SGD: Concepts in Regulation OS 201

Department of Physiology Exam 6

25 Nov 2019 Trans 6

OUTLINE Figure 1. Fractional volumes of the various body fluid compartments.

I. Case Summary D. How is body fluid volume
II. Guide Questions regulated? 60-40-20-5 Rule
A. What is the normal body E. What happens if he drinks
fluid distribution and his urine? What properties  Computation of fractional volumes of body fluids:
osmotic balance? does urine have that affect  Total body water = 0.60 × (body weight)
B. What changes in the body fluid and electrolyte  ICF = 0.40 × (body weight)
fluid distribution and balance?  ECF = 0.20 × (body weight)
osmolality occur in the F. If you were the emergency  Plasma = 0.05 × (body weight) or ¼ × ECF
person who has no access room officer, how are you  Interstitial fluid = 0.15 × (body weight) or ¾ × ECF
to food and water? going to treat him? Define
C. How is body fluid tonicity of a solution. Normal osmotic balance
osmolality regulated? G. What happens to brain
Explain the mechanisms by cells if you use hyptonic  Different ions and nutrients needed to sustain life can be found in
which ADH is released and solution? the ECF:
thirst is stimulated. III. References  Sodium, chloride, and bicarbonate ions
IV. Appendix  Cellular nutrients such as oxygen, glucose, fatty acids and
TG Notes: “This trans was based mainly on the faculty guide for amino acids
SGD, with additional input from 2023 Trans and Dr. Ibanez.”  Carbon dioxide and other cellular waste products
 ICF contains large amounts of potassium, magnesium and
I. CASE SUMMARY phosphate ions.
A 24-year old male was pulled out of the rubble caused by a strong  Concentration of these ions are maintained through different
earthquake that occurred 5 days ago. He was without food and transport processes resulting to a normal osmotic balance value of
water. He was very weak, with low blood pressure, tachycardic, and 290 mOsm/L for the body.
very thirsty. He said he survived because he drank his urine.  Osmotic pressures of both ICF and ECF are in the range of
280-295 mOsm/kg H2O (Berne & Levy, 2018)
II. GUIDE QUESTIONS  Osmotic forces – prime determinant of water distribution in the
A. WHAT IS THE NORMAL BODY FLUID DISTRIBUTION AND body
OSMOTIC BALANCE?  Water can freely move across all cell membranes; as a result,
the body fluids are in osmotic equilibrium as the osmolalities of
Normal body fluid distribution the ICF and ECF are the same.
 60% of total body weight = water (total body water)  Osmosis – movement of water from a solution of lower
 Varies among individuals due to the different amounts of concentration to higher concentration
adipose tissue present
 Increased adipose tissue lowers the percentage of water in
the total body weight
 For newborn, approximately 75% of the body weight is water.
 Total body water is distributed between two major compartments:
 Intracellular compartment (ICF) = ⅔ of the total body water
 Extracellular compartment (ECF) = ⅓ of the total body water
 ECF compartment is subdivided into:
 Plasma – found within the vascular compartments
 Interstitial fluid – surrounds the various tissues of the body

Figure 2. Darrow-Yanet Diagram. This demonstrates how the body fluid

volumes are altered in response to different conditions.

