Investigation of thyroid hormones in the regulation of metabolism. Hormonal regulation of calsium and phosphorus
homeostasis.
Tissue hormones. Investigation of molecular – cellular mechanisms of adrenal and sex glands hormones.
Hormones
of thyroid and parathyroid glands
Thyroid synthesizes two kinds of hormones: iodine
containing hormones and calcitonin.
Iodine containing hormones - thyroxine and
triiodthyronine.
Thyroid hormone is produced by the thyroid gland, which
consists of follicles in which thyroid hormone is synthesized through
iodination of tyrosine residues in the glycoprotein thyroglobulin. Thyroid
stimulating hormone (TSH), secreted by the anterior pituitary in response to
feedback from circulating thyroid hormone, acts directly on the TSH receptor
(TSH-R) expressed on the thyroid follicular cell basolateral membrane. TSH
regulates iodide uptake mediated by the sodium/iodide symporter, followed by a
series of steps necessary for normal thyroid hormone synthesis and secretion.
Thyroid hormone is essential for normal development, growth, neural
differentiation, and metabolic regulation in mammals.
TH synthesis and
secretion is exquisitely regulated by a negative-feedback system that involves
the hypothalamus, pituitary, and thyroid gland [hypothalamic/pituitary/thyroid
(HPT) axis]. Thyrotropin releasing hormone (TRH) is a tripeptide
(PyroGlu-His-Pro) synthesized in the paraventricular nucleus of the hypothalamus.
It is transported via axons to the median eminence and then to the anterior
pituitary via the portal capillary plexus. TRH binds to TRH receptors in
pituitary thyrotropes, a subpopulation of pituitary cells that secrete thyroid
stimulating hormone (TSH). TRH receptors are members of the seven-transmembrane
spanning receptor family and are coupled to Gq11. TRH stimulation leads to release and synthesis
of new TSH in thyrotropes. TSH is a 28-kDa glycoprotein composed of α- and
β-subunits designated as glycoprotein hormone α- and TSH
β-subunits. The α-subunit also is shared with other hormones such as
luteinizing hormone, follicle stimulating hormone, and chorionic gonadotropin.
Both TRH and TSH secretion are negatively regulated by TH. An important mechanism
for the negative regulation of TSH may be the intrapituitary conversion of
circulating T4 to T3 by
type II deiodinase. Additionally, somatostatin and dopamine from the
hypothalamus can negatively regulate TSH secretion.
TSH is the primary regulator of TH release and
secretion. It also has a critical role in thyroid growth and development. TSH
binds to the TSH receptor (TSHr), which also is a seven-transmembrane spanning
receptor coupled to Gs. Activation of
TSHr by TSH or autoantibodies in Graves' disease leads to an increase in
intracellular cAMP and stimulation of protein kinase A-mediated pathways. A
number of thyroid genes, including Na+/I− symporter (NIS), thyroglobulin (Tg),
and thyroid peroxidase (TPO), are stimulated by TSH and promote the synthesis
of TH.
The THs, T4 and
the more potent T3, are synthesized
in the thyroid gland. Iodide is actively transported and concentrated into the
thyroid by NIS (102,475). The
trapped iodide is oxidized by TPO in the presence of hydrogen peroxide and
incorporated into the tyrosine residues of a 660-kDa glycoprotein, Tg. This
iodination of specific tyrosines located on Tg yields monoiodinated and
diiodinated residues (MIT, monoiodo-tyrosines; DIT, diiodo-tyrosines) that are
enzymatically coupled to form T4 and T3. The iodinated Tg containing MIT, DIT, T4, and T3, then is stored
as an extracellular storage polypeptide in the colloid within the lumen of
thyroid follicular cells. Genetic defects along the synthetic pathway of THs
have been described in humans and are major causes of congenital hypothyroidism
in iodine-replete environments.
The
secretion of THs requires endocytosis of the stored iodinated Tg from the
apical surface of the thyroid follicular cell. The internalized Tg is
incorporated in phagolysosomes and undergoes proteolytic digestion, recapture
of MIT and DIT, and release of T4 and T3 into
the circulation via the basal surface. The majority of released TH is in the
form of T4, as total serum T4 is
40-fold higher than serum T3 (90 vs. 2 nM). Only 0.03% of the total
serum T4 is free (unbound), with the remainder
bound to carrier proteins such as thyroxine binding globulin (TBG), albumin,
and thyroid binding prealbumin. Approximately 0.3% of the total serum T3 is
free, with the remainder bound to TBG and albumin. It is the free TH that
enters target cells and generates a biological response.
The
major pathway for the production of T3 is
via 5′-deiodination of the outer ring of T4 by
deiodinases and accounts for the majority of the circulating T3. Type I deioidinase is found in peripheral tissues
such as liver and kidney and is responsible for the conversion of the majority
of T4 to T3 in
circulation. Type II deiodinase is found in brain, pituitary, and brown adipose
tissue and primarily converts T4 to T3for intracellular use. These deiodinases recently
have been cloned and demonstrated to be selenoproteins. 5′-Deiodination
by type I deiodinase and type III deioidinase, which is found primarily in
placenta, brain, and skin, leads to the generation of rT3, the key step in the inactivation of TH. rT3 and T3 can
be further deiodinated in the liver and are sulfo- and glucuronide-conjugated
before excretion in the bile. There also is an enterohepatic circulation of TH
as intestinal flora deconjugates some of these compounds and promotes the
reuptake of TH.
Although THs may exert their effects
on a number of intracellular loci, their primary effect is on the
transcriptional regulation of target genes. Early studies showed that the
effects of THs at the genomic level are mediated by nuclear TRs, which are
intimately associated with chromatin and bind TH with high affinity and
specificity. Similar to steroid hormones that also bind to nuclear receptors,
TH enters the cell and proceeds to the nucleus. It then binds to TRs, which may
already be prebound to TREs located in promoter regions of target genes. The
formation of ligand-bound TR complexes that are also bound to TREs is the
critical first step in the positive or negative regulation of target genes and
the subsequent regulation of protein synthesis. Given their abilities to bind
both ligand and DNA as well as their ability to regulate transcription, TRs can
be regarded as ligand-regulatable transcription factors.
General model for thyroid
hormone action in the nucleus. TR, thyroid hormone receptor; RXR, retinoid X
receptor
Thyroid hormone regulates a wide range of genes after
its activation from the prohormone, thyroxine (T4), to the active form,
triiodothyronine (T3). The signaling pathway is complex and highly regulated
due to the expression of cell and tissue-specific thyroid hormone transporters,
multiple thyroid hormone receptor (TR) isoforms, and interactions with
corepressors and coactivators. Furthermore, in many cases, thyroid signals are
involved in cross-talk with a range of other signaling pathways.
