Molecular mechanisms of the effect of protein-peptide hormones on the target cells.
Molecular mechanisms of the effect of catecholamines and another biological amines on target cells.
Biomedical Importance 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.
The survival of multicellular organisms depends on their ability to adapt to a constantly changing environment. Intercellular communication mechanisms are necessary requirements for this adaptation. The nervous system and the endocrine system provide this intercellular, organism- wide communication. The nervous system was originally viewed as providing a fixed communication system, whereas the endocrine system supplied hormones, which are mobile messages. In fact, there is a remarkable convergence of these regulatory systems. For example, neural regulation of the endocrine system is important in the production and secretion of some hormones; many neurotransmitters resemble hormones in their synthesis, transport, and mechanism of action; and many hormones are synthesized in the nervous system.
The word “hormone” is derived from a Greek term that means to arouse to activity. As classically defined, a hormone is a substance that is synthesized in one organ and transported by the circulatory system to act on another tissue. They are secreted in response to changes in the environment inside or outside the body. These are released into the extracellular fluid, where they are diffused into the blood stream. The latter carries them from the site of production to the site of action. They act on specific organs called target organs. The blood contains all the hormones but the cells of a target organ can pick up the specific required hormone only and ignore all others. It has been found that the target cell has on its surface or in its cytoplasm a specific protein molecule, called a receptor, which can recognise and pick out the specific hormone capable of action in that cell. The hormone delivers its message to the target cell by changing the shape of the receptor cell and binds to it. The receptors new shape sets up certain changes in the cell such as alteration in permeability, enzyme activity or gene transcription.
Hormones may stimulate or inhibit specific biological processes in the target organs to modify their activities thus acting as regulators. There is considerable co-ordination between nerves and hormones. Nerves regulate synthesis and release of some hormones. Some times hormones may also influence nerve activities. Thus, hormonal co-ordination plays an important role in regulating body functions.
Calcitonin secreted by thyroid gland regulates the concentration of calcium and phosphorus in the blood. When the concentration of calcium rises in the blood, the secretion of calcitonin is seen which lowers the concentration of calcium and phosphorus in the plasma by decreasing the release for the bones.
Feedback controls
Maintenance of internal chemical environment of the body to a constant is called homeostasis. Hormones play a major role in maintaining homeostasis by their intergrated action and feed back controls.
Feedback control is mostlly negative, rarely positive. In a negative feedback control, synthesis of a hormone slows or halts when its level in the blood rises above normal. Some of examples of feedback control is given below.
Rise of testosterone level in the blood above normal inhibits ICSH secretion by the anterior pituitary lobe. This negative feedback checks oversecretion of testosterone
Hypothalamus in response to some external stimulus, produces a thyrotrophin-releasing hormone for the secretion of thyrotrophic hormone. The thyrotrophin-releasing hormone (TRH) stimulates the anterior pituitary lobe to secrete thyrotrophic hormone. The latter in turn stimulates the thyroid gland to produce thyroxine. If thyroxine is in excess, it exerts an influence on the hypothalamus and anterior pituitary lobe, which then secrete less releasing hormone and thyroid-stimulating hormone (TSH) respectively. A rise in the TSH level in the blood may also exert negative feed back effect on the hypothalmus and retard the secretion of TRH. This restores the normal blood-thyroxine level.
Sometimes, accumulation of a biochemical increases its own production. For example uterine contraction at the onset of labour stimulates the release of the hormone oxytocin, which intensifies uterine contractions. The contractions futher stimulate the production of oxytocin. The cycle of increase stops suddenly after the birth of the baby. This is a positive feedback control.
Functions of hormones.
Hormones regulate the following processes:
Growth and differentiation of cells, tissues, and organs These processes include cell proliferation, embryonic development, and sexual differentiation— i. e., processes that require a prolonged time period and involve proteins de novo synthesis. For this reason, mainly steroid hormones which function via transcription regulation are active in this field
Metabolic pathways Metabolic regulation requires rapidly acting mechanisms. Many of the hormones involved therefore regulate interconversion of enzymes. Themain processes subject to hormonal regulