What are the 2 sub-compartments of ECF?
Intravascular space (plasma)
Interstitial space (interstitial fluid)
True or False: ECF volume is determined more so by sodium balance than water balance.
True or False: ECF osmolarity is determined more so by water balance than sodium balance.
How do you clinically investigate ECF volume vs. ECF osmolarity?
ECF volume is assessed by physical exam findings (orthostatics, edema, JVD, etc).
ECF osmolarity is assessed by lab tests (serum Osm, serums Na)
What sensors regulate ECF volume and what are they sensing?
What sensors regulate ECF osmolarity and what are they sensing?
Stretch receptors sense effective vascular volume to regulate ECF volume.
Osmoreceptors sense plasma osmolarity to regulate ECF osmolarity.
What are effectors of ECF volume?
What are effectors of ECF osmolarity?
ECF volume effectors = AngII/Aldo/ADH/ANP (atrial naturitic peptide)
ECF osmolarity effectors = ADH
What is the body's response to ECF volume irregularity?
What is the body's response to ECF osmolarity irregularity?
When the body has irregular ECF volume, the response is renal Na absorption/excretion.
When the body has irregular ECF osmolarity, the response is excretion (urine osm/H2O) or intake (thirst - H2O)
High-pressure baroreceptors sense effective arterial blood volume to regulate ECF volume/Na balance. Where are these receptors?
Carotid sinus and aortic arch
Does effective arterial blood volume (detected by the high-pressure baroreceptors in the carotid sinus and aortic arch), always correspond to ECF volume?
Not always. In heart failure, there is a high ECF volume but low EABV.
Where are the low-pressure baroreceptors that sense and regulate ECF volume/Na balance?
Cardiac atria, left ventricle, and pulmonary vasculature
Where are the intrarenal sensors (the juxtaglomerular apparatus) that sense and regulate ECF volume/Na balance?
Glomerular afferent arteriole and the macula densa
Of all the sensors that regulate ECF volume and Na balance, which are the most important?
The high-pressure and low-pressure baroreceptors. These sense pressure and filling of vessels and chambers (not sodium concentration).
What is EABV?
effective arterial blood volume. This is the volume that exerts pressure that stretches the baroreceptors.
When EABV increases, renal excretion of Na _____.
What is this reaction called?
Increases. "pressure natriuresis"
What is Natriuresis?
Natriuresis is the process of excretion of sodium in the urine via action of the kidneys.
When EABV decreases, renal excretion of Na _____ and renal reabsorption of Na _____.
During states of volume contraction (low volume), what are the effectors that send signals to the kidney to increase sodium absorption? (2)
1. Renal sympathetic nervous system (catecholamines)
2. Renin-angiotensin-aldosterone system (AngII, aldosterone)
During states of volume expansion (high volume), what are the effectors that send signals to the kidney to increase sodium excretion? (4)
Natriuretic peptides (ANP)
Effectors of ECF volume/Na balance act directly on _____ or indirectly via _____ _____.
tubules, renal hemodynamics
Sympathetic nervous system activity promotes sodium _____.
_____ arterial pressure and ____ vascular volume evokes sympathetic nervous system activity.
What are the effects of sympathetic nervous system activity in the kidney? (4)
2. Release of renin
3. Decreased renal blood flow and GFR
4. Increased renal reabsorption of NaCl
The renin-angiotensin-aldosterone system is stimulated in states of ____ ECF volume
How does the renin-angiotensin-aldosterone system increase sodium retention for increased blood pressure?
- Renin converts Angiotensinogen to Angiotensin I
- Angiotensin I is converted to Angiotensin II by the Angiotensin Converting Enzyme
- Angiotensin II acts on the adrenal gland (zona glomerulosa) to stimulate the synthesis of aldosterone
- Aldosterone acts on the mineralocorticoid receptors in the principal cells in the collecting duct which results in sodium retention and increased blood pressure.
What happens to sodium handling when there is ECF volume expansion? (ANP)
- ECF volume expansion causes an increase in atrial filling and distension.