TG 01: Abad, Abdulghaffar, Abella, Abu [Teh] 1 of 8


B. WHAT CHANGES OCCUR IN THE BODY FLUID
DISTRIBUTION AND OSMOLALITY IN THE PERSON WHO
HAS NO ACCESS TO FOOD AND WATER?
 Dehydration occurs in this sequence:
 Loss of water in the ECF compartment which establishes
osmotic gradient between ECF and ICF
 Increase in osmolality of ECF
 Movement of water from ICF to ECF
 Decreased volume and increased osmolality of both ICF
and ECF
 With each upward step of ECF osmolality, there is a
compensatory upward step in the ICF osmolality.
 In systems such as this, losses or gains of water are evenly
distributed throughout the total body water.
 e.g. increased plasma osmolality  flow of water from
interstitial fluid to plasma  increased interstitial osmolality 
flow of water from intracellular fluid to interstitium
C. HOW IS BODY FLUID OSMOLALITY REGULATED?
EXPLAIN THE MECHANISMS BY WHICH ADH IS RELEASED
AND THIRST IS STIMULATED.
 Increase in ECF osmolality  release of ADH and thirst 
reduction of water losses by urine concentration
 Water deficit (hyperosmolality) can be corrected only by increased
water intake
 Stimulation of ADH secretion is more sensitive to blood osmolality
than volume
 1% change in osmolarity needed while 10% change in blood
volume needed to stimulate a regulatory response (2023 trans)
Antidiuretic Hormone (ADH)
 Formed primarily in the supraoptic nucleus and to a lesser
extent in the paraventricular nucleus in the thalamus under the
stimulation of the osmoreceptors and baroreceptors
 Transported down the hypothalamohypophyseal tract and stored
in secretory granules in the posterior pituitary, where it can be
released into the blood
 Mechanisms regulating the release of ADH: hyperosmolarity,
decrease in effective circulating volume, and increased production
of angiotensin II
1. Hyperosmolarity
 Increment in plasma osmolality perceived by hypothalamic
receptors as an effective osmotic gradient between the plasma
and receptor cell  water movement out of the cell  reduction in
cell volume or increase in concentration of some intracellular
solute  ADH secretion
 Plasma Na+ concentration = primary osmotic determinant of
ADH release
 Na+ salts are the major effective extracellular solutes.
2. Decrease in effective circulating volume (ECV)
 Decrease in ECV  decreased central venous pressure +
decreased firing rate of stretch receptors due to fall in atrial
pressure  release of ADH + enhanced sympathetic activity (2023
trans)
3. Increase in angiotensin II
 Increased production of angiotensin II  release of ADH (2023 trans)
TG 01: Abad, Abdulghaffar, Abella, Abu [Teh]
OS 201: SGD Concepts in Regulation
E06 | T06
Thirst
 Increased thirst = major defense against hyperosmolality and
hypernatremia
 Controlled by hypothalamic center near the production site of ADH
 Osmoreceptors and non-osmotic receptors (high- and low-
pressure baroreceptors) provide input to the thirst center
 Also stimulated by angiotensin II
Figure 3. The threshold for thirst is a plasma osmolarity of about 295 mOsm/L
and is rapid in onset. As long as water is readily available, the normal human
will not become hypernatremic due to water loss.
D. HOW IS BODY FLUID VOLUME REGULATED?
How is effective circulating volume preserved?
 Mechanism of preservation is done in two steps
 Change is sensed by volume receptors
 Receptors activate a series of effectors which restore
normovolemia by varying the following:
 Vascular resistance
 Cardiac Output
 Renal Na+
 Water Excretion
 Effective Circulating Volume
 Part of the ECF that is within the vascular space and is
effectively perfusing the tissues
 Not a quantitatively measurable entity but refers to the
rate of perfusion of the capillary circulation
 Decreased ECV leads to: decreased venous return,
decreased cardiac output, and decreased blood pressure
1. What are the volume sensors? (afferent limb)
 Primary volume receptors: in the cardiopulmonary circulation,
carotid sinuses and aortic arch
 Serve to monitor changes in the circulatory function within the
vasculature
 Kinds of Baroreceptors: Low pressure baroreceptors, High
pressure baroreceptors, Intrarenal baroreceptor system
 Cardiopulmonary Receptors
 Central circulation contains low-pressure receptors found in the
left ventricle and the pulmonary vascular bed.
 Decrease in filling of pulmonary vessels & cardiac atria 
decrease in central venous pressure  lower rate of discharge
from low-pressure baroreceptors (cardiopulmonary receptors)
 inhibition of vasomotor center in the brain and increase in
sympathetic outflow  increase in heart rate, peripheral
2 of 8
 OS 201: SGD Concepts in Regulation
E06 | T06

