An important intermediate in industrial chemistry,
nitric oxide forms in combustion systems and can be generated by
lightning in thunderstorms. In mammals, including humans, nitric oxide
is a signaling molecule in many physiological and pathological processes. It was proclaimed the "Molecule of the Year" in 1992. The 1998 Nobel Prize in Physiology or Medicine was awarded for discovering nitric oxide's role as a cardiovascular signalling molecule.
Upon condensing to a liquid, nitric oxide dimerizes to dinitrogen dioxide, but the association is weak and reversible. The N–N distance in crystalline NO is 218 pm, nearly twice the N–O distance.
Since the heat of formation of ·NO is endothermic, NO can be decomposed to the elements. Catalytic converters in cars exploit this reaction:
With NO2, also a radical, NO combines to form the intensely blue dinitrogen trioxide:
NO + NO2 ⇌ ON−NO2.
Organic chemistry
The addition of a nitric oxide moiety to another molecule is often referred to as nitrosylation. The Traube reaction is the addition of a two equivalents of nitric oxide onto an enolate, giving a diazeniumdiolate (also called a nitrosohydroxylamine). The product can undergo a subsequent retro-aldol reaction, giving an overall process similar to the haloform reaction. For example, nitric oxide reacts with acetone and an alkoxide to form a diazeniumdiolate on each α position, with subsequent loss of methyl acetate as by-product:
This reaction, which was discovered around 1898, remains of interest in nitric oxide prodrug research. Nitric oxide can also react directly with sodium methoxide, ultimately forming forming sodium formate and nitrous oxide by way of an N-methoxydiazeniumdiolate.
Coordination complexes
Nitric oxide reacts with transition metals to give complexes called metal nitrosyls. The most common bonding mode of nitric oxide is the terminal linear type (M−NO).
Alternatively, nitric oxide can serve as a one-electron pseudohalide.
In such complexes, the M−N−O group is characterized by an angle between
120° and 140°. The NO group can also bridge between metal centers
through the nitrogen atom in a variety of geometries.
The uncatalyzed endothermic reaction of oxygen (O2) and nitrogen (N2),
which is effected at high temperature (>2000 °C) by lightning has
not been developed into a practical commercial synthesis:
N2 + O2 → 2 NO
Laboratory methods
In the laboratory, nitric oxide is conveniently generated by reduction of dilute nitric acid with copper:
The iron(II) sulfate route is simple and has been used in undergraduate laboratory experiments. So-called NONOate compounds are also used for nitric oxide generation.
Detection and assay
Nitric oxide (white) in conifer cells, visualized using DAF-2 DA (diaminofluorescein diacetate)
Nitric oxide concentration can be determined using a chemiluminescent reaction involving ozone. A sample containing nitric oxide is mixed with a large quantity of ozone. The nitric oxide reacts with the ozone to produce oxygen and nitrogen dioxide, accompanied with emission of light (chemiluminescence):
NO + O3 → NO2 + O2 + hν
which can be measured with a photodetector. The amount of light produced is proportional to the amount of nitric oxide in the sample.
Other methods of testing include electroanalysis
(amperometric approach), where ·NO reacts with an electrode to induce a
current or voltage change. The detection of NO radicals in biological
tissues is particularly difficult due to the short lifetime and
concentration of these radicals in tissues. One of the few practical
methods is spin trapping of nitric oxide with iron-dithiocarbamate complexes and subsequent detection of the mono-nitrosyl-iron complex with electron paramagnetic resonance (EPR).
Nitric oxide reacts with the hydroperoxy radical (HO2•) to form nitrogen dioxide (NO2), which then can react with a hydroxyl radical (•OH) to produce nitric acid (HNO3):
·NO participates in ozone layer depletion. Nitric oxide reacts with stratospheric ozone to form O2 and nitrogen dioxide:
·NO + O3 → NO2 + O2
This reaction is also utilized to measure concentrations of ·NO in control volumes.
Precursor to NO2
As
seen in the Acid deposition section, nitric oxide can transform into
nitrogen dioxide (this can happen with the hydroperoxy radical, HO2•, or diatomic oxygen, O2). Symptoms of short-term nitrogen dioxide exposure include nausea, dyspnea and headache. Long-term effects could include impaired immune and respiratory function.
Biological functions
NO is a gaseous signaling molecule. It is a key vertebratebiological messenger, playing a role in a variety of biological processes. It is a known bioproduct in almost all types of organisms, ranging from bacteria to plants, fungi, and animal cells.
Nitric oxide, known as an endothelium-derived relaxing factor (EDRF), is biosynthesized endogenously from L-arginine, oxygen, and NADPH by various nitric oxide synthase (NOS) enzymes. Reduction of inorganic nitrate may also serve to make nitric oxide. One of the main enzymatic targets of nitric oxide is guanylyl cyclase. The binding of nitric oxide to the haem region of the enzyme leads to activation, in the presence of iron.
Nitric oxide is highly reactive (having a lifetime of a few seconds),
yet diffuses freely across membranes. These attributes make nitric oxide
ideal for a transient paracrine (between adjacent cells) and autocrine (within a single cell) signaling molecule. Once nitric oxide is converted to nitrates and nitrites by oxygen and water, cell signaling is deactivated.
The endothelium (inner lining) of blood vessels uses nitric oxide to signal the surrounding smooth muscle to relax, thus resulting in vasodilation and increasing blood flow. Sildenafil
(Viagra) is a common example of a drug that uses the nitric oxide
pathway. Sildenafil does not produce nitric oxide, but enhances the
signals that are the downstream of the nitric oxide pathway by
protecting cyclic guanosine monophosphate (cGMP) from degradation by cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, allowing for the signal to be enhanced, and thus vasodilation. Another endogenous gaseous transmitter, hydrogen sulfide (H2S) works with NO to induce vasodilation and angiogenesis in a cooperative manner.
Many extracellular proteins such as the plasma proteins and membrane proteins of the body's cells are very sensitive for their three dimensional structures to the extracellular pH. Stringent mechanisms therefore exist to maintain the pH within very narrow limits. Outside the acceptable range of pH, proteins are denatured (i.e. their 3-D structure is disrupted), causing enzymes and ion channels (among others) to malfunction.