Receptors for thyroid hormones are intracellular DNA-binding proteins that
function as hormone-responsive transcription factors, very similar conceptually
to the receptors for steroid hormones.
Thyroid hormones enter cells through
membrane transporter proteins. A number of plasma membrane transporters have
been identified, some of which require ATP hydrolysis; the relative importance
of different carrier systems is not yet clear and may differ among tissues.
Once inside the nucleus, the hormone binds its receptor, and the
hormone-receptor complex interacts with specific sequences of DNA in the
promoters of responsive genes. The effect of the hormone-receptor complex
binding to DNA is to modulate gene expression, either by stimulating or
inhibiting transcription of specific genes.
Nuclear
action of thyroid hormone.
For the purpose of illustration, consider one mechanism by which thyroid
hormones increase the strength of contraction of the heart. Cardiac
contractility depends, in part, on the relative ratio of different types of
myosin proteins in cardiac muscle. Transcription of some myosin genes is
stimulated by thyroid hormones, while transcription of others in inhibited. The
net effect is to alter the ratio toward increased contractility.
Metabolism: Thyroid hormones stimulate
diverse metabolic activities most tissues, leading to an increase in basal
metabolic rate. One consequence of this activity is to increase body heat
production, which seems to result, at least in part, from increased oxygen
consumption and rates of ATP hydrolysis. By way of analogy, the action of
thyroid hormones is akin to blowing on a smouldering fire. A few examples of
specific metabolic effects of thyroid hormones include:
Lipid metabolism: Increased thyroid hormone
levels stimulate fat mobilization, leading to increased concentrations of fatty
acids in plasma. They also enhance oxidation of fatty acids in many tissues.
Finally, plasma concentrations of cholesterol and triglycerides are inversely correlated
with thyroid hormone levels - one diagnostic indiction of hypothyroidism is
increased blood cholesterol concentration.
Carbohydrate metabolism: Thyroid hormones stimulate
almost all aspects of carbohydrate metabolism, including enhancement of insulin-dependent
entry of glucose into cells and increased gluconeogenesis and glycogenolysis to
generate free glucose.
Protein metabolism: in normal concentration
stimulate the synthesis of proteins and nucleic acids; in excessive concentration
activate the catabolic processes.
Growth: Thyroid hormones are
clearly necessary for normal growth in children and young animals, as evidenced
by the growth-retardation observed in thyroid deficiency. Not surprisingly, the
growth-promoting effect of thyroid hormones is intimately intertwined with that
of growth hormone, a clear indiction that complex
physiologic processes like growth depend upon multiple endocrine controls.
Development: Of critical importance
in mammals is the fact that normal levels of thyroid hormone are essential
to the development of the fetal and neonatal brain.
Other Effects: As mentioned above,
there do not seem to be organs and tissues that are not affected by thyroid
hormones. A few additional, well-documented effects of thyroid hormones
include:
Cardiovascular system: Thyroid hormones increases
heart rate, cardiac contractility and cardiac output. They also promote vasodilation,
which leads to enhanced blood flow to many organs.
Central nervous system: Both decreased and increased
concentrations of thyroid hormones lead to alterations in mental state. Too
little thyroid hormone, and the individual tends to feel mentally sluggish,
while too much induces anxiety and nervousness.
Reproductive system:
Thyroid Disease States
Disease is associated with both
inadequate production and overproduction of thyroid hormones. Both types of
disease are relatively common afflictions of man and animals.
Hypothyroidism is the result from any
condition that results in thyroid hormone deficiency. Two well-known examples
include:
Iodine deficiency: Iodide is absolutely necessary for production of
thyroid hormones; without adequate iodine intake, thyroid hormones cannot be
synthesized. Historically, this problem was seen particularly in areas with
iodine-deficient soils, and frank iodine deficiency has been virtually
eliminated by iodine supplementation of salt.
Primary thyroid disease: Inflammatory diseases of the thyroid that destroy
parts of the gland are clearly an important cause of hypothyroidism.
Common symptoms of hypothyroidism arising after early
childhood include lethargy, fatigue, cold-intolerance, weakness, hair loss and
reproductive failure. If these signs are severe, the clinical condition is
called myxedema. In the case of iodide deficiency, the thyroid
becomes inordinantly large and is called a goiter.
About 95 percent of the active
thyroid hormone is thyroxine, and most of the remaining 5 percent is
triiodothyronine. Both of these require iodine for their synthesis. Thyroid
hormone secretion is regulated by a negative feedback mechanism that involves
the amount of circulating hormone, hypothalamus, and adenohypophysis.
If there is an iodine deficiency, the thyroid cannot
make sufficient hormone. This stimulates the anterior pituitary to secrete
thyroid-stimulating hormone, which causes the thyroid gland to increase in size
in a vain attempt to produce more hormones. But it cannot produce more hormones
because it does not have the necessary raw material, iodine. This type of
thyroid enlargement is called simple goiter or iodine deficiency goiter.
Calcitonin is secreted by the parafollicular cells of
the thyroid gland. This hormone opposes the action of the parathyroid glands by
reducing the calcium level in the blood. If blood calcium becomes too high,
calcitonin is secreted until calcium ion levels decrease to normal.
The most severe and devestating form of hypothyroidism is
seen in young children with congenital thyroid deficiency. If
that condition is not corrected by supplemental therapy soon after birth, the
child will suffer from cretinism,
a form of irreversible growth and mental retardation.
Congenital hypothyroidism can be endemic, genetic, or sporadic.
If untreated, it results in mild to severe impairment of both physical and mental
growth and development. Poor
length growth is apparent as early as the first year of life. Adult stature
without treatment ranges from 1 to
Sporadic
and genetic cretinism results from abnormal development or function of the
foetal thyroid gland. This type of cretinism has been almost completely
eliminated in developed countries by early diagnosis by newborn
screening schemes
followed by lifelong treatment with thyroxine (T4).
Thyroxine must be dosed as tablets only, even to
newborns, as the liquid oral suspensions and compounded forms cannot be
depended on for reliable dosing. In the case of dosing infants, the T4 tablets
are generally crushed and mixed with breast milk, formula milk or water. If the
medication is mixed with formulas containing iron or soya products, larger
doses may be required, as these substances may alter the absorption of thyroid
hormone from the gut. Frequent
monitoring (every 2–3 weeks during the first months of life) is recommended to
ensure that infants with congenital hypothyroidism remain within the high end
of normal range, or euthyroid.