vascular resistance, antinatriuresis and antidiuresis 

increase in cardiac output, blood pressure and volume
conservation

TG 01: Abad, Abdulghaffar, Abella, Abu [Teh] 3 of 8

 OS 201: SGD Concepts in Regulation
E06 | T06

 High pressure baroreceptors (carotid sinus and aortic arch
baroreceptors)
 Receptors respond to the stretching of the arterial wall so that
increase in arterial pressure  passive expansion of arterial
wall  stimulated firing of high-pressure baroreceptors (arterial
receptors)  stimulate receptors to send signals to the nucleus
tractus solitarius in the medulla  stimulate release of
inhibitory signals (activate parasympathetic nerve activity) &
decrease catecholamine response
 Low pressure baroreceptors
 High compliance allows them to respond mainly to the
distension of the vascular system, specifically the walls of
the atria, right ventricle and large pulmonary vessels
 Send signals to the brainstem via afferent fibers in the
cranial nerves IX & X (glossopharyngeal & vagus nerves)
to modulate sympathetic nerve fibers and ADH secretion
 Intrarenal Baroreceptor System
 Aldosterone acts to enhance renal sodium reabsorption,
which is a critical factor for maintaining and eventually
restoring effective circulating volume
 Juxtaglomerular apparatus (JGA) of the kidneys,
particularly the afferent arteriole, responds directly to
changes in pressure.
 Reduced perfusion pressure in afferent arteriole 
release of renin from granular cells
 Increased perfusion pressure  suppressed renin
secretion
 Renin determines blood levels of angiotensin II and
aldosterone, both of which reduce renal NaCl excretion.

2. What are the volume effectors? (efferent limb)

 The kidney is a major effector organ in the body fluid volume
homeostasis loop
 Stimulation of afferent volume-sensing system  activation of
efferent limb
Figure 4. High pressure baroreceptors.
 Major efferent mechanisms regulating ECF volume:
 In hypovolemia or decreased effective plasma circulating  Glomerular filtration rate
volume, decrease stretch of arterial walls cause a decrease in  Sodium reabsorption at the renal tubules
receptor firing which would lead to increased sympathetic  Humoral effector mechanisms
activity  Renin-angiotensin-aldosterone system
 Intrarenal Baroreceptor System  Vasopressin
 Kidneys have a vital role in volume homeostasis of afferent  Catecholamines
limb  Atrial natriuretic peptides
 Endothelium-derived factors
 Intrarenal sensors are located in juxtaglomerular apparatus
(JGA) which release renin into the plasma that culminates in  Renal sympathetic nerves
the formation of angiotensin II and aldosterone  In order to preserve intravascular volume, sodium is retained

Table 1. Comparison of location and function of baroreceptors.

LOW
PRESSURE HIGH PRESSURE
CATEGORY
BARORECEPT BARORECEPTOR
OR
Venous side of Bifurcation of carotid artery
LOCATION central (carotid sinus body) and the
circulation aortic arch (aortic body)
 Assess filling
 Assess pressure of
of central
arterial circulation
venous
 Maintain mean arterial
circulation
FUNCTION pressure
 Monitor
 Protect the brain from
changes in
wide fluctuations in
intrathoracic
perfusion pressure
volume