In humans and many other animals, acid–base homeostasis is maintained by multiple mechanisms involved in three lines of defense:
1. Chemical: The first lines of defense are immediate – the various chemical buffers which minimize pH changes that would otherwise occur in their absence. These buffers include the bicarbonate buffer system, the phosphate buffer system, and the protein buffer system.
2. Respiratory Component: The second line of defense of the extracellular fluid pH is rapid, measured by PCO2, and consists of controlling the carbonic acid concentration in the ECF by changing the rate and depth of breathing (i.e. by hyperventilation or hypoventilation). This blows off or retains carbon dioxide (and thus carbonic acid) in the blood plasma as required.
3. Metabolic Component: The third line of defense is slow, best measured by the Base Excess, and mostly depends on the renal system which can add or remove bicarbonate ions to or from the ECF. The bicarbonate is derived from metabolic carbon dioxide which is enzymatically converted to carbonic acid in the renal tubular cells. The carbonic acid spontaneously dissociates into hydrogen ions and bicarbonate ions.
When the pH in the ECF tends to fall (i.e. become more acidic) the
hydrogen ions are excreted into the urine, while the bicarbonate ions
are secreted into the blood plasma, causing the plasma pH to rise
(correcting the initial fall).
The converse happens if the pH in the ECF tends to rise: the
bicarbonate ions are then excreted into the urine and the hydrogen ions
into the blood plasma.
The second and third lines of defense operate by making changes to
the buffers, each of which consists of two components: a weak acid and
its conjugate base. It is the ratio concentration of the weak acid to its conjugate base that determines the pH of the solution. Thus, by manipulating firstly the concentration of the weak acid, and secondly that of its conjugate base, the pH of the extracellular fluid (ECF) can be adjusted very accurately to the correct value. The bicarbonate buffer, consisting of a mixture of carbonic acid (H2CO3) and a bicarbonate (HCO− 3)
salt in solution, is the most abundant buffer in the extracellular
fluid, and it is also the buffer whose acid to base ratio can be changed
very easily and rapidly.
Aqueousbuffer solutions will react with strong acids or strong bases by absorbing excess hydrogenH+ ions, or hydroxideOH− ions, replacing the strong acids and bases with weak acids and weak bases.
This has the effect of damping the effect of pH changes, or reducing
the pH change that would otherwise have occurred. But buffers cannot
correct abnormal pH levels in a solution, be that solution in a test
tube or in the extracellular fluid. Buffers typically consist of a pair
of compounds in solution, one of which is a weak acid and the other a
weak base. The most abundant buffer in the ECF consists of a solution of carbonic acid (H2CO3), and the bicarbonate (HCO− 3) salt of, usually, sodium (Na+). Thus, when there is an excess of OH− ions in the solution carbonic acid partially neutralizes them by forming H2O and bicarbonate (HCO− 3) ions. Similarly an excess of H+ ions is partially neutralized by the bicarbonate component of the buffer solution to form carbonic acid (H2CO3), which, because it is a weak acid, remains largely in the undissociated form, releasing far fewer H+ ions into the solution than the original strong acid would have done.
The pH of a buffer solution depends solely on the ratio of the molar
concentrations of the weak acid to the weak base. The higher the
concentration of the weak acid in the solution (compared to the weak
base) the lower the resulting pH of the solution. Similarly, if the weak
base predominates the higher the resulting pH.
This principle is exploited to regulate the pH of the extracellular fluids (rather than just buffering the pH). For the carbonic acid-bicarbonate buffer,
a molar ratio of weak acid to weak base of 1:20 produces a pH of 7.4;
and vice versa - when the pH of the extracellular fluids is 7.4 then
the ratio of carbonic acid to bicarbonate ions in that fluid is 1:20.
This relationship is accurately defined by the simple Henderson Equation:
[H+] x [HCO3-] = K x [CO2] x [H2O]
which relates the concentrations of the four variables with K being the dissociation constant of carbonic acid
However this can be further simplified because:
[H2O] is constant and the partial pressure of CO2 is more familiar which leaves us:
[H+] x [HCO3-] = K x PCO2
Recognition of an acute change now becomes simple:
With a constant PCO2, an increase in [H+] must lower the [HCO3-]
And an increase in the PCO2 initially at least increases both [H+] and [HCO3-]
For more chronic changes there is time for compensation – see below.
Unfortunately, Hasselbalch entered:
This is not the equation most commonly taught.
With no benefit and a huge penalty in complexity the Henderson–Hasselbalch is used.
The Logarithmic notation makes recognition much harder.
It is described here because it is customary, not because it is useful.
pH is the negative logarithm (or cologarithm)
of molar concentration of hydrogen ions in the ECF. It indicates the
acidity in the ECF in an inverse manner: the lower the pH the greater
the acidity of the solution.
[HCO− 3] is the molar concentration of bicarbonate in the blood plasma
[H2CO3] is the molar concentration of carbonic acid in the ECF.
However, since the carbonic acid concentration is directly proportional to the partial pressure of carbon dioxide () in the extracellular fluid, the equation can be rewritten as follows:
where:
pH is the negative logarithm of molar concentration of hydrogen ions in the ECF, as before.
[HCO− 3] is the molar concentration of bicarbonate in the plasma
The pH of the extracellular fluids can thus be controlled by the regulation of the Respiratory Acid (PCO2), and the Metabolic Acids (Every other acid).
Compensation:
In general, metabolism produces more waste acids than bases. Respiratory Acidosis tends to cause an acid pH. When Acute, e.g., from poisoning or trauma, there is no time for compensation. There is a Pure Respiratory Acidosis and the change in pH is Typical. However, lung disease usually causes Chronic Respiratory Acidosis and Metabolic Compensation returns the pH roughly Half Way Back to Normal. Metabolic Acidosis also tends to cause an acid pH but normal lungs usually compensate promptly to maintain the pH roughly Half Way Back to Normal.