Cretinism arises from a diet deficient in iodine. It has affected
many people worldwide and continues to be a major public health problem
in many countries. Iodine is an essential trace element, necessary primarily
for the synthesis of thyroid hormones. Iodine deficiency is the most common
preventable cause of brain damage worldwide. Although iodine
is found in many foods, it is not universally present in all soils in adequate
amounts. Most iodine, in iodide form, is in the oceans where the iodide ions
oxidize to elemental iodine, which then enters the atmosphere and falls to
earth as rain, introducing iodine to soils. Earth deficient in iodine is most
common inland and in mountainous areas and areas of frequent flooding, but can
also occur in coastal regions owing to past glaciation, and leaching by snow,
water and heavy rainfall, which removes iodine from the soil. Plants and animals grown in iodine
deficient soils are correspondingly deficient. Populations living in those
areas without outside food sources are most at risk ofiodine deficiency diseases.
Most cases of hypothyroidism are readily treated by oral administration of
synthetic thyroid hormone. In times past, consumption of dessicated animal
thyroid gland was used for the same purpose.
Hyperthyroidism results from secretion of thyroid
hormones. In most species, this condition is less common than hypothyroidism.
In humans the most common form of hyperthyroidism is Graves disease, an immune
disease in which autoantibodies bind to and activate the thyroid-stimulating hormone
receptor, leading to continual stimulation of thyroid hormone synthesis.
Another interesting, but rare cause of hyperthyroidism is so-called hamburger thyrotoxicosis.
exophthalmic goiter
Common signs of hyperthyroidism are basically the opposite of those seen in
hypothyroidism, and include nervousness, insomnia, high heart rate, eye disease
and anxiety. Graves disease is commonly treated with anti-thyroid drugs (e.g.
propylthiourea, methimazole), which suppress synthesis of thyroid hormones
primarily by interfering with iodination of thyroglobulin by thyroid
peroxidase.
Calcitonin.
Calcitonin is synthesized by the parafollicle cells of
thyroid.
Chemical structure: peptide.
Functions: - promotes the transition of calcium from
blood in bones;
-
inhibits the reabsorption of phosphorus in
kidneys.
Thus, calcitonin decreases the Ca and P contents in
blood.
Parathyroid
glands.
Parathyroid
Gland
Four small masses of epithelial tissue are embedded in
the connective tissue capsule on the posterior surface of the thyroid glands.
These are parathyroid glands, and they secrete parathyroid hormone or
parathormone. Parathyroid hormone is the most important regulator of blood
calcium levels. The hormone is secreted in response to low blood calcium
levels, and its effect is to increase those levels.
Parathyroid hormone. Chemical structure: protein.
Functions:
1.
promotes the transition of calcium from bones to blood;
2.
promotes the absorption of Ca in the intestine;
3.
inhibits the reabsorption of phosphorus in kidneys.
Thus,
parathyroid hormone increases the Ca amount in blood and decreases the P amount in blood.
Body
Distribution of Calcium and Phosphate
There are three major pools of
calcium in the body:
Intracellular calcium:
·
A large majority of calcium within cells is sequestered in mitochondria
and endoplasmic reticulum. Intracellular free calcium concentrations fluctuate
greatly, from roughly 100 nM to greater than 1 uM, due to release from cellular
stores or influx from extracellular fluid. These fluctuations are integral to
calcium's role in intracellular signaling, enzyme activation and muscle
contractions.
Calcium in blood and extracellular fluid:
Roughly half of the calcium in blood is bound to proteins.
The concentration of ionized calcium in this compartment is normally almost
invariant at approximately
Bone calcium:
A vast majority of body calcium is in bone. Within
bone, 99% of the calcium is tied up in the mineral phase, but the remaining 1%
is in a pool that can rapidly exchange with extracellular calcium.
As with calcium, the majority of body phosphate
(approximately 85%) is present in the mineral phase of bone. The remainder of
body phosphate is present in a variety of inorganic and organic compounds
distributed within both intracellular and extracellular compartments. Normal
blood concentrations of phosphate are very similar to calcium.
Fluxes of
Calcium and Phosphate
Maintaining
constant concentrations of calcium in blood requires frequent adjustments, which
can be described as fluxes of calcium between blood and other body
compartments. Three organs participate in supplying calcium to blood and
removing it from blood when necessary:
·
The small intestine is the site where dietary calcium is
absorbed. Importantly, efficient absorption of calcium in the small intestine
is dependent on expression of a calcium-binding protein in epithelial cells.
·
Bone serves
as a vast reservoir of calcium. Stimulating net resorption of bone mineral
releases calcium and phosphate into blood, and suppressing this effect allows
calcium to be deposited in bone.
The kidney
is critcally important in calcium homeostasis. Under normal blood calcium
concentrations, almost all of the calcium that enters glomerular filtrate is
reabsorbed from the tubular system back into blood, which preserves blood
calcium levels. If tubular reabsorption of calcium decreases, calcium is lost
by excretion into urine.
Hormonal
Control Systems
Maintaining normal blood calcium and phosphorus
concentrations is managed through the concerted action of three hormones that
control fluxes of calcium in and out of blood and extracellular fluid:
Calcitonin is a hormone that functions to
reduce blood calcium levels. It is secreted in response to hypercalcemia and
has at least two effects:
·
Suppression of renal tubular reabsorption of calcium. In other words,
calcitonin enhances excretion of calcium into urine.
·
Inhibition of bone resorption, which would minimize fluxes of calcium
from bone into blood.
Although calcitonin has significant calcium-lowing
effects in some species, it appears to have a minimal influence on blood
calcium levels in humans.
Vitamin D acts also to increase blood
concentrations of calcium. It is generated through the activity of parathyroid hormone within the
kidney. Far and away the most important effect of vitamin D is to facilitate
absorption of calcium from the small intestine. In concert with parathyroid
hormone, vitamin D also enhances fluxes of calcium out of bone.
http://www.youtube.com/watch?v=JwPVibQ6_3Y&feature=related
http://www.youtube.com/watch?v=n7vybcT9_F4
Parathyroid
hormone serves to increase blood concentrations of calcium. Mechanistically, parathyroid
hormone preserves blood calcium by several major effects:
·
Stimulates production of the biologically-active form of vitamin D
within the kidney.
·
Facilitates mobilization of calcium and phosphate from bone. To prevent
detrimental increases in phosphate, parathyroid hormone also has a potent
effect on the kidney to eliminate phosphate (phosphaturic effect).
·
Maximizes tubular reabsorption of calcium within the kidney. This
activity results in minimal losses of calcium in urine.