TG 01: Abad, Abdulghaffar, Abella, Abu [Teh] 4 of 8

 OS 201: SGD Concepts in Regulation
E06 | T06

 Mechanisms for regulating ECF Volume Regulation of cell volume

 Glomerular filtration  Done by either gain or loss of osmotically active solutes, primarily
 First step in formation of urine inorganic ions (Na+, K+, Cl−) or organic osmolytes (small organic
 Filtrate from plasma glomerular capillaries goes into molecules)
Bowman’s capsule
 Mediated exclusively by changes in the activity of membrane
 Sodium reabsorption at the renal tubules carriers and channels
 Two-step process, both of which may occur via active
 These transport pathways rapidly activate after volume
or passive transport
perturbation which indicates that the carriers and channels are
− Movement of water and dissolved substances from
either:
the fluid inside the tubule through the tubule wall
 Residing in the cell membrane
into the space outside
 Rapidly inserted from preexisting cytoplasmic pool
− Water and these substances move through the
 Organic osmolytes: compatible/non perturbing solutes with
capillary walls back into your bloodstream, again,
unique biophysical and biochemical properties which allow
either by passive or active transport.
accumulation of high levels in cells.
 Humoral effector mechanisms
 These properties also allow them to withstand large shifts in
 Renin-angiotensin-aldosterone system (RAAS):
their concentration without deleterious effects on cellular
increases ECF volume by increasing sodium
structure and function
reabsorption
 Vasopressin (Antidiuretic Hormone or ADH)  Two kinds: rapid adaptation and slow adaptation
 Atrial natriuretic peptides reduce plasma volume by  Rapid adaptation
increasing GFR (increased excretion of salt and  Regulatory volume decrease and regulatory volume increase
water), vasodilation, and increased vascular  Accumulation of these salts is brought about when either
permeability Na+/H+ and Cl−/HCO3− exchangers or when Na+-K+-Cl−
 Renal sympathetic nerves function: cotransporter activates
 Constriction of the renal arterioles, which decreases  Activation of transport pathways is rapid and occurs within
GFR if the sympathetic activation is severe seconds to minutes after volume perturbation
 Increased tubular reabsorption of salt and water  Rapid stimulation is made possible because mediators either
 Stimulation of renin release and increased Ang II and reside in the plasma membrane or are stored in submembrane
aldosterone formation, both of which further increase cytoplasmic vesicles
tubular reabsorption.  Slow adaptation
 Volume regulatory organic osmolyte accumulation is mediated
by changes in:
How is cell volume preserved? Explain mechanisms  Activity of Na+-coupled membrane transporters
regulating cell volume.  Rates of synthesis and degradation
 Organic osmolyte accumulation: typically slow process and
Table 2. Types of cell volume changes: anisosmotic and isosmotic. needs many hours to reach completion
ANISOSMOTIC  Slow because activation of pathways requires transcription
ISOSMOTIC VOLUME and translation of genes coding for organic osmolyte
CATEGORY VOLUME
CHANGES accumulation
CHANGES
Alterations in Alterations in intracellular  Organic osmolyte loss: mediated largely by passive efflux
INDUCED BY mechanisms
extracellular activity solute content
Intracellular solute levels  Activation of mechanisms is rapid and occurs within seconds
Most mammalian after cell swelling is initiated
are maintained by:
cells (except cells
 Precise balance
UNDER in renal medulla
between solute influx  Short-term adjustments (within seconds)
NORMAL and gastrointestinal
and efflux across the  Made by alterations in Cardiac Output (CO) and total
PHYSIO- tract) are protected
plasma membrane peripheral resistance
LOGICAL from changes by
 Metabolic production  Mediated by means of autonomic nervous system
CONDITIONS kidney’s precise
and removal of influences on the heart, veins and arterioles
regulation of
osmotically active  Increase in co-transport of Na+-K+-Cl- inside the
plasma osmolality
substances cell, water will then follow inside

 All cells though are threatened with possible isosmotic swelling or

shrinkage as a variety of physiological and pathophysiological  Long term control (minutes to days)
conditions can disrupt the balance maintained.  Involves adjusting total blood volume by restoring normal
 For example, cell swelling in the brain after a stroke or head salt and water balance
trauma can cause isosmotic volume increase due to  Through mechanisms that regulate urine output and
intracellular accumulation of NaCl and other solutes thirst
 Activation of cell’s volume regulatory mechanisms happens as a  In turn, the total blood volume has a profound effect
response to volume perturbations. on cardiac output and mean arterial pressure
 Regulatory volume increase: Shrunken cells return to normal
volume, occurs by uptake of both KCl and NaCl
 Regulatory volume decrease: Swollen cells return to normal
volume, occurs through loss of KCl via activation of either
separate K+ and Cl− channels