The central chemoreceptors send their information to the respiratory centres in the medulla oblongata and pons of the brainstem. The respiratory centres then determine the average rate of ventilation of the alveoli of the lungs, to keep the partial pressure carbon dioxide in the arterial blood constant. The respiratory center does so via motor neurons which activate the muscles of respiration (in particular the diaphragm).
A rise in the partial pressure of carbon dioxide in the arterial blood
plasma above 5.3 kPa (40 mmHg) reflexly causes an increase in the rate
and depth of breathing. Normal breathing is resumed when the partial pressure of carbon dioxide has returned to 5.3 kPa.
The converse happens if the partial pressure of carbon dioxide falls
below the normal range. Breathing may be temporally halted, or slowed
down to allow carbon dioxide to accumulate once more in the lungs and
arterial blood.
The sensor for the plasma HCO− 3 concentration is not known for certain. It is very probable that the renal tubular cells of the distal convoluted tubules are themselves sensitive to the pH of the plasma. The metabolism of these cells produces CO2, which is rapidly converted to H+ and HCO− 3 through the action of carbonic anhydrase. When the extracellular fluids tend towards acidity, the renal tubular cells secrete the H+ ions into the tubular fluid from where they exit the body via the urine. The HCO− 3
ions are simultaneously secreted into the blood plasma, thus raising
the bicarbonate ion concentration in the plasma, lowering the carbonic
acid/bicarbonate ion ratio, and consequently raising the pH of the
plasma.
The converse happens when the plasma pH rises above normal: bicarbonate
ions are excreted into the urine, and hydrogen ions into the plasma.
These combine with the bicarbonate ions in the plasma to form carbonic
acid (H+ + HCO− 3 = H2CO3), thus raising the carbonic acid:bicarbonate ratio in the extracellular fluids, and returning its pH to normal.
Urine is generally acid which, to a certain extent, is usually neutralized by the ammonia (NH3) which is excreted into the urine when glutamate and glutamine (carriers of excess, no longer needed, amino groups) are deaminated by the distal renal tubular epithelial cells. Thus some of the "acid content" of the urine resides in the resulting ammonium ion (NH4+) content of the urine, though this has no effect on pH homeostasis of the extracellular fluids.
Imbalance
An Acid Base Diagram for human plasma, showing the effects on the plasma pH when PCO2 in mmHg or Standard Base Excess (SBE) occur in excess or are deficient in the plasma
Acid–base imbalance occurs when a significant insult causes the blood pH to shift out of the normal range (7.32 to 7.42). An abnormally low pH in the ECF is called an acidemia and an abnormally high pH is called an Alkalemia.
"Acidemia" and "alkalemia",
refer unambiguously to the actual change in the pH of the ECF. Two
other similar sounding terms are "acidosis" and "alkalosis". They refer
to the customary effect of a component, respiratory or metabolic.
Acidosis would on its own (i.e. if left "uncompensated" by an alkalosis) cause an acidemia. Similarly an alkalosis would on its own cause an alkalemia. The terms acidosis and alkalosis should always be qualified by an adjective to indicate the cause of the disturbance: "respiratory" (indicating a change in the partial pressure of carbon dioxide), or "metabolic" (indicating a change in the Base Excess of the ECF). There are therefore four different acid-base problems: metabolic acidosis, respiratory acidosis, metabolic alkalosis, and respiratory alkalosis. One or a combination these conditions may occur simultaneously. For instance, a metabolic acidosis (as in uncontrolled diabetes mellitus)
is almost always partially compensated by a respiratory alkalosis
(hyperventilation), or a respiratory acidosis can be completely or
partially corrected by a metabolic alkalosis.
In biology, homeostasis is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and includes many variables, such as body temperature and fluid balance, being kept within certain pre-set limits (homeostatic range). Other variables include the pH of extracellular fluid, the concentrations of sodium, potassium and calciumions, as well as that of the blood sugar level,
and these need to be regulated despite changes in the environment,
diet, or level of activity. Each of these variables is controlled by one
or more regulators or homeostatic mechanisms, which together maintain
life.
Homeostasis is brought about by a natural resistance to change when already in the optimal conditions,
and equilibrium is maintained by many regulatory mechanisms. All
homeostatic control mechanisms have at least three interdependent
components for the variable being regulated: a receptor, a control
centre, and an effector.
The receptor is the sensing component that monitors and responds to
changes in the environment, either external or internal. Receptors
include thermoreceptors, and mechanoreceptors. Control centres include the respiratory centre, and the renin–angiotensin system.
An effector is the target acted on, to bring about the change back to
the normal state. At the cellular level, receptors include nuclear receptors that bring about changes in gene expression through up-regulation or down-regulation, and act in negative feedback mechanisms. An example of this is in the control of bile acids in the liver.
Some centers, such as the renin–angiotensin system,
control more than one variable. When the receptor senses a stimulus, it
reacts by sending action potentials to a control center. The control
center sets the maintenance range—the acceptable upper and lower
limits—for the particular variable, such as temperature. The control
center responds to the signal by determining an appropriate response and
sending signals to an effector, which can be one or more muscles, an organ, or a gland.
When the signal is received and acted on, negative feedback is provided
to the receptor that stops the need for further signaling.
The cannabinoid receptor type 1 (CB1), located at the presynapticneuron, is a receptor that can stop stressful neurotransmitter release to the postsynaptic neuron; it is activated by endocannabinoids (ECs) such as anandamide (N-arachidonoylethanolamide; AEA) and 2-arachidonoylglycerol (2-AG) via a retrograde signaling
process in which these compounds are synthesized by and released from
postsynaptic neurons, and travel back to the presynaptic terminal to
bind to the CB1 receptor for modulation of neurotransmitter release to
obtain homeostasis.
The polyunsaturated fatty acids (PUFAs) are lipid derivatives of omega-3 (docosahexaenoic acid, DHA, and eicosapentaenoic acid, EPA) or of omega-6 (arachidonic acid, ARA) are synthesized from membranephospholipids and used as a precursor for endocannabinoids (ECs) mediate significant effects in the fine-tune adjustment of body homeostasis.