Hypoparathyroidism, or insufficient secretion of
parathyroid hormone, leads to increased nerve excitability. The low blood
calcium levels trigger spontaneous and continuous nerve impulses, which then
stimulate muscle contraction.
Since parathyroid gland disease (hyperparathyroidism)
was first described in 1925, the symptoms have become known as "moans,
groans, stones, and bones...with psychic overtones". Although about 5-7% of people with
parathyroid disease (hyperparathyroidism) claim they don't have symptoms and to
feel fine when the diagnosis of hyperparathyroidism is made, almost 100% of
parathyroid patients will actually say they feel better after the parathyroid
problem has been cured--proving they had symptoms. The bottom line: Nearly ALL
patients with parathyroid problems have symptoms. Sometimes the symptoms are
real obvious, like kidney stones, frequent headaches, and depression. Sometimes
the symptoms are not so obvious, like high blood pressure and the inability to
concentrate. If you have symptoms, you are almost guaranteed to feel remarkably
better once the parathyroid tumor has been removed. As we often tell our
parathyroid patients: "you will be amazed at how a 16 minute mini-procedure
will change your life!"
Hormones of adrenal cortex
Adrenal
glands consist of two parts: external - cortex, internal - medulla.
Each
part secrets specific hormones.
Hormones
synthesized in adrenal cortex are named corticosteroids.
Mechanism of steroid hormones action (permeating into the cells):
http://www.youtube.com/watch?v=oOj04WsU9ko
In
difference to hormones of protein and peptide nature, receptors for steroid
hormones are located within the cells - in the cytoplasm. From cytoplasm the
hormone-receptor complexes is translocated
into the nucleus where they interact with DNA of nuclear chromatin
causing the activation of genes for respective enzyme proteins. So, if hormones
of the first group cause the activation of existing enzyme molecules, the
acting on the target cells of steroids and thyroid hormones results in the biosynthesis
of new enzyme molecules.
http://www.youtube.com/watch?v=0ss8YIoKw0g
Receptors
for steroid and thyroid hormones are located inside target cells, in the
cytoplasm or nucleus, and function as ligand-dependent
transcription factors. That is to say, the hormone-receptor complex binds
to promoter regions of responsive genes and stimulate or sometimes inhibit
transcription from those genes.
Thus, the mechanism of action of steroid hormones is to
modulate gene expression in target cells. By selectively affecting
transcription from a battery of genes, the concentration of those respective
proteins are altered, which clearly can change the phenotype of the cell.
Steroid and thyroid hormone receptors are members of a
large group ("superfamily") of transcription factors. In some cases,
multiple forms of a given receptor are expressed in cells, adding to the
complexity of the response. All of these receptors are composed of a single
polypeptide chain that has, in the simplist analysis, three distinct domains:
·
The amino-terminus: In
most cases, this region is involved in activating or stimulating transcription
by interacting with other components of the transcriptional machinery. The
sequence is highly variable among different receptors.
·
DNA binding domain: Amino
acids in this region are responsible for binding of the receptor to specific
sequences of DNA.
·
The carboxy-terminus or ligand-binding
domain: This is the region that binds hormone.
In addition to these three core domains, two other
important regions of the receptor protein are a nuclear localization sequence,
which targets the the protein to nucleus, and a dimerization domain, which is
responsible for latching two receptors together in a form capable of binding
DNA.
Being lipids, steroid hormones enter the cell by simple
diffusion across the plasma membrane. Thyroid hormones enter the cell by
facilitated diffusion. The receptors exist either in the cytoplasm or nucleus,
which is where they meet the hormone. When hormone binds to receptor, a
characteristic series of events occurs:
·
Receptor activation is the term used to describe
conformational changes in the receptor induced by binding hormone. The major
consequence of activation is that the receptor becomes competent to bind DNA.
·
Activated receptors bind to
"hormone response elements", which are short specific
sequences of DNA which are located in promoters of hormone-responsive genes. In
most cases, hormone-receptor complexes bind DNA in pairs, as shown in the
figure below.
·
Transcription from those genes to which
the receptor is bound is affected. Most
commonly, receptor binding stimulates transcription. The hormone-receptor
complex thus functions as a transcription factor.
As might
be expected, there are a number of variations on the themes described above,
depending on the specific receptor in question. For example, in the absense of
hormone, some intracellular receptors do bind their hormone response elements
loosely and silence transcription, but, when complexed to hormone, become
activated and strongly stimulate transcription. Some receptors bind DNA not
with another of their kind, but with different intracellular receptor.
Corticosteroids have potent
regulatory effect on all kinds of metabolism. Cholesterol is the precursor of
corticosteroids. According to the biological effect corticosteroids are divided
on two groups: glucocorticoids and
mineralocorticoids. Glucocorticoids
regulate the protein, lipid and carbohydrate metabolism, mineralocorticoids -
metabolism of water and mineral salt.
The most important glucocorticoids: corticosterone,
hydrocortisone, cortisol. The
most important mineralocorticoid: aldosterone.
All biological active hormones of
adrenal cortex consist of 21 carbon atom and can be reviewed as derivatives of
carbohydrate pregnane.
The synthesis of corticosteroids is regulated by ACTH.
In the blood corticosteroids are
connected with proteins and transported to different organs.
Time half-life for corticosteroids
is about 1 hour.
These forms of hormones are lipids. They can enter the
cell membrane quite easily and enter right into the nuclei. Steroid hormones
are generally carried in the blood bound to specific carrier proteins such as sex hormone binding
globulin or corticosteroid binding globulin. Further conversions and catabolism
occurs in the liver, other "peripheral" tissues, and in the target
tissues.
Ways of metabolism of corticosteroids:
1.
Reduction. Corticosteroids accept 4 or 6 hydrogen atoms and form couple
compounds with glucuronic acid. These compounds ere excreted by kidneys.
2.
Oxidation of 21-st carbon atom.
3.
Reduction of ring and decomposition of side chain. As result 17-ketosteroids
are formed that are excreted with urine.
The determination of 17-ketosteroids in urine - important diagnostic indicator.
This is the indicator of adrenal cortex function. In men 17-ketosteroids are
also the terminal products of sex hormones metabolism giving important
information about testicles function.
4.
Corticosteroids can be excreted
by kidneys in native structure.
Synthesis of steroid hormons
The name "glucocorticoid" derives from early observations that
these hormones
were involved in glucose metabolism. In the fasted state, cortisol stimulates several processes that
collectively serve to increase and maintain normal concentrations of glucose in
blood.