- This triggers an increased release of proANP granules from cardiocytes
- which results in an increased ANP (Atrial natriuretic peptide) in the plasma.
- ANP in the plasma decreases renin release and blocks the action of aldosterone on the tubules.
- Blocking renin slows down the renin-angiotensin-aldosterone axis which decreases sodium reabsorption and blocking the aldosterone action at the tubules also decreases sodium reabsorption.
- This causes an increase in sodium excretion.
True or False: mechanisms of Na and H2O regulation are dependent of one another.
False. They are independent of each other.
_____ balance affects tonicity/osmolarity
_____ water balance causes hypertonicity. _____ water balance causes hypotonicity.
Negative water balance (less water intake than elimination) causes hypertonicity. Positive water balance (more water intake than elimination) causes hypotonicity.
Changes in ECF tonicity are reflected by changes in _____
Water balance is an interplay between _____ and _____.
thirst, action of vasopressin
The goal is to maintain serum osmolarity (Sosm) between _____ mOsm/kg.
Osmoreceptors are in the _____
What do osmoreceptors detect?
Osmoreceptors sense serum osmolarity which is primarily determined by [Na]plasma
[Na]plasma is determined by ____ content and _____ content.
_____ is the most abundant component of the ECF.
True or False: ECF water regulation is primarily an osmoregulatory system with an emergency low-volume override.
What is the main effector for osmolarity?
Where is vasopressin (ADH) produced?
Where is vasopressin (ADH) stored and secreted?
True or False: Without vasopressin (ADH), there is no reabsorption of water in the collecting duct
What receptor does vasopressin bind to?
Vasopressin receptors (V2)
When vasopressin binds to vasopressin receptors (V2), what happens?
There is upregulation of the insertion of aquaporin channels (AQP2) in the apical membrane of the collecting duct.
What are the stimuli for vasopressin release?
Hypertonicity (elevated PNa)
Non-osmotic stimuli (unrelated to tonicity)
Decreased EABV - overrides tonicity
Endocrine disorders (e.g. adrenal insufficiency, hypothyroidism)
Pain, nausea, medications (e.g. SSRIs, NSAIDs, antipsychotics, etc), CNS disorders, pulmonary disorders, drugs.
True or False: When serum osmolarity is less than 280 mOsm/L, vasopressin is completely suppressed
True. The kidney will not retain water in the collecting ducts and will excrete excess water.
Above what serum osmolarity does thirst happen?
Above 290 mOsm/L. This is when the urine osmolarity reaches its highest concentration and the kidney cannot do anything more to hold on to water.
What is the highest urinary osmolarity that can be obtained by the kidneys?
The osmotic gradient is about 300 in the cortex to 1200 in the deep medulla. Your urine concentration cannot be greater than whatever the medullary concentration is.
What are the 2 feedback loops for water balance?
Abnormal Serum [Na+] , osmostat (hypothalamus), vasopressin release/suppression by posterior pituitary, renal water reabsorption/excretion, change in Serum [Na+].
Abnormal Serum [Na+], osmostat (hypothalamus), increase/decrease thirst, increase/decrease water intake, change in Serum [Na+].
Low EABV is a non-osmotic stimulant for vasopressin when the ECF is diminished by more than _____ %
What is SIADH?
Syndrome of Inappropriate ADH
Explain osmotic vs volume-related ADH release
ADH release due to plasma osmolarity is linear while ADH release due to volume decrease increases greatly when EABV declines by more than 8%.
Why does hyponatremia occur with chronic heart failure?
With chronic heart failure, there is a lower EABV even though total body fluid is not decreased. This decrease in EABV causes ADH release which causes water retention even if Sosm/SNa is low.
What happens to water handling when there is ECF volume expansion? (ANP)
ECF volume expansion causes an increase in atrial filling and distension. This increases the release of proANP granules from cardiocytes which results in an increase in ANP in the plasma. ANP blocks ADH action on tubules and also blocks secretion of ADH. Both of these actions decrease water reabsorption and increase water excretion.