History
The concept of the regulation of the internal environment was described by French physiologist Claude Bernard in 1849, and the word homeostasis was coined by Walter Bradford Cannon in 1926. In 1932, Joseph Barcroft a British physiologist, was the first to say that higher brain
function required the most stable internal environment. Thus, to
Barcroft homeostasis was not only organized by the brain—homeostasis
served the brain.
Homeostasis is an almost exclusively biological term, referring to the
concepts described by Bernard and Cannon, concerning the constancy of
the internal environment in which the cells of the body live and
survive. The term cybernetics is applied to technological control systems such as thermostats, which function as homeostatic mechanisms, but is often defined much more broadly than the biological term of homeostasis.
Etymology
The word homeostasis (/ˌhoʊmioʊˈsteɪsɪs/) uses combining forms of homeo- and -stasis, New Latin from Greek: ὅμοιος homoios, "similar" and στάσις stasis, "standing still", yielding the idea of "staying the same".
Overview
The metabolic processes
of all organisms can only take place in very specific physical and
chemical environments. The conditions vary with each organism, and with
whether the chemical processes take place inside the cell or in the interstitial fluid
bathing the cells. The best known homeostatic mechanisms in humans and
other mammals are regulators that keep the composition of the extracellular fluid (or the "internal environment") constant, especially with regard to the temperature, pH, osmolality, and the concentrations of sodium, potassium, glucose, carbon dioxide, and oxygen. However, a great many other homeostatic mechanisms, encompassing many aspects of human physiology,
control other entities in the body. Where the levels of variables are
higher or lower than those needed, they are often prefixed with hyper- and hypo-, respectively such as hyperthermia and hypothermia or hypertension and hypotension.
Circadian variation in body temperature, ranging from about 37.5 °C from 10 a.m. to 6 p.m., and falling to about 36.4 °C from 2 a.m. to 6 a.m.
If an entity is homeostatically controlled it does not imply that its value is necessarily absolutely steady in health. Core body temperature is, for instance, regulated by a homeostatic mechanism with temperature sensors in, amongst others, the hypothalamus of the brain. However, the set point of the regulator is regularly reset. For instance, core body temperature in humans varies during the course of the day (i.e. has a circadian rhythm), with the lowest temperatures occurring at night, and the highest in the afternoons. Other normal temperature variations include those related to the menstrual cycle. The temperature regulator's set point is reset during infections to produce a fever.
Organisms are capable of adjusting somewhat to varied conditions such
as temperature changes or oxygen levels at altitude, by a process of acclimatisation.
Homeostasis does not govern every activity in the body. For instance the signal (be it via neurons or hormones) from the sensor to the effector is, of necessity, highly variable in order to convey information about the direction and magnitude of the error detected by the sensor.
Similarly the effector's response needs to be highly adjustable to
reverse the error – in fact it should be very nearly in proportion (but
in the opposite direction) to the error that is threatening the internal
environment. For instance, the arterial blood pressure in mammals is homeostatically controlled, and measured by stretch receptors in the walls of the aortic arch and carotid sinuses at beginnings of the internal carotid arteries. The sensors send messages via sensory nerves to the medulla oblongata of the brain indicating whether the blood pressure has fallen or risen, and by how much. The medulla oblongata then distributes messages along motor or efferent nerves belonging to the autonomic nervous system
to a wide variety of effector organs, whose activity is consequently
changed to reverse the error in the blood pressure. One of the effector
organs is the heart whose rate is stimulated to rise (tachycardia) when the arterial blood pressure falls, or to slow down (bradycardia) when the pressure rises above set point.
Thus the heart rate (for which there is no sensor in the body) is not
homeostatically controlled, but is one of effector responses to errors
in the arterial blood pressure. Another example is the rate of sweating.
This is one of the effectors in the homeostatic control of body
temperature, and therefore highly variable in rough proportion to the
heat load that threatens to destabilize the body's core temperature, for
which there is a sensor in the hypothalamus of the brain.
Controls of variables
Core temperature
Birds huddling for warmth
Mammals regulate their core temperature using input from thermoreceptors in the hypothalamus, brain, spinal cord, internal organs, and great veins. Apart from the internal regulation of temperature, a process called allostasis can come into play that adjusts behaviour to adapt to the challenge of very hot or cold extremes (and to other challenges).These adjustments may include seeking shade and reducing activity, or
seeking warmer conditions and increasing activity, or huddling.
Behavioural thermoregulation takes precedence over physiological
thermoregulation since necessary changes can be affected more quickly
and physiological thermoregulation is limited in its capacity to respond
to extreme temperatures.
When core temperature falls, the blood supply to the skin is reduced by intense vasoconstriction.
The blood flow to the limbs (which have a large surface area) is
similarly reduced, and returned to the trunk via the deep veins which
lie alongside the arteries (forming venae comitantes). This acts as a counter-current exchange system
which short-circuits the warmth from the arterial blood directly into
the venous blood returning into the trunk, causing minimal heat loss
from the extremities in cold weather. The subcutaneous limb veins are tightly constricted,
not only reducing heat loss from this source, but also forcing the
venous blood into the counter-current system in the depths of the limbs.
When core temperature rises are detected by thermoreceptors, the sweat glands in the skin are stimulated via cholinergicsympathetic nerves to secrete sweat
onto the skin, which, when it evaporates, cools the skin and the blood
flowing through it. Panting is an alternative effector in many
vertebrates, which cools the body also by the evaporation of water, but
this time from the mucous membranes of the throat and mouth.
Blood glucose
Negative
feedback at work in the regulation of blood sugar. Flat line is the
set-point of glucose level and sine wave the fluctuations of glucose.