Metabolic
effects:
·
Stimulation of gluconeogenesis,
particularly in the liver: This pathway results in the synthesis of glucose
from non- hexose substrates such as amino acids and glycerol from triglyceride
breakdown, and is particularly important in carnivores and certain herbivores.
Enhancing the expression of enzymes involved in gluconeogenesis is probably the
best-known metabolic function of glucocorticoids.
·
Mobilization of amino acids from
extrahepatic tissues: These serve as substrates for gluconeogenesis.
·
Inhibition of glucose uptake in muscle
and adipose tissue: A mechanism to conserve glucose.
·
Stimulation of fat breakdown in adipose
tissue: The fatty acids released by lipolysis are used for production of energy
in tissues like muscle, and the released glycerol provide another substrate for
gluconeogenesis.
Excessive
glucocorticoid levels resulting from administration as a drug or
hyperadrenocorticism have effects on many systems. Some examples include
inhibition of bone formation, suppression of calcium absorption (both of which
can lead to osteoporosis),
delayed wound healing, muscle weakness, and increased risk of infection. These
observations suggest a multitude of less-dramatic physiologic roles for
glucocorticoids.
http://www.youtube.com/watch?v=0ss8YIoKw0g
The effect of glucocorticoids on protein
metabolism:
1. stimulate the catabolic processes
(protein decomposition) in connective, lymphoid and muscle tissues and activate
the processes of protein synthesis in liver;
2. stimulate the activity of
aminotransferases;
3. activate the synthesis of urea.
The effect of glucocorticoids on
carbohydrate metabolism:
1.
activate the gluconeogenesis;
2.
inhibit the activity of hexokinase;
3.
activate the glycogen synthesis in liver.
Glucocorticoids causes the
hyperglycemia.
The effect of glucocorticoids on
lipid metabolism:
1.
promote the absorption of lipids in intestine;
2.
activate lipolisis;
3.
activate the conversion of fatty acids in carbohydrates.
Hypercholesterolemia
Hyperfunction of adrenal cortex
causes Icenko-Kushing syndrome. This
state is called steroid diabetes. Symptoms:
hyperglycemia, glucosuria, hypercholesterolemia, hypernatriemia,
hyperchloremia, hypokaliemia.
http://www.youtube.com/watch?v=ku-QJyQ0j7M&feature=related
Adrenal cortex hormones and their
artificial analogs are often used in clinic: for treatment of allergic and
autoimmune diseases, in hard shock states.
Blood and urine cortisol, together with the determination
of adrenocorticotropic hormone (ACTH), are the three most important tests in
the investigation of Cushing's syndrome (caused by an overproduction of
cortisol) and Addison's disease (caused by the underproduction of
cortisol).
Cushing's syndrome
Reference ranges for cortisol vary from laboratory to
laboratory but are usually within the following ranges for blood:
·
adults (
·
child one to six years (
·
newborn: 1/24 mg/dL.
Reference ranges for cortisol vary from laboratory to
laboratory, but are usually within the following ranges for 24-hour urine
collection:
·
adult: 10-100 mg/24 hours
·
adolescent: 5-55 mg/24 hours
·
Child: 2-27 mg/24 hours.
Abnormal results
Increased levels of cortisol are found in Cushing's
syndrome, excess thyroid (hyperthyroidism), obesity,
ACTH-producing tumors, and high levels of stress.
Decreased levels of cortisol are found in Addison's
disease, conditions of low thyroid, and hypopituitarism, in which
pituitary activity is diminished.
Cushing's syndrome
A hormonal disorder caused by an
abnormally high level of corticosteroid hormones. Symptoms include high blood
sugar levels, a moon face, weight gain, and increased blood pressure
In
Since cortisol
production by the adrenal glands is normally under the control of the pituitary (like the thyroid
gland), overproduction can be caused by a tumor in the pituitary or within
the adrenal glands themselves. When a pituitary tumor secretes too much
ACTH (Adrenal Cortical Tropic Hormone), it simply causes the otherwise normal
adrenal glands to produce too much cortisol. This type of Cushings syndrome is
termed "Cushings Disease" and it is diagnosed like other endocrine
disorders by measuring the appropriateness of hormone production. In this case,
serum cortisol will be elevated, and, serum ACTH will be elevated at the same
time.
When the adrenal
glands develop a tumor, like any other endocrine gland, they usually produce
excess amounts of the hormone normally produced by these cells. If the adrenal
tumor is composed of cortisol producing cells, excess cortisol will be produced
which can be measured in the blood. Under these conditions, the normal
pituitary will sense the excess cortisol and will stop making ACTH in an
attempt to slow the adrenal down. In this manner, physicians can readily
distinguish whether excess cortisol is the result of a pituitary tumor, or an
adrenal tumor.
Even more rare (but
placed here for completion sake) is when excess ACTH is produced somewhere
other than the pituitary. This is extremely uncommon, but certain lung cancers
can make ACTH (we don't know why) and the patients develop Cushings Syndrome in
the same way they do as if the ACTH was coming from the pituitary.
Causes of Cushings Syndrome
ACTH Dependent (80%)
Pituitary Tumors (60%)
Lung Cancers (5%)
ACTH Independent (20%)
Benign Adrenal Tumors (adenoma) (25%)
Malignant Adrenal Tumors (adrenal
cell carcinoma) (10%)
Testing for Cushings Syndrome
The most sensitive test to check for
the possibility of this disease is to measure the amount of cortisol
excreted in the during during a 24
hour time period. Cortisol is normally secreted in different amounts during the
day and night, so this test usually will be repeated once or twice to eliminate
the variability which is normally seen. This normal variability is why simply
checking the amount of cortisol in the blood is not a very reliable test. A 24
hour free cortisol level greater than 100 ug is diagnostic of Cushings
syndrome. The second test which helps confirms this diagnosis is the
suppression test which measures the cortisol secretion following the
administration of a powerful synthetic steroid which will shut down steroid
production in everybody with a normal adrenal gland. Subsequent tests will
distinguish whether the disease is due to an ACTH dependent or independent
cause.
Invariably, once the diagnosis is
made, patients will undergo a CT scan (or possibly an MRI or Ultrasound) of the
adrenal glands to look for tumors in one or both of them (more information on adrenal x-ray tests on another page). If the laboratory test suggest a
pituitary origin, a CT or MRI of the brain (and possibly of the chest as well)
will be performed.
Treatment of Cushings Syndrome
Obviously, the treatment of this disease depends upon the cause.
Pituitary tumors are usually removed surgically and often treated with
radiation therapy. Neurosurgeons and some ENT surgeons specialize in these
tumors. If the cause is determined to be within a single adrenal gland, this is
treated by surgical removal. If the tumor has characteristics of cancer on any
of the x-ray tests, then a larger, conventional operation is in order. If a
single adrenal gland possesses a small, well defined tumor, it can usually be
removed by the new technique of laparoscopic adrenalectomy.
