Foundations of physiology
What is physiology?
Physiology is the dynamic study of life. It describes the “vital” functions of living organisms.
Physiology can be the function of the whole person, it can be the function of individual organ
systems, and it may focus on cellular principles. The last field is called general physiology or cellular
and molecular physiology.
Physiology can be divided according to varying degrees of reductionism, but it can also be divided in
branches of physiology that focus on differences and similarities among species (e.g. comparative
physiology), which deals with all degrees of reductionism. Medical physiology deals with the way the
human body functions, but doing so, it requires an understanding of events at all degrees of
reductionism. Physiology is the base of many biological sciences (e.g. biochemistry, biophysics,
neuroscience). The boundaries of physiology are not sharply defined and it has evolved over
centuries.
Physiological genomics is the link between the organ and the gene
The life in the body can only function properly if organ systems and cells function both individually
and together. All actions must be interdependent, information has to be shared.
Sharing of information between organs and between cells mostly takes place at the level of atoms or
molecules. It can be as simple as H⁺, K⁺ or Ca²⁺, but messengers can also be complex chemicals. Cells
can release molecules that act on nearby cells or on further cells via the bloodstream. Neurons can
send axons centimetres till metres away to modulate, through a neurotransmitter, the activity of
another cell/organ. The method of communication is almost always molecular.
The genome with its epigenetic modifications controls the cells, molecules, organs and the way they
interact.
Physiological genomics or functional genomics is a new branch of physiology devoted to the
understanding of the roles that genes play in physiology. Traditionally, physiologists have moved in a
reductionistic direction. Physiology is unique among the medical sciences in that it is broad in scope
and integrative in its outlook.
Cells live in a highly protected milieu intérieur
According to Claude Bernard animals have a milieu extérieur that physically surrounds the whole
organism and a milieu intérieur in which the tissues and cells of the organism live (1878). This
internal environment is a well-controlled liquid environment that he called “the organic liquid that
circulates and bathes all the anatomic elements of the tissues, the lymph or the plasma”. We call this
the extracellular fluid. According to Bernard, physiological functions continue despite changing
environments because of the isolating milieu intérieur. He described it as a greenhouse. According to
Bernard, some fluids within the body are not really inside the body (gastrointestinal tract, sweat
ducts, renal tubules). They are all continuous with the milieu extérieur. Bernard describes an
organism as an ensemble of anatomical elements that live together inside the milieu intérieur.
Another theme developed by Bernard was that the “fixité du milieu intérieur” (constancy of the
extracellular fluid) is the condition of free, independent life. He says that organ differentiation is
exclusive to higher organisms and that each organ contributes to compensate and equilibrate against
1
,changes in the exterior. In that sense, all body systems together maintain a constant internal
environment. Individual cells act to support the constancy of the internal milieu and the internal
milieu provides the cells with a medium in which they can thrive.
Physiology deals with those characteristics that are the property of a living organism as opposed to a
non-living organism. There are four fundamental properties.
- Only living organisms exchange matter and energy with the environment to survive.
- Only living organisms can receive and react to signals from the environment.
- Only living organisms have a life cycle of growth and reproduction.
- Only living organisms are able to adapt to changing circumstances.
Homeostatic mechanisms -operating through sophisticated feedback control
mechanisms- are responsible for maintaining the constancy of the milieu intérieur.
Homeostasis is the control of a vital parameter, and occurs on many levels in the body. The body
controls endless parameters. Arterial pressure and blood volume are examples of parameters that
affect nearly the whole body. At the level of the milieu intérieur, parameters include body core
temperature and plasma levels of oxygen, glucose, potassium ions (K⁺), calcium ions and hydrogen
ions.
Negative-feedback mechanism is responsible for homeostasis. It requires at least four elements.
1. The system senses the vital parameter or something related to it (e.g., glucose level).
2. The system compares the input with an internal reference value called a set-point, thereby
forming a different signal.
3. The system multiplies the error signal by a proportionality factor (i.e., the gain) to produce an
output signal (e.g., release of insulin).
4. The output signal activates an effector mechanism (e.g., glucose uptake and metabolism) that
opposes the source of the input signal, and thereby brings the vital parameter closer to the set-point
(e.g., decrease of blood glucose levels back to normal).
Positive-feedback loops are sometimes applied.
Redundancy = the more vital a parameter is, the more systems the body mobilizes to regulate it.
Homeostasis takes energy. Equilibrium is a state that does not involve energy consumption. A well-
regulated parameter is in a steady state. Cells must act to the needs of the body, that places
priorities when necessary. The adaptability of an organism depends on its ability to alter its response.
For example, after acclimatization at high attitudes, the body will alter to generate a faster breathing
than before. Genetic factors can contribute to adaptability as well.
Medicine is the study of “physiology gone awry”.
Physicochemical principles come from physiology. In medicine, physiology is needed to understand
chain-reactions that can happen when a malfunction leads to a primary pathological effect that
generates secondary effects.
Examples of tests developed in physiology: cardiac monitoring, pulmonary function tests, renal
clearance tests, assays to measure plasma levels of ions, gases and hormones.
2
,Transport of solutes and water
P102-p111, p115-117
Intracellular fluid (ICF) = fluid in the cells.
Extracellular fluid (ECF) = fluid outside of the cells.
Cell membranes separate these two compartments. The body must maintain the volume and
composition of the ICF and ECF. Cell membranes regulate the distribution of ions and water.