Blood sugar levels are regulated within fairly narrow limits. In mammals the primary sensors for this are the beta cells of the pancreatic islets. The beta cells respond to a rise in the blood sugar level by secreting insulin into the blood, and simultaneously inhibiting their neighboring alpha cells from secreting glucagon into the blood.This combination (high blood insulin levels and low glucagon levels) act on effector tissues, chief of which are the liver, fat cells and muscle cells. The liver is inhibited from producing glucose, taking it up instead, and converting it to glycogen and triglycerides. The glycogen is stored in the liver, but the triglycerides are secreted into the blood as very low-density lipoprotein (VLDL) particles which are taken up by adipose tissue, there to be stored as fats. The fat cells take up glucose through special glucose transporters (GLUT4),
whose numbers in the cell wall are increased as a direct effect of
insulin acting on these cells. The glucose that enters the fat cells in
this manner is converted into triglycerides (via the same metabolic
pathways as are used by the liver) and then stored in those fat cells
together with the VLDL-derived triglycerides that were made in the
liver. Muscle cells also take glucose up through insulin-sensitive GLUT4
glucose channels, and convert it into muscle glycogen.
A fall in blood glucose, causes insulin secretion to be stopped, and glucagon
to be secreted from the alpha cells into the blood. This inhibits the
uptake of glucose from the blood by the liver, fats cells and muscle.
Instead the liver is strongly stimulated to manufacture glucose from
glycogen (through glycogenolysis) and from non-carbohydrate sources (such as lactate and de-aminated amino acids) using a process known as gluconeogenesis. The glucose thus produced is discharged into the blood correcting the detected error (hypoglycemia). The glycogen stored in muscles remains in the muscles, and is only broken down, during exercise, to glucose-6-phosphate and thence to pyruvate to be fed into the citric acid cycle or turned into lactate.
It is only the lactate and the waste products of the citric acid cycle
that are returned to the blood. The liver can take up only the lactate,
and by the process of energy consuming gluconeogenesis convert it back to glucose.
Too little carbon dioxide, and, to a lesser extent, too much
oxygen in the blood can temporarily halt breathing, a condition known as
apnea, which freedivers use to prolong the time they can stay underwater.
The partial pressure of carbon dioxide is more of a deciding factor in the monitoring of pH. However, at high altitude (above 2500 m) the monitoring of the partial pressure of oxygen takes priority, and hyperventilation
keeps the oxygen level constant. With the lower level of carbon
dioxide, to keep the pH at 7.4 the kidneys secrete hydrogen ions into
the blood, and excrete bicarbonate into the urine. This is important in the acclimatization to high altitude.
Blood oxygen content
The kidneys measure the oxygen content rather than the partial pressure of oxygen in the arterial blood. When the oxygen content of the blood is chronically low, oxygen-sensitive cells secrete erythropoietin (EPO) into the blood. The effector tissue is the red bone marrow which produces red blood cells (RBCs)(erythrocytes). The increase in RBCs leads to an increased hematocrit in the blood, and subsequent increase in hemoglobin
that increases the oxygen carrying capacity. This is the mechanism
whereby high altitude dwellers have higher hematocrits than sea-level
residents, and also why persons with pulmonary insufficiency or right-to-left shunts
in the heart (through which venous blood by-passes the lungs and goes
directly into the systemic circulation) have similarly high hematocrits.
Regardless of the partial pressure of oxygen in the blood, the
amount of oxygen that can be carried, depends on the hemoglobin content.
The partial pressure of oxygen may be sufficient for example in anemia, but the hemoglobin content will be insufficient and subsequently as will be the oxygen content. Given enough supply of iron, vitamin B12 and folic acid, EPO can stimulate RBC production, and hemoglobin and oxygen content restored to normal.
Arterial blood pressure
The brain can regulate blood flow over a range of blood pressure values by vasoconstriction and vasodilation of the arteries.
High pressure receptors called baroreceptors in the walls of the aortic arch and carotid sinus (at the beginning of the internal carotid artery) monitor the arterial blood pressure. Rising pressure is detected when the walls of the arteries stretch due to an increase in blood volume. This causes heart muscle cells to secrete the hormone atrial natriuretic peptide
(ANP) into the blood. This acts on the kidneys to inhibit the secretion
of renin and aldosterone causing the release of sodium, and
accompanying water into the urine, thereby reducing the blood volume.
This information is then conveyed, via afferent nerve fibers, to the solitary nucleus in the medulla oblongata. From here motor nerves belonging to the autonomic nervous system are stimulated to influence the activity of chiefly the heart and the smallest diameter arteries, called arterioles. The arterioles are the main resistance vessels in the arterial tree,
and small changes in diameter cause large changes in the resistance to
flow through them. When the arterial blood pressure rises the arterioles
are stimulated to dilate
making it easier for blood to leave the arteries, thus deflating them,
and bringing the blood pressure down, back to normal. At the same time,
the heart is stimulated via cholinergicparasympathetic nerves to beat more slowly (called bradycardia),
ensuring that the inflow of blood into the arteries is reduced, thus
adding to the reduction in pressure, and correction of the original
error.
Low pressure in the arteries, causes the opposite reflex of
constriction of the arterioles, and a speeding up of the heart rate
(called tachycardia). If the drop in blood pressure is very rapid or excessive, the medulla oblongata stimulates the adrenal medulla, via "preganglionic" sympathetic nerves, to secrete epinephrine (adrenaline) into the blood. This hormone enhances the tachycardia and causes severe vasoconstriction
of the arterioles to all but the essential organ in the body
(especially the heart, lungs, and brain). These reactions usually
correct the low arterial blood pressure (hypotension) very effectively.
Calcium levels
Calcium homeostasis
The plasma ionized calcium (Ca2+) concentration is very tightly controlled by a pair of homeostatic mechanisms. The sensor for the first one is situated in the parathyroid glands, where the chief cells sense the Ca2+ level by means of specialized calcium receptors in their membranes. The sensors for the second are the parafollicular cells in the thyroid gland. The parathyroid chief cells secrete parathyroid hormone (PTH) in response to a fall in the plasma ionized calcium level; the parafollicular cells of the thyroid gland secrete calcitonin in response to a rise in the plasma ionized calcium level.