Functions of mineralocorticoids.
Secretion of mineralocorticoids is
regulated by renin-angiotensine system
-
activates the reabsorption of Na+, Cl- and water
in kidney canaliculuses;
-
promote the excretion of K+ by kidneys, skin and saliva.
Deficiency of corticosteroids causes
Addison's disease.
For this disease the
hyperpigmentation is typical because the deficiency of corticosteroids results in
the excessive synthesis of ACTH.
http://www.youtube.com/watch?v=FK1pPqWMXjM
Addison's disease
A rare
disorder in which symptoms are caused by a deficiency of hydrocortisone (cortisol)
and aldosterone, two corticosteroid hormones normally produced by a part of the
adrenal glands called the adrenal cortex. Symptoms include weakness, tiredness,
vague abdominal pain, weight loss, skin pigmentation and low blood pressure.
.
Conn's syndrome is an aldosterone-producing adenoma. Conn's syndrome
is named after Jerome W.
Conn (1907–1994), the Americanendocrinologist who first described the condition at
the University of Michigan in 1955.
Primary hyperaldosteronism has
many causes, including adrenal hyperplasia and adrenal carcinoma.[2]
The syndrome is due to:
·
Bilateral (micronodular) adrenal
hyperplasia, 60%
·
Adrenal (Conn's) adenoma,
40%
·
Glucocorticoid-remediable
hyperaldosteronism (dexamethasone-suppressible hyperaldosteronism), <1%
·
rare forms, including disorders of the renin-angiotensin system, <1%
Aldosterone
enhances exchange of sodium for potassium in the kidney, so increased
aldosteronism will lead to hypernatremia (elevated sodium level) and hypokalemia (low blood potassium). Once the
potassium has been significantly reduced by aldosterone, a sodium/hydrogen pump
in the nephron becomes more active, leading to
increased excretion of hydrogen ions and further exacerbating the elevated
sodium level resulting in a further increase in hypernatremia.
The hydrogen ions exchanged for sodium are generated by carbonic anhydrase in the renal tubule epithelium,
causing increased production of bicarbonate.
The increased bicarbonate and the excreted hydrogen combine to generate a metabolic alkalosis.
The high pH of the blood makes calcium less
available to the tissues and causes symptoms of hypocalcemia (low calcium levels).
The sodium
retention leads to plasma volume expansion and elevated blood pressure. The
increased blood pressure will lead to an increased glomerular filtration rate and cause a decrease inrenin release from the granular cells of the juxtaglomerular apparatus in the kidney. If a patient is thought
to suffer from primary hyperaldosteronism, the aldosterone:renin activity ratio
is used to assess this. The decreased renin levels and in turn the reactive
down-regulation of angiotensin
II are thought to be
unable to down-regulate the constitutively formed aldosterone, thus leading to
an elevated [plasma aldosterone:plasma renin activity] ratio (lending the assay
to be a clinical tool for diagnostic purposes).
Aside from
hypertension, other manifesting problems include myalgias, weakness, and
chronic headaches. The muscle cramps are due to neuron hyperexcitability
seen in the setting of hypocalcemia, muscle
weakness secondary to
hypoexcitability of skeletal muscles in the setting of low blood potassium
(hypokalemia), and headaches which are thought to be due to both
electrolyte imbalance (hypokalemia) and hypertension.
Secondary
hyperaldosteronism is often related to decreased cardiac
output, which is associated with elevated renin levels.
Measuring
aldosterone alone is not considered adequate to diagnose primary
hyperaldosteronism. The screening test of choice for diagnosis is the plasma
aldosterone:plasma renin activity ratio. Renin activity, not simply plasma
renin level, is assayed. Both renin and
aldosterone are measured, and a ratio greater than 30 is indicative of primary
hyperaldosteronism.
In the
absence of proper treatment, individuals with hyperaldosteronism often suffer
from poorly controlled high blood pressure, which may be associated with
increased rates of stroke, heart disease, and kidney failure. With appropriate
treatment, the prognosis is excellent.
Sex hormones.
Sex hormones are synthesized in
testes, ovaries. Smaller amount of sex hormones are produced in adrenal cortex
and placenta. Small amount of male sex hormones are produced in ovaries and
female sex hormones - in testes.
Male sex hormones are called androgens and female - estrogens.
Chemical structure - steroids.
Synthesis and secretion of the sex
hormones are controlled by the pituitary honadotropic hormones. Sex hormones
act by means of the activation of gene apparatus of cells. Catabolism of sex
hormones takes place in liver. The time half-life is 70-90 min.
The main estrogens: estradiol,
estrole, estriole (are produced by follicles) and progesterone (is produced
by yellow body and placenta). The main biological role of estrogens -
conditioning for the reproductive female function (possibility of ovum
fertilization). Estradiol results in the proliferation of endometrium and
progesterone stimulates the conversion of endometrium in decidual tissue which
is ready for ovum implantation. Estrogens also cause the development of secondary
sexual features.
Estrogens originate in the adrenal
cortex and gonads and primarily affect maturation and function of secondary sex
organs (female sexual determination).
Estrogens,
in females, are produced primarily by the ovaries, and during
pregnancy, the placenta. Follicle-stimulating hormone(FSH)
stimulates the ovarian production of estrogens by the granulosa
cells of the ovarian
follicles and corpora lutea.
Some estrogens are also produced in smaller amounts by other tissues such as
the liver, adrenal
glands, and the breasts. These secondary
sources of estrogens are especially important in postmenopausal women.Fat cells produce estrogen as well.
In females,
synthesis of estrogens starts in theca interna cells in the ovary, by the synthesis
of androstenedionefrom cholesterol.
Androstenedione is a substance of weak androgenic activity which serves
predominantly as aprecursor for more potent androgens such as
testosterone as well as estrogen. This compound crosses thebasal
membrane into the
surrounding granulosa cells, where it is converted either immediately into
estrone, or into testosterone and then estradiol in an additional step. The
conversion of androstenedione to testosterone is catalyzed by 17β-hydroxysteroid dehydrogenase (17β-HSD), whereas the conversion
of androstenedione and testosterone into estrone and estradiol, respectively is
catalyzed by aromatase, enzymes which are both expressed in granulosa cells. In
contrast, granulosa cells lack 17α-hydroxylase and 17,20-lyase,
whereas theca cells express these enzymes and 17β-HSD but lack aromatase.
