECF?
What 3 things does ECF consist of?
- Total body water: 60% is ICF and 40% is ECF
- 3 things ECF consists of:
1) Blood plasma
2) Interstitial fluid
3) Transcellular fluid
What % of each component make up Extracellular fluid (ECF)?
Where is each found?
- Extracellular fluid (ECF) components:
1) Plasma – 20% of ECF
* Total volume (blood volume) is 6L
* Half of this is plasma
* Half of this is haematocrit (red blood cells, white blood cells, platelets)
* Plasma is found in the cardiac chambers and blood vessels
2) Interstitial fluid – 75% of ECF
* Found outside the intravascular compartment, bathing non-blood cells of the body
* Includes bulk interstitial fluid and 2 smaller compartments: dense connective tissue and bone matrix
3) Transcellular fluid – 5% of ECF
* Found in small spaces enclosed by epithelial cells
* E.g. synovial fluid in joints and cerebrospinal fluid (CSF) of brain and spinal cord
What are the concentrations of Na+, K+, Cl- and protein in the blood plasma?
What is the osmolality of the blood plasma (in photo)
What does ECF volume maintain?
How is ECF volume maintained?
What does ECF osmolality contain? How is ECF osmolality maintained?
What are 3 components that allow for ECF volume and osmolality to be maintained?
- ECF volume maintains blood pressure: essential for adequate tissue perfusion and function
- ECF volume is maintained by adjusting total body content of NaCl
- ECF osmolality maintains cell volume: essential for cell function (avoiding hypertonic and hypotonic osmolalities)
- ECF osmolality is maintained by adjusting total body H2O content
- 3 components that allow for ECF volume and osmolality to be maintained:
1) Sensors
2) Transducers
3) Effectors
Describe the control of ECF volume flowchart
What is the main osmotic constituent of the ECF?
When will H2O move?
What is the ECF osmolality maintained as?
What is the major determinant of ECF volume?
What happens if the kidneys excrete extra Na+?
What happens if NaCl is added to ECF?
How is total body Na+ regulated?
- Na+ (with its associated anions Cl- and HCO3 -) is the main osmotic constituent of the ECF
- Where Na+ moves, H2O must follow
- The body maintains ECF osmolality ~290 mOsm within narrow limits * Thus, whole-body Na+ content – which the kidneys control – is the major determinant of ECF volume
- If kidneys excrete an extra 145mEq Na+ - they must excrete an additional 1L of water in urine to prevent serious fall in osmolality
- Addition of 145 mMol “dry” NaCl to ECF would require an addition of 1L of H2O to the ECF: ingestion of H2O / reducing H2O excretion
- Precise and sensitive control mechanisms safeguard total body Na+
Describe the flowchart for control of ECF osmolality (in picture)
Control of ECF volume and osmolality summary
What is the formula for oral Na+ intake?
When can extrarenal Na+ output not be negligible?
How would the kidneys respond to this?
What do the kidneys do when there is excessive Na+ intake?
What does renal excretion of Na+ depend on?
What is the formula for total body Na+?
What acts as a signal for Na+ homeostasis?
- Oral Na+ intake = Renal Na+ output + Extrarenal Na+ output
- Normally, extrarenal Na+ output is negligible, except for large fluid losses:
1) GI tract (vomiting or diarrhoea)
2) Skin (excessive sweating, extensive burns) - These will result in substantial extrarenal Na+ losses
- The kidneys would respond to this by reducing Na+ excretion
- Excessive Na+ intake, kidneys excrete surplus Na+
- Renal excretion of Na+ depends on the amount of Na+ in the body (not concentration of Na+ in the ECF)
- Total body Na+ = ECF volume x [Na+]ECF (with osmolality ~constant)
- It is the volume of ECF that acts as a signal for Na+ homeostasis
Describe the following diagram. What is the difference between ECF and ECV?
- Description of diagram in picture:
- 0kg subject on unusually low Na+ diet (with low urine output), rapidly increases Na+ intake and maintains for several days
- Initial stage of positive Na+ balance. Increased ECF osmolality triggers thirst / AVP release, increases total body H2O
- Weight gain, ECF volume has now expanded – triggers Na+ excretion
- After 5 days Na+ output increases to match intake, but this is due to ECV expansion, not the initial change in ECF sodium concentration
- Unlike the ECF, the ECV is not a measurable and distinct body fluid compartment.
- The ECV refers to the portion of the ECF that is contained within the vascular system and is “effectively” perfusing the tissues (effective blood volume is another commonly used term).
What must happen for ECF volume expansion to stimulate Na+ secretion?
What is ECV a critical parameter for?
What does the ECV reflect?
What do changes in ECV parallel normally?
When will changes in the ECV not parallel changes in total ECF volume?