The effector organs of the first homeostatic mechanism are the bones, the kidney, and, via a hormone released into the blood by the kidney in response to high PTH levels in the blood, the duodenum and jejunum. Parathyroid hormone (in high concentrations in the blood) causes bone resorption, releasing calcium into the plasma. This is a very rapid action which can correct a threatening hypocalcemia within minutes. High PTH concentrations cause the excretion of phosphate ions via the urine. Since phosphates combine with calcium ions to form insoluble salts (see also bone mineral),
a decrease in the level of phosphates in the blood, releases free
calcium ions into the plasma ionized calcium pool. PTH has a second
action on the kidneys. It stimulates the manufacture and release, by the
kidneys, of calcitriol into the blood. This steroid
hormone acts on the epithelial cells of the upper small intestine,
increasing their capacity to absorb calcium from the gut contents into
the blood.
The second homeostatic mechanism, with its sensors in the thyroid
gland, releases calcitonin into the blood when the blood ionized
calcium rises. This hormone acts primarily on bone, causing the rapid
removal of calcium from the blood and depositing it, in insoluble form,
in the bones.
The two homeostatic mechanisms working through PTH on the one
hand, and calcitonin on the other can very rapidly correct any impending
error in the plasma ionized calcium level by either removing calcium
from the blood and depositing it in the skeleton, or by removing calcium
from it. The skeleton
acts as an extremely large calcium store (about 1 kg) compared with the
plasma calcium store (about 180 mg). Longer term regulation occurs
through calcium absorption or loss from the gut.
Another example are the most well-characterised endocannabinoids like anandamide (N-arachidonoylethanolamide; AEA) and 2-arachidonoylglycerol (2-AG), whose synthesis occurs through the action of a series of intracellularenzymes activated in response to a rise in intracellular calcium levels to introduce homeostasis and prevention of tumor development through putative protective mechanisms that prevent cell growth and migration by activation of CB1 and/or CB2 and adjoining receptors.
Sodium concentration
The homeostatic mechanism which controls the plasma sodium
concentration is rather more complex than most of the other homeostatic
mechanisms described on this page.
The sensor is situated in the juxtaglomerular apparatus
of kidneys, which senses the plasma sodium concentration in a
surprisingly indirect manner. Instead of measuring it directly in the
blood flowing past the juxtaglomerular cells, these cells respond to the sodium concentration in the renal tubular fluid after it has already undergone a certain amount of modification in the proximal convoluted tubule and loop of Henle.
These cells also respond to rate of blood flow through the
juxtaglomerular apparatus, which, under normal circumstances, is
directly proportional to the arterial blood pressure, making this tissue an ancillary arterial blood pressure sensor.
In response to a lowering of the plasma sodium concentration, or
to a fall in the arterial blood pressure, the juxtaglomerular cells
release renin into the blood. Renin is an enzyme which cleaves a decapeptide (a short protein chain, 10 amino acids long) from a plasma α-2-globulin called angiotensinogen. This decapeptide is known as angiotensin I. It has no known biological activity. However, when the blood circulates through the lungs a pulmonary capillary endothelial enzyme called angiotensin-converting enzyme (ACE) cleaves a further two amino acids from angiotensin I to form an octapeptide known as angiotensin II. Angiotensin II is a hormone which acts on the adrenal cortex, causing the release into the blood of the steroid hormone, aldosterone.
Angiotensin II also acts on the smooth muscle in the walls of the
arterioles causing these small diameter vessels to constrict, thereby
restricting the outflow of blood from the arterial tree, causing the
arterial blood pressure to rise. This, therefore, reinforces the
measures described above (under the heading of "Arterial blood
pressure"), which defend the arterial blood pressure against changes,
especially hypotension.
The angiotensin II-stimulated aldosterone released from the zona glomerulosa of the adrenal glands has an effect on particularly the epithelial cells of the distal convoluted tubules and collecting ducts of the kidneys. Here it causes the reabsorption of sodium ions from the renal tubular fluid, in exchange for potassium ions which are secreted from the blood plasma into the tubular fluid to exit the body via the urine.
The reabsorption of sodium ions from the renal tubular fluid halts
further sodium ion losses from the body, and therefore preventing the
worsening of hyponatremia. The hyponatremia can only be corrected
by the consumption of salt in the diet. However, it is not certain
whether a "salt hunger" can be initiated by hyponatremia, or by what
mechanism this might come about.
When the plasma sodium ion concentration is higher than normal (hypernatremia),
the release of renin from the juxtaglomerular apparatus is halted,
ceasing the production of angiotensin II, and its consequent
aldosterone-release into the blood. The kidneys respond by excreting
sodium ions into the urine, thereby normalizing the plasma sodium ion
concentration. The low angiotensin II levels in the blood lower the
arterial blood pressure as an inevitable concomitant response.
The reabsorption of sodium ions from the tubular fluid as a
result of high aldosterone levels in the blood does not, of itself,
cause renal tubular water to be returned to the blood from the distal convoluted tubules or collecting ducts. This is because sodium is reabsorbed in exchange for potassium and therefore causes only a modest change in the osmotic gradient
between the blood and the tubular fluid. Furthermore, the epithelium of
the distal convoluted tubules and collecting ducts is impermeable to
water in the absence of antidiuretic hormone (ADH) in the blood. ADH is part of the control of fluid balance. Its levels in the blood vary with the osmolality of the plasma, which is measured in the hypothalamus of the brain. Aldosterone's action on the kidney tubules prevents sodium loss to the extracellular fluid
(ECF). So there is no change in the osmolality of the ECF, and
therefore no change in the ADH concentration of the plasma. However, low
aldosterone levels cause a loss of sodium ions from the ECF, which
could potentially cause a change in extracellular osmolality and
therefore of ADH levels in the blood.
Aldosterone acts primarily on the distal convoluted tubules and collecting ducts of the kidneys, stimulating the excretion of potassium ions into the urine. It does so, however, by activating the basolateralNa+/K+ pumps
of the tubular epithelial cells. These sodium/potassium exchangers pump
three sodium ions out of the cell, into the interstitial fluid and two
potassium ions into the cell from the interstitial fluid. This creates
an ionic concentration gradient which results in the reabsorption of sodium (Na+) ions from the tubular fluid into the blood, and secreting potassium (K+) ions from the blood into the urine (lumen of collecting duct).