TG 01: Abad, Abdulghaffar, Abella, Abu [Teh] 5 of 8

 OS 201: SGD Concepts in Regulation
E06 | T06

Table 3. Summary of events during cell swelling and shrinkage. Intravenous solutions
DURING CELL SWELLING DURING CELL SHRINKAGE
 A list of the characteristics of some balanced intravenous
 Release of ions through  Accumulation through
solutions can be found in the appendix
activation of K+ channels/ activation of Na+ channels
anion channels  Stimulates Na+-K+-Cl− co-
 Stimulates K+-Cl− co- transport Common Intravenous Fluids for Administration
transport  Na+/H+ exchange parallel to  Lactated ringer (Hartmann solution)
 Parallel activation of K+/H+ Cl−/HCO3− exchange
 Isotonic, 273 mOsm/L
exchange and Cl−/HCO3−  Further accumulate organic
 Lactate is used instead of bicarbonate
exchange osmolytes through altered
 One of the recommended IVs for fluid replacement
 Release of osmolytes during metabolism and Na+-coupled
swelling transport
Table 4. Composition of lactated ringer (Hartmann solution).
COMPONENT CONCENTRATION (in mEq/L)
E. WHAT HAPPENS IF HE DRINKS HIS URINE? WHAT
Na+ 130
PROPERTIES DOES URINE HAVE THAT AFFECT FLUID AND
K+ 4
ELECTROLYTE BALANCE?
Ca2+ 3
 The urine is maximally concentrated and may have an osmolarity Cl− 109
of 1200 mOsm/L (the maximum concentrating capacity of the Lactate 28
kidneys).
 The person is now forced to excrete 1200 mOsm plus the
 Normal Saline Solution (NSS)
additional solutes he ingested.
 0.9% NaCl
 (Assuming functional kidneys) increase in solute load  greater
 310 mOsm/L
obligatory loss of water
 One of the recommended IVs for fluid replacement
 Intake of fluid with very high osmolarity (e.g. ingestion of urine):
 Increase in ECF volume (hyperosmolar fluid stays in the ECF)
Table 5. Composition of normal saline solution.
 Increase in ECF osmolarity
COMPONENT CONCENTRATION (in mEq/L)
 Decrease in ICF volume
Na+ 154
 Concentrated urine
Cl− 154
F. IF YOU WERE THE EMERGENCY ROOM OFFICER, HOW
 Dextrose 5% in water (D5W)
ARE YOU GOING TO TREAT HIM? DEFINE TONICITY OF A
 Dextrose at about 50 gm/L
SOLUTION
 Considered isotonic, 250 mOsm/L
 First, resuscitate if hypotensive using isotonic saline or  Composition: No ions, just 5 grams of Dextrose.
intravenous balanced solution
 Then correct the volume deficit and the plasma osmolality G. WHAT WILL HAPPEN TO THE BRAIN CELLS IF YOU USE
A HYPOTONIC SOLUTION FOR RESUSCITATION?
Tonicity
 Rapid correction of hypernatremia using hypotonic solution may
 Tonicity refers to effective osmolality or the ability of particles in a rapidly decrease ECF osmolality.
solution to exert an osmotic force.  Decrease in the extracellular osmolality results to the
 Na+ and K+ can create an osmotic force because they are movement of water into the cell thus increasing the extracellular
impermeable to the cell membrane and remain in the ECF. volume and causing edema.
 Glucose under physiologic conditions does not remain in the ECF  Edema in the brain increases intracranial pressure since brain
because it is taken up by the cells. cells are confined within the cranium and may lead to herniation
 In the presence of insulin deficiency or insulin resistance, of the brain out of the cranium.
however, glucose becomes an effective osmole.  Intracranial edema may result to death.
 Urea is not an effective osmole because it can diffuse freely into
the cell.

Types of tonicity
 Tonicity is computed through this formula:
Tonicity (mmol/liter) = 2 x Na+[(meq/L) or (mmol/L)] +
glucose[(mmol/L) or (mg/dL + 18)]

 It can be classified into three categories:

1. Hypotonic or hypoosmolar – solution has an osmolarity or
tonicity < 280 mosmol/L
2. Isotonic or isoosmolar – solution has an osmolarity or
tonicity of 280-300 mosmol/L
3. Hypertonic or hyperosmolar – solution has an osmolarity or
tonicity > 300 mosmol/L
Fig 5. Brain edema. A decrease in extracellular osmolality cause movement
of water into the cells, increasing the intracellular volume and thus causing
tissue edema. This cellular edema within the fixed confines of the cranium
causes increased intracranial pressure, leading to neurologic symptoms.

TG 01: Abad, Abdulghaffar, Abella, Abu [Teh] 6 of 8

 OS 201: SGD Concepts in Regulation
E06 | T06

Activation of mechanisms regulating cell volume

 A regulatory volume increase mediated by the uptake of III. REFERENCES
electrolytes and a regulatory volume decrease mediated by the 2023 Trans
loss of electrolytes and organic osmolytes occur over a period of SGD Concepts in Regulation Faculty Guide
time. Koeppen, B. M. & Stanton, B. A. (eds.) (2018). Berne & Levy Physiology, 7th ed.
Philadelphia: Elsevier.
 When cells that have undergone a regulatory volume increase or
decrease are returned to normotonic conditions, they swell above
or shrink below their resting volume. END OF TRANS
 This is due to volume-regulatory accumulation or loss of solutes,
which effectively makes the cytoplasm hypertonic or hypotonic, as
compared with the normotonic ECF

TG 01: Abad, Abdulghaffar, Abella, Abu [Teh] 7 of 8

 OS 201: SGD Concepts in Regulation
E06 | T06

IV. APPENDIX

Table 6. Intravenous balanced solutions: quantitative and qualitative composition.

TG 01: Abad, Abdulghaffar, Abella, Abu [Teh] 8 of 8