Hence, both granulosa and theca cells are essential for the production of
estrogen in the ovaries.
Estrogen
levels vary through the menstrual
cycle, with levels highest near the end of the follicular
phase just before ovulation.
The
actions of estrogen are mediated by the estrogen
receptor (ER), a
dimeric nuclear protein that binds to DNA and controls gene expression. Like
other steroid hormones, estrogen enters passively into the cell where it binds
to and activates the estrogen receptor. The estrogen:ER complex binds to
specific DNA sequences called a hormone response element to activate the transcription of
target genes (in a study using a estrogen-dependent breast cancer cell line as
model, 89 such genes were identified).[ Since estrogen enters all cells, its
actions are dependent on the presence of the ER in the cell. The ER is
expressed in specific tissues including the ovary, uterus and breast.
While estrogens
are present in both men and women, they are usually
present at significantly higher levels in women of reproductive age. They
promote the development of female secondary sexual characteristics, such as breasts, and are also
involved in the thickening of the endometrium and other aspects of regulating the
menstrual cycle. In males, estrogen regulates certain functions of the reproductive system important to the maturation of sperm and may be necessary for a healthy libido. Furthermore, there are several other
structural changes induced by estrogen in addition to other functions.
Structural
·
Promote formation of female secondary sex characteristics
·
Accelerate metabolism
·
Increase fat stores
·
Stimulate endometrial growth
·
Increase uterine growth
·
Increase vaginal lubrication
·
Thicken the vaginal wall
·
Maintenance of vessel and skin
·
Reduce bone
resorption, increase bone formation
Protein synthesis
·
Increase hepatic production of binding
proteins
·
Increase circulating level of factors 2, 7, 9, 10, plasminogen
·
Decrease antithrombin III
·
Increase platelet adhesiveness
·
Increase HDL, triglyceride
·
Decrease LDL, fat deposition
Fluid balance
·
Salt (sodium)
and water retention
·
Reduce bowel motility
·
Increase cholesterol in bile
·
Increase pheomelanin,
reduce eumelanin
Cancer
·
Support hormone-sensitive breast cancers (see section below)
·
Promotes lung function by supporting alveoli (in rodents but probably in humans).
Uterus lining
·
Estrogen together with progesterone promotes and maintains the uterus
lining in preparation for implantation of fertilized egg and maintenance of
uterus function during gestation period, also upregulates oxytocin receptor in myometrium
·
Surge in estrogen level induces the release of luteinizing hormone, which then triggers
ovulation by releasing the egg from the Graafian
follicle in the ovary.
Progestins
Progestins
originate from both ovaries and placenta, and mediate menstrual cycle and
maintain pregnancy.
Progesterone has
key effects via non-genomic signalling on human sperm as they migrate through
the female tract before fertilization occurs, though the receptor(s) as yet
remain unidentified. Detailed
characterisation of the events occurring in sperm in response to progesterone
has elucidated certain events including intracellular calcium transients and
maintained changes, slow calcium oscillations, now thought to possibly regulate
motility. Interestingly progesterone
has also been shown to demonstrate effects on octopus spermatozoa.
Progesterone
modulates the activity of CatSper (cation
channels of sperm) voltage-gated Ca2+ channels. Since eggs release
progesterone, sperm may use progesterone as a homing signal to swim toward eggs
(chemotaxis).
Hence substances that block the progesterone binding site on CatSper channels
could potentially be used in male contraception.
Progesterone is
sometimes called the "hormone of pregnancy", and it has many roles relating to the
development of the fetus:
·
Progesterone converts the endometrium to its secretory stage to prepare the
uterus for implantation. At the same time progesterone affects the vaginal epithelium and cervical
mucus, making it thick and impenetrable to sperm. If pregnancy does
not occur, progesterone levels will decrease, leading, in the human, to menstruation.
Normal menstrual bleeding is progesterone-withdrawal bleeding. If ovulation
does not occur and the corpus luteum does not develop, levels of progesterone
may be low, leading to anovulatory dysfunctional uterine bleeding.
·
During implantation and gestation, progesterone
appears to decrease the maternal immune response to allow for the acceptance
of the pregnancy.
·
Progesterone decreases contractility of
the uterine smooth muscle.
·
In addition progesterone inhibits lactation during pregnancy. The fall in
progesterone levels following delivery is one of the triggers for milk
production.
·
A drop in progesterone levels is
possibly one step that facilitates the onset of labor.
The fetus metabolizes placental progesterone in the
production of adrenal steroids.
Androgens
Androgens originate in the adrenal
cortex and gonads and primarily affect maturation and function of secondary sex
organs (male sexual determination).
http://www.youtube.com/watch?v=nLmg4wSHdxQ&feature=fvwrel
The main androgen is testosterone. Its synthesis is regulated by the luteinizing hormone.
Testosterone forms the secondary sexual features in males.
A
subset of androgens, adrenal androgens, includes any of the 19-carbon steroids
synthesized by the adrenal
cortex, the inner-most layer of the adrenal
cortex (zonula
reticularis—innermost region of the adrenal cortex), that function as weak
steroids or steroid precursors, including dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate
(DHEA-S), and androstenedione.
Besides testosterone, other
androgens include:
·
Dehydroepiandrosterone (DHEA) is a steroid hormone produced
in the adrenal
cortex from cholesterol.
It is the primary precursor of natural estrogens. DHEA is also
called dehydroisoandrosterone ordehydroandrosterone.
·
Androstenedione (Andro) is an androgenic steroid
produced by the testes, adrenal
cortex, and ovaries. While
androstenediones are converted metabolically to testosterone and other androgens, they are also the
parent structure of estrone. Androstenediol is the steroid metabolite thought to act as the main regulator
of gonadotropin secretion.
·
Androsterone is a chemical byproduct created during
the breakdown of androgens, or derived fromprogesterone,
that also exerts minor masculinising effects, but with one-seventh the intensity
of testosterone. It is found in approximately equal amounts in the plasma and urine of both males and females.
·
Dihydrotestosterone (DHT) is a metabolite of testosterone, and a more potent
androgen than testosterone in that it binds more strongly to androgen
receptors. It is produced in the adrenal
cortex.
Testosterone is the primary androgenic
hormone. It instills its effects on the body both directly, and through its
conversion to metabolites (DHT,
estradiol etc). Androgens and other steroid hormones primarily exert their
direct activities through binding to specific receptors present in the cytosol
of cells. Upon binding to the receptor, the hormone forms a complex that then
travels to the nucleus of cells where it interacts with DNA to promote the
formation of specific proteins that then direct the actual biological changes.