Fluid balance
The total amount of water in the body needs to be kept in balance. Fluid balance involves keeping the fluid volume stabilized, and also keeping the levels of electrolytes in the extracellular fluid stable. Fluid balance is maintained by the process of osmoregulation and by behavior. Osmotic pressure is detected by osmoreceptors in the median preoptic nucleus in the hypothalamus. Measurement of the plasma osmolality to give an indication of the water content of the body, relies on the fact that water losses from the body, (through unavoidable water loss through the skin which is not entirely waterproof and therefore always slightly moist, water vapor in the exhaled air, sweating, vomiting, normal feces and especially diarrhea) are all hypotonic,
meaning that they are less salty than the body fluids (compare, for
instance, the taste of saliva with that of tears. The latter has almost
the same salt content as the extracellular fluid, whereas the former is
hypotonic with respect to the plasma. Saliva does not taste salty,
whereas tears are decidedly salty). Nearly all normal and abnormal
losses of body water therefore cause the extracellular fluid to become hypertonic. Conversely, excessive fluid intake dilutes the extracellular fluid causing the hypothalamus to register hypotonic hyponatremia conditions.
When the hypothalamus detects a hypertonic extracellular environment, it causes the secretion of an antidiuretic hormone (ADH) called vasopressin which acts on the effector organ, which in this case is the kidney. The effect of vasopressin on the kidney tubules is to reabsorb water from the distal convoluted tubules and collecting ducts, thus preventing aggravation of the water loss via the urine. The hypothalamus simultaneously stimulates the nearby thirst center
causing an almost irresistible (if the hypertonicity is severe enough)
urge to drink water. The cessation of urine flow prevents the hypovolemia and hypertonicity from getting worse; the drinking of water corrects the defect.
Hypo-osmolality results in very low plasma ADH levels. This
results in the inhibition of water reabsorption from the kidney tubules,
causing high volumes of very dilute urine to be excreted, thus getting
rid of the excess water in the body.
Urinary water loss, when the body water homeostat is intact, is a compensatory water loss, correcting
any water excess in the body. However, since the kidneys cannot
generate water, the thirst reflex is the all-important second effector
mechanism of the body water homeostat, correcting any water deficit in the body.
Blood pH
The plasma pH can be altered by respiratory changes in the partial pressure of carbon dioxide; or altered by metabolic changes in the carbonic acid to bicarbonate ion ratio. The bicarbonate buffer system
regulates the ratio of carbonic acid to bicarbonate to be equal to
1:20, at which ratio the blood pH is 7.4 (as explained in the Henderson–Hasselbalch equation). A change in the plasma pH gives an acid–base imbalance.
In acid–base homeostasis there are two mechanisms that can help regulate the pH. Respiratory compensation a mechanism of the respiratory center, adjusts the partial pressure of carbon dioxide
by changing the rate and depth of breathing, to bring the pH back to
normal. The partial pressure of carbon dioxide also determines the
concentration of carbonic acid, and the bicarbonate buffer system can
also come into play. Renal compensation can help the bicarbonate buffer
system.
The sensor for the plasma bicarbonate concentration is not known for
certain. It is very probable that the renal tubular cells of the distal
convoluted tubules are themselves sensitive to the pH of the plasma.
The metabolism of these cells produces carbon dioxide, which is rapidly
converted to hydrogen and bicarbonate through the action of carbonic anhydrase.
When the ECF pH falls (becoming more acidic) the renal tubular cells
excrete hydrogen ions into the tubular fluid to leave the body via
urine. Bicarbonate ions are simultaneously secreted into the blood that
decreases the carbonic acid, and consequently raises the plasma pH.
The converse happens when the plasma pH rises above normal:
bicarbonate ions are excreted into the urine, and hydrogen ions released
into the plasma.
When hydrogen ions are excreted into the urine, and bicarbonate
into the blood, the latter combines with the excess hydrogen ions in the
plasma that stimulated the kidneys to perform this operation. The
resulting reaction in the plasma is the formation of carbonic acid which
is in equilibrium with the plasma partial pressure of carbon dioxide.
This is tightly regulated to ensure that there is no excessive build-up
of carbonic acid or bicarbonate. The overall effect is therefore that
hydrogen ions are lost in the urine when the pH of the plasma falls. The
concomitant rise in the plasma bicarbonate mops up the increased
hydrogen ions (caused by the fall in plasma pH) and the resulting excess
carbonic acid is disposed of in the lungs as carbon dioxide. This
restores the normal ratio between bicarbonate and the partial pressure
of carbon dioxide and therefore the plasma pH.
The converse happens when a high plasma pH stimulates the kidneys to
secrete hydrogen ions into the blood and to excrete bicarbonate into the
urine. The hydrogen ions combine with the excess bicarbonate ions in
the plasma, once again forming an excess of carbonic acid which can be
exhaled, as carbon dioxide, in the lungs, keeping the plasma bicarbonate
ion concentration, the partial pressure of carbon dioxide and,
therefore, the plasma pH, constant.
Cerebrospinal fluid
Cerebrospinal fluid (CSF) allows for regulation of the distribution of substances between cells of the brain, and neuroendocrine factors, to which slight changes can cause problems or damage to the nervous system. For example, high glycineconcentration disrupts temperature and blood pressure control, and high CSF pH causes dizziness and syncope.
Neurotransmission
Inhibitory neurons in the central nervous system play a homeostatic role in the balance of neuronal activity between excitation and inhibition. Inhibitory neurons using GABA, make compensating changes in the neuronal networks preventing runaway levels of excitation. An imbalance between excitation and inhibition is seen to be implicated in a number of neuropsychiatric disorders.
Neuroendocrine system
The neuroendocrine system is the mechanism by which the hypothalamus maintains homeostasis, regulating metabolism, reproduction, eating and drinking behaviour, energy utilization, osmolarity and blood pressure.
The liver also has many regulatory functions of the metabolism. An important function is the production and control of bile acids. Too much bile acid can be toxic to cells and its synthesis can be inhibited by activation of FXR a nuclear receptor.
The amount of energy taken in through nutrition needs to match the amount of energy used. To achieve energy homeostasis appetite is regulated by two hormones, grehlin and leptin. Grehlin stimulates hunger and the intake of food and leptin acts to signal satiety (fullness).