- For ECF volume expansion to stimulate Na+ excretion, this must occur in ECF compartments with volume sensors, such as blood-filled compartments
- Critical parameter for regulating Na+ excretion is the effective circulating volume (ECV - “functional blood volume”)
- The ECV reflects extent of tissue perfusion in specific regions (detected as fullness/pressure in their blood vessels)
- Normally, changes in the ECV parallel changes in total ECF volume
- ECV does not parallel changes in total ECF volume in certain cases of disease
What are 3 diseases in which changes in ECV does not parallel changes in total ECF volume?
Describe this in congestive heart failure
- 3 diseases in which changes in ECV does not parallel changes in total ECF volume:
1) Congestive heart failure
* E.g. in congestive heart failure with extensive oedema - ECF volume is greatly increased
* But low cardiac output fails to expand the blood-filled compartments, leading to ECV being low and the body not detecting this increase in ECF due to the compartments with sensors not being filled
* So renal Na+ reabsorption remains high (high Na+ intake but low urinary Na+ excretion) – exacerbating systemic congestion
2) Nephrotic syndrome
3) Liver cirrhosis
- In all of these conditions, Total ECF volume is grossly expanded (oedema/ascites), but the ECV is low, therefore increasing Na+ retention
When can expansion of fluid volume occur?
What does the body do in this situation?
What can happen when this is severe?
- Expansion in fluid volume can occur when Na+ intake persists in the face of impaired Na+ excretion
- This will result in the body retaining isosmotic fluid and expansion of plasma fluid volume and of the interstitial fluid compartment
- When severe, interstitial volume increase so severe that subepidermal tissues swell (e.g. ankles) - pitting oedema
What do kidneys regulate?
What volume of plasma do the kidneys filter a day?
How volume of urine is produced a day?
Filtration/reabsorption of what substances in the kidney tubules regulates blood pressure?
What must Na+ excretion match?
How demanding is the reabsorption of Na+?
- Kidneys regulate our circulating volume
- Kidneys filter 180 L plasma/day
- 1.5-2.0 L of urine is produced a day
- Filtration / reabsorption of Na+ and Water in the kidney tubules regulates blood pressure
- Na+ excretion must match Na+ intake
- The necessity to retrieve almost all filtered Na+ before it reaches the urine is a challenging regulatory and energetic demand
What % of Na+ is reabsorbed at different parts of the kidney tubule?
How does this occur at each location?
- % of Na+ reabsorbed at different parts of the kidney tubule:
1) Proximal tubule – about 67% of Na+ reabsorption
* Via NHE3
2) LOH – about 25% of Na+ reabsorption
* Via NKCC2 (at thick ascending limb)
3) Distal convoluted tubule and collecting duct – about 8% of Na+ reabsorption
* Via NCC and ENaC
What are 4 hormone systems that control ECF volume?
- 4 hormone systems that control ECF volume:
1) Renin-angiotensin-aldosterone system (RAAS)
2) Sympathetic Nervous System (SNS)
3) Atrial Natriuretic Peptide (ANP)
4) Arginine Vasopressin (AVP)
What is the most important factor for long-term regulation of Na+ excretion and thus BP?
Describe the flow chart for a decrease in ECV (in picture)
- Renal perfusion pressure most important for long-term regulation of Na+ excretion and thus BP
- flow chart for a decrease in ECV (in picture)
RASS.
What is angiotensinogen?
What is it synthesised by?
Where is it released?
What is renin?
What is it produced by?
What is its action?
How quickly is it cleared from the plasma?
- RAAS
- Angiotensinogen is an a2 globulin synthesised by the liver
- It is released into the circulation
- Renin is a proteolytic enzyme
- Renin is released by granular cells in the juxtaglomerular apparatus (JGA) of the kidney
- It cleaves Angiotensinogen to Angiotensin I
- Renin is cleared rapidly from the plasma
What is the function of Angiotensin 1? What is ACE?
Where is it found?
What is its purpose?
- Angiotensin 1 appears to have no biological activity, but acts as a precursor to Angiotensin II
- ACE is Angiotensin converting enzyme
- ACE is found in vascular endothelium in the lungs and the renal afferent and efferent arterioles
- It converts Angiotensin I to Angiotensin II
What receptors does AngII work on?
What 3 places have AngII receptors?
What are 3 effects AngII has on the Renal tubules of the kidney?
- AngII works on AT1 receptors
- 3 places that have AngII receptors:
1) Vascular smooth muscle cells of blood vessels
2) Hypothalamus
3) Renal tubules of the kidney - 3 effects AngII has on the Renal tubules of the kidney:
1) Stimulates secretion of aldosterone from adrenal glands
2) Increased Na+ reabsorption in the kidney
3) Increased ECV
How does renal sympathetics stimulation directly affect Na+ reabsorption from the ultrafiltrate?