Within the central nervous system (CNS), androgen receptors are heavily
located in specific places. Androgens and other steroid hormones are able to
penetrate the blood brain barrier and interact with their appropriate CNS
cytosolic receptors. The hypothalamus and anterior pituitary gland are
particularly dense in androgen receptors, and here they help regulate the
secretion of androgens as well as other hormones that control a wide variety of
biological functions. Androgen receptors are also located in parts of the
cerebral cortex, medulla, and amygdala. Here their specific functions are not
as well characterized.
The processes of androgen action that involve receptor binding and DNA
translation are known as receptor mediated, or “genomic”, hormone actions.
However, there are also lesser known actions of steroid hormones that are
non-genomic in mechanism. Non-genomic activities are particularly key in the
central nervous system where they combine with genomic activities to produce
specific effects.
Non-genomic actions of steroid hormones differ in a very important way from
genomic actions. Genomic effects are manifested over a relatively long period
of time (days) because they require a complex cascade of events (binding,
translation, transcription, accumulation of active enzyme products) before the
actual physiology of the target organ is altered. On the other hand, genomic actions
are extremely rapid (<1 minute). They are rapid because their effects
involve an immediate modulation of the membranes of cells (particularly neural
cells). These modulations may include changes to the permeability of the
membrane, as well as effects on the opening of vital ligand gated ion channels.
The end result is a quick and significant influence upon the activities of key
areas of the brain, and the relevance of this to the medicinal use of
androgenic hormones or prohormones should not be overlooked.
Effect of sex hormones on protein metabolism:
1.
stimulate the processes of protein, DNA, RNA synthesis;
2.
cause the positive nitrogenous equilibrium.
Effect
of sex hormones on carbohydrate metabolism:
1.
activate the Krebs cycle;
2.
activate the synthesis of glycogen in liver.
Effect of sex hormones on lipid metabolism:
1.
enhance the oxidation of lipids;
2.
inhibit the synthesis of cholesterol.
Effect of sex hormones on energy metabolism:
-
stimulate the Krebs cycle, tissue respiration and ATP production.
Sex hormones are used for treatment
of variety diseases. For example, testosterone and its analogs are used as
anabolic remedies; male sex hormones are used for the treatment of malignant
tumor of female sex organs and vice versa.
Tissue hormones.
Prostaglandins. The precursor of
prostaglandins is arachidonic acid. Time half-life - 30 s. There are different
prostaglandins and they have a lot of physiological and pharmacological effects
and different prostaglandins have different effects.
Prostaglandins were first
discovered and isolated from human semen in the 1930s by Ulf von Euler of
Sweden. Thinking they had come from the prostate gland, he named them
prostaglandins. It has since been determined that they exist and are
synthesized in virtually every cell of the body.
Prostaglandins, are like
hormones in that they act as chemical messengers, but do not move to other
sites, but work right within the cells where they are synthesized.
Prostaglandins are unsaturated carboxylic acids,
consisting of of a 20 carbon skeleton that also contains a five member ring.
They are biochemically synthesized from the fatty acid, arachidonic acid.
The unique shape of the arachidonic acid caused by a
series of cis double bonds helps to put it into position to make the five
member ring. See the prostaglandin in the next panel.
Functions of Prostaglandins:
There are a
variety of physiological effects including:
-
1. Activation of the inflammatory response, production of pain, and
fever. When tissues are damaged, white blood cells flood to the site to try to
minimize tissue destruction. Prostaglandins are produced as a result.
-
2. Blood clots form when a blood vessel is damaged. A type of
prostaglandin called thromboxane stimulates constriction and clotting of
platelets. Conversely, PGI2, is produced to have the opposite effect on the
walls of blood vessels where clots should not be forming.
-
3. Certain prostaglandins are involved with the induction of labor and
other reproductive processes. PGE2 causes uterine contractions and has been
used to induce labor.
-
4. Prostaglandins are involved in several other organs such as the
gastrointestinal tract (inhibit acid synthesis and increase secretion of
protective mucus), increase blood flow in kidneys, and leukotriens promote
constriction of bronchi associated with asthma.
Effects of Aspirin and other Pain Killers:
When you see
that prostaglandins induce inflammation, pain, and fever, what comes to mind
but aspirin. Aspirin blocks an enzyme called cyclooxygenase, COX-1 and COX-2,
which is involved with the ring closure and addition of oxygen to arachidonic
acid converting to prostaglandins.
The acetyl group on aspirin is hydrolzed and then bonded to the alcohol
group of serine as an ester. This has the effect of blocking the channel in the
enzyme and arachidonic can not enter the active site of the enzyme.
By inhibiting or blocking this enzyme, the synthesis of prostaglandins is
blocked, which in turn relives some of the effects of pain and fever.
Aspirin is also
thought to inhibit the prostaglandin synthesis involved with unwanted blood
clotting in coronary heart disease. At the same time an injury while taking
aspirin may cause more extensive bleeding.
Kallicrein-kinin system. Kinins -
group of peptides with similar structure and biological properties. The main
kinins - bradykinin and kallidine.
Kinins are formed from their precursors
kininogens that are synthesized in
liver owing to acting of kallicreins. Kallicreins are also formed from inactive
precursors prekallicreins by means of proteolysis.
Functions: - kinins relax the smooth
muscles of blood vessels and decrease the blood pressure;
-
increase the capillaries permeability;
-
takes part in the inflammatory processes.
Bradykinin
is a potent endothelium-dependent vasodilator,
causes contraction of non-vascular smooth muscle,
increases vascular permeability and also is involved in the mechanism
of pain. Bradykinin also
causes natriuresis,
contributing to a drop in blood pressure.
Bradykinin
raises internal calcium levels in neocortical astrocytes causing them to release glutamate.
Bradykinin is
also thought to be the cause of the dry cough in some patients on angiotensin converting enzyme (ACE) inhibitor drugs. It is thought
that bradykinin is converted to inactive metabolites by angiotensin converting enzyme (ACE), therefore inhibition of this
enzyme leads to increased levels of bradykinin which causes a dry cough. This
refractory cough is a common cause for stopping ACE inhibitor therapy. In which case angiotensin II receptor antagonists (ARBs) are the next line of treatment.
Renin-angiotensin system.
Renin - enzyme that is synthesized in special cells located near the
renal glomerules.
Renin acts on angiotensinogen. As result angiotensin-I
is formed. Under the effect of peptidase
angiotensin-I is converted to angiotensin-II.
Angiotensin-II causes 2 effects:
-
narrows the vessels and increases the blood pressure;
-
stimulates the secretion of aldosterone.
The decrease of renal blood stream
is the specific stimulant for renin secretion.