A 2019 review of weight-change interventions, including dieting, exercise and overeating, found that body weight homeostasis could not precisely correct for "energetic errors", the loss or gain of calories, in the short-term.
Clinical significance
Many
diseases are the result of a homeostatic failure. Almost any
homeostatic component can malfunction either as a result of an inherited defect, an inborn error of metabolism,
or an acquired disease. Some homeostatic mechanisms have inbuilt
redundancies, which ensures that life is not immediately threatened if a
component malfunctions; but sometimes a homeostatic malfunction can
result in serious disease, which can be fatal if not treated. A
well-known example of a homeostatic failure is shown in type 1 diabetes mellitus. Here blood sugar regulation is unable to function because the beta cells of the pancreatic islets are destroyed and cannot produce the necessary insulin. The blood sugar rises in a condition known as hyperglycemia.
The plasma ionized calcium homeostat can be disrupted by the constant, unchanging, over-production of parathyroid hormone by a parathyroid adenoma resulting in the typically features of hyperparathyroidism, namely high plasma ionized Ca2+
levels and the resorption of bone, which can lead to spontaneous
fractures. The abnormally high plasma ionized calcium concentrations
cause conformational changes in many cell-surface proteins (especially
ion channels and hormone or neurotransmitter receptors) giving rise to lethargy, muscle weakness, anorexia, constipation and labile emotions.
The body water homeostat can be compromised by the inability to secrete ADH in response to even the normal daily water losses via the exhaled air, the feces, and insensible sweating.
On receiving a zero blood ADH signal, the kidneys produce huge
unchanging volumes of very dilute urine, causing dehydration and death
if not treated.
As organisms age, the efficiency of their control systems becomes
reduced. The inefficiencies gradually result in an unstable internal
environment that increases the risk of illness, and leads to the
physical changes associated with aging.
Various chronic
diseases are kept under control by homeostatic compensation, which
masks a problem by compensating for it (making up for it) in another
way. However, the compensating mechanisms eventually wear out or are
disrupted by a new complicating factor (such as the advent of a
concurrent acute viral infection), which sends the body reeling through a
new cascade of events. Such decompensation unmasks the underlying
disease, worsening its symptoms. Common examples include decompensated heart failure, kidney failure, and liver failure.
Biosphere
In the Gaia hypothesis, James Lovelock stated that the entire mass of living matter on Earth (or any planet with life) functions as a vast homeostatic superorganism
that actively modifies its planetary environment to produce the
environmental conditions necessary for its own survival. In this view,
the entire planet maintains several homeostasis (the primary one being
temperature homeostasis). Whether this sort of system is present on
Earth is open to debate. However, some relatively simple homeostatic
mechanisms are generally accepted. For example, it is sometimes claimed
that when atmospheric carbon dioxide levels rise, certain plants may be
able to grow better and thus act to remove more carbon dioxide from the
atmosphere. However, warming has exacerbated droughts, making water the
actual limiting factor on land. When sunlight is plentiful and the atmospheric temperature climbs, it has been claimed that the phytoplankton of the ocean surface waters, acting as global sunshine, and therefore heat sensors, may thrive and produce more dimethyl sulfide (DMS). The DMS molecules act as cloud condensation nuclei, which produce more clouds, and thus increase the atmospheric albedo,
and this feeds back to lower the temperature of the atmosphere.
However, rising sea temperature has stratified the oceans, separating
warm, sunlit waters from cool, nutrient-rich waters. Thus, nutrients
have become the limiting factor, and plankton levels have actually
fallen over the past 50 years, not risen. As scientists discover more
about Earth, vast numbers of positive and negative feedback loops are
being discovered, that, together, maintain a metastable condition,
sometimes within a very broad range of environmental conditions.
Predictive
Predictive
homeostasis is an anticipatory response to an expected challenge in the
future, such as the stimulation of insulin secretion by gut hormones
which enter the blood in response to a meal.
This insulin secretion occurs before the blood sugar level rises,
lowering the blood sugar level in anticipation of a large influx into
the blood of glucose resulting from the digestion of carbohydrates in
the gut. Such anticipatory reactions are open loop systems which are based, essentially, on "guess work", and are not self-correcting.
Anticipatory responses always require a closed loop negative feedback
system to correct the 'over-shoots' and 'under-shoots' to which the
anticipatory systems are prone.
Other fields
The term has come to be used in other fields, for example:
Risk
An actuary may refer to risk homeostasis,
where (for example) people who have anti-lock brakes have no better
safety record than those without anti-lock brakes, because the former
unconsciously compensate for the safer vehicle via less-safe driving
habits. Previous to the innovation of anti-lock brakes, certain
maneuvers involved minor skids, evoking fear and avoidance: Now the
anti-lock system moves the boundary for such feedback, and behavior
patterns expand into the no-longer punitive area. It has also been
suggested that ecological crises are an instance of risk homeostasis in
which a particular behavior continues until proven dangerous or dramatic
consequences actually occur.
Stress
Sociologists and psychologists may refer to stress homeostasis, the tendency of a population or an individual to stay at a certain level of stress, often generating artificial stresses if the "natural" level of stress is not enough.
Jean-François Lyotard, a postmodern theorist, has applied this term to societal 'power centers' that he describes in The Postmodern Condition,
as being 'governed by a principle of homeostasis,' for example, the
scientific hierarchy, which will sometimes ignore a radical new
discovery for years because it destabilizes previously accepted norms.
A thermostat operates by switching heaters or air-conditioners on and off in response to the output of a temperature sensor.
Cruise control adjusts a car's throttle in response to changes in speed.
An autopilot operates the steering controls of an aircraft or ship in response to deviation from a pre-set compass bearing or route.
Process control systems in a chemical plant or oil refinery maintain fluid levels, pressures, temperature, chemical composition, etc. by controlling heaters, pumps and valves.
The centrifugal governor of a steam engine, as designed by James Watt
in 1788, reduces the throttle valve in response to increases in the
engine speed, or opens the valve if the speed falls below the pre-set
rate.
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