The intracellular and extracellular fluids
Total-body water is the sum of the ICF and ECF volumes.
Total-body water (TBW) is:
- ~60% of total-body weight in a young adult male.
- ~50% of total-body weight in a young adult female. (It’s lower because of a higher ratio of adipose
tissue to muscle, and fat cells have a lower water content than muscle).
- 65% to 75% of total-body weight in an infant.
TBW is not constant for all individuals. Changes in TBW can be detected by monitoring body weight,
since it takes up such a large fraction of the body weight. ~60% of TBW is intracellular fluid, ~40% is
extracellular (see figure 5.1). ECF is composed of blood plasma, interstitial fluid and transcellular
fluid.
Plasma volume
Only ~20% of ECF is contained within cardiac chambers and blood vessels (intravascular
compartment). The total volume of the intravascular compartment is the blood volume (~6L). The
extracellular 3L of the blood volume is the plasma volume. The other 3L consist of erythrocytes,
leukocytes and platelets. The fraction of blood volume that is occupied by these cells is the
haematocrit. It’s determined by centrifuging blood that is treated with an anticoagulant and
measuring the fraction of the total volume that is occupied by the packed cells.
Interstitial fluid
About ~75% of the ECF is outside the intravascular compartment, in non-blood cells. Within are two
smaller compartments that communicate slowly with the bulk of the interstitial fluid: dense
connective tissue (cartilage, tendons) and bone matrix. The walls of capillaries separate the
intravascular and interstitial compartments. Water and solutes can cross capillary walls and cell
membranes.
Transcellular fluid
~5% of ECF is within spaces surrounded by epithelial cells. Transcellular fluid includes synovial fluid
within joints and cerebrospinal fluid surrounding the brain and spinal cord.
ICF is rich in K⁺, ECF is rich in Na⁺ and Cl⁻
This is because the cell maintains a relatively high K⁺ concentration and low Na⁺ concentration using
a Na-K pump.
Transcellular fluids differ greatly from each other and from plasma, because they are secreted by
different epithelia. Plasma and interstitial fluid have similar composition as far as small solutes are
concerned. In most cells, the composition of the interstitial fluid enveloping the cells is the relevant
parameter. The major difference between plasma and interstitial fluid is the absence of plasma
3
, proteins in the interstitium: plasma proteins cannot equilibrate across the walls of capillaries. Plasma
proteins affect solute distribution because of their volume and electrical charge.
Volume occupied by plasma proteins
The proteins (and lipids) in plasma occupy ~7% of the total plasma volume. In clinical laboratories
plasma composition of ions is in units of milliequivalents per liter of plasma solution. For cells inside
interstitial fluid, milliequivalents per liter of protein-free plasma solution is more accurate, because
only the protein-free portion of plasma can equilibrate across the capillary wall.
Plasma water is protein-free plasma.
'(12/(-2/3 4('5. 62/ &'()*( [7( 8 ]
[𝑁𝑎$ ]&'()*( ,(-./ = &'()*( ,(-./ 92:-.:-
The plasma water content is usually 93% à 0,93.
Because of hyperproteinaemia (high levels of protein in blood) or hyperlipemia (high levels of lipid in
blood), values may appear abnormal even though the solute concentration per liter of plasma water
is normal. So when the plasma water is a smaller percentage of the plasma, the concentration can
still be normal if the laboratory value is low.
Effect of Protein Charge
For noncharged solutes like glucose, the correction for protein and lipid volume is the only correction
needed to predict interstitial concentrations from plasma concentrations. Because plasma proteins
are negatively charged and the capillary wall confines them to the plasma, they retain cations
(positively charged ions) in plasma. Therefore the cation concentration of protein-free solution of the
interstitium is lower by ~5%. Because the negatively charged plasma proteins repel anions
(negatively charged ions), the anion concentration of the protein-free solution of the interstitium is
higher by ~5%. So, for a cation like Na+, the interstitial concentration is 95% of the [Na+] of the
protein-free plasma water:
[𝑁𝑎$ ];:-./)-;-;5* = [𝑁𝑎$ ]&'()*( ,(-./ ∗ 0,95
For cations the two corrections (0,93/0,95) nearly cancel each other. For anions the two corrections
(1,05/0,93) are cumulative and give a total correction of ~13%.
All body fluids have approximately the same osmolality, and each fluid has equal
numbers of positive and negative charges.
Osmolality
All types of ECF have the same osmolality. Particles bound to macromolecules don’t contribute to
osmolality. Osmolality is expressed as the number of particles per kilogram of water. All body fluid
compartments in humans have an osmolality of ~290 milliosmoles / kg H2O (290 mOsm).
Plasma proteins contribute ~14 meq/L. However, they have many negative charges per molecule, so
not many particles (~mM) are necessary to account for these milliequivalents. If the protein
concentration in grams per liter is high, the protein concentration in moles per liter is very low,
because of the high molecular weight of proteins. Thus, proteins contribute only slightly to the total
number of osmotically active particles (~1 mOsm).
Summing the total concentrations, we would see that the total solute concentration of the
intracellular compartment is higher than that of the interstitium. This seems illogical because of the
water flow across cell membranes. Explanation: Ions and can be bound to other solutes, and proteins
can be attached to non-solutes. Because each particle is counted once, the osmolality may seem odd.
4