Hypovolemia is a ______ Na balance
Negative sodium balance is an DECREASE in Na+ content that causes a decrease in ECF volume, blood volume and usually decrease in arterial pressure
Hyponatremia is a ____ water balance
Positive water balance is an increase in water content.
Are hypo/hypernatremia and hypo/hypervolemia independent of each other?
Yes, they are 2 different homeostatic systems.
You can have hypovolemia with hyponatremia if you have negative Na balance and are consuming excess water.
You can have hypovolemia with hypernatremia if you have negative Na balance and are not consuming any water.
You can have hyponatremia with euvolemia if you have a positive water balance with SIADH (syndrome of inappropriate ADH secretion).
You can have hyponatremia with hypervolemia if you have positive water balance with CHF, cirrhosis, or ESRD.
Is sweat hypotonic or hypertonic fluid?
Hypotonic. There is more water loss than salt loss.
Severe sweating causes a _____ in ECF volume and _____ in ECF osmolarity.
How does severe sweating cause secretion of ADH and eventually an addition of water to ECF? (osmotic and non-osmotic pathways)
Severe sweating causes an increase to ECF osmolarity because more water is lost in sweat than salt. This increase in ECF osmolarity is detected by hypothalamic osmoreceptors which activate ADH synthesizing neurons. These neurons increase secretion of ADH from the posterior pituitary which increase water reabsorption in the late distal tubules and collecting ducts. This results in an addition of ingested water to the ECF.
Severe sweating causes a decrease in ECF volume. This decrease in volume decreases left atrial filling pressure which stimulates baroreceptor reflex to the hypothalamus which activate ADH synthesizing neurons. These neurons increase secretion of ADH from the posterior pituitary which increase water reabsorption in the late distal tubules and collecting ducts. This results in an addition of ingested water to the ECF.
Explain ADH secretion in context of severe diarrhea.
With severe diarrhea, a sudden loss of isotonic fluid (fluid loss in diarrhea is about equal w/ water and salt) -- let's say 3 liters -- causes activation of the low volume pathway which results in ADH secretion (non-osmotic release of ADH). In the recovery phase of diarrhea, if a patient drinks 2 liters of pure water, the 2 liters is not enough to make up for the 3 liters that was lost so the patient is still volume-depleted and the volume pathway is still active which results in ADH secretion. However, from drinking pure water, the osmolarity of the ECF will decrease and the patient will become hyponatremic. This will decrease the activation of the osmolarity pathway which decreases ADH secretion. So, in this case, you have two conflicting stimuli for ADH and depending on how severe the water depletion is, the kidney will either secrete water or absorb water.
Explain the difference in fluid distribution when giving 1 liter of pure water intravenously and 1 liter of isotonic saline intravenously.
If 1 liter of pure water is given IV, it is distributed between the ICF and ECF equally so that [ICF] = [ECF]. Since the ICF volume is twice that of ECF, two times as much water goes to the ICF (666.6 ml) than ECF (333.3ml). Remember that the ECF is made up of plasma (intravascular) and interstitial fluid (interstitium). Only about 80ml of the 333 stays in the intravascular space as plasma.
If 1 liter of isotonic saline is given IV, it all stays extracellularly. This is because it is isotonic fluid and Na and Cl are primarily extracellular ions. So, the ECF volume would expand by 1000 ml. Remember that the ECF is made up of plasma (intravascular) and interstitial fluid (interstitium). About 250 ml of the 1 liter given IV stays in the intravascular space as plasma while 750 ml goes to the interstitium as interstitial fluid.
When giving IV isotonic saline, about what percent goes to the intravascular space?
E.g. if you give 1 liter of isotonic saline IV, all 1000 ml of it will go to the ECF. Remember that the ECF is made up of two spaces: intravascular (plasma) and interstitium (interstitial fluid). Of the 1000 ml, about 25% of it stays in the intravascular space as plasma (250ml).