What indirect effect does it have?
What effect do these direct and indirect effects have together?
How does sympathetic nerve activity in the kidney differ in an unstressed state?
- Enhanced activity of the renal sympathetic nerves has 2 direct effects on Na+ reabsorption from the ultrafiltrate (thereby reducing excretion):
1) Increased vascular resistance
2) Increased Na+ reabsorption by tubule cells - Indirectly, renal sympathetic stimulation enhances renin release from granular cells
- Together these reduce GFR and enhance Na+ reabsorption, Increasing Na+ retention and ECV
- In an unstressed state – role of sympathetic nerve activity in kidney function appears to be modest
What is another name for Arginine Vasopressin (AVP)?
Where is AVP released from?
When is it released primarily?
What does AVP promote? What is another situation where AVP can be released?
What are secondary actions of AVP?
- Arginine Vasopressin (AVP) is also known as anti-diuretic hormone – ADH
- The posterior pituitary releases AVP primarily in response to increases in extracellular osmolality
- It promotes water reabsorption in the distal nephron
- The posterior pituitary also releases AVP in response to large reductions in ECV E.g. haemorrhage
- Secondary actions of AVP - vasoconstriction and increasing renal Na+ retention
Where is atrial natriuretic peptide (ANP) synthesised and stored?
When is it released?
What do effects of ANP promote?
What are 5 effects of ANP?
When do ECV levels fall?
What does this produce a net change in?
- Atrial natriuretic peptide (ANP) is synthesised and stored in atrial myocytes
- ANP is released in response to stress
- ANP has multiple synergistic effects which promote natriuresis and diuresis (Na+ excreting)
- 5 effects of ANP:
1) Increases GFR and renal blood flow
2) Inhibits Na+ transport in the inner medullary collecting duct
3) Decreases release of renin
4) Inhibits aldosterone release from adrenals
5) Decreases release of AVP - Decreased ECV leads to a fall in ANP
- This produces a net decrease in Na+ and H2O excretion
What are diuretics?
How do they affect blood pressure?
What are 4 different types of diuretics?
- Diuretics are substances that help the body get rid of water (target Na+ absorption to do this – “natriuretics”)
- They reduce BP by decreasing ECV
- 4 different types of diuretics:
1) Osmotic diuretics
2) Loop diuretics
3) Thiazide diuretics
4) K+ sparing diuretics
What is the purpose of osmotic diuretics?
What is an example of an osmotic diuretic?
Where are they filtered/reabsorbed?
How does this aid in their mechanism of action?
Which 2 parts of the nephron do they act upon?
In what condition are osmotic diuretics used?
- Osmotic diuretics modify the content of the filtrate e.g mannitol
- Osmotic diuretics are freely filtered across the glomerulus, but cannot be reabsorbed along tubules - the presence of solutes that cannot be reabsorbed reduces passive H2O absorption due to increased osmolality
- This leads to their main effect being to increase H2O excreted, with a small secondary increase in Na+ excretion
- They have their main effect upon portions of the nephron permeable to H2O:
1) Proximal convoluted tubule
2) Descending limb in the Loop of Henle - Osmotic diuretics are used in acute renal failure
How powerful and thiazide diuretics?
What are 2 examples of thiazide diuretics?
How do thiazide diuretics work?
What line of treatment for hypertension are thiazide diuretics?
- Thiazide diuretics are less powerful than loop diuretics
- 2 examples of thiazide diuretics:
1) Bendroflumethiazide
2) Hydrochlorothiazide - Thiazide diuretics work by inhibiting the NCC (Na+/Cl- co-transporter), leading to a reduction in Na+ and Cl- reabsorption
- They also cause vasodilation
- Thiazide diuretics are common 2nd / 3rd line treatment for hypertension
What diuretics are K+ diuretics also used with?
What are the 2 types of K+ sparing diuretics?
What are 2 exampled of each?
What is their mechanism of action?
Why do K+ sparing diuretics need to be combined with loop diuretics?
- K+ diuretics have limited diuretic action alone, but powerful antihypertensive agents in combination with loop/thiazide diuretics
- 2 types of K+ sparing diuretics:
1) Aldosterone receptor antagonists
* e.g. Spironolactone, eplerenone
* Competitively inhibit the mineralocorticoid receptor
2) ENaC inhibitors
* e.g. Amiloride, triamterene
* Block the epithelial Na+ channel (ENaC)
- K+ sparing diuretics reduce driving force for K+ secretion in CT (from ROMK), so would cause hyperkalaemia if used alone
- They are combined with loop diuretics to balance plasma [K+]
K+ sparing diuretics mechanism of action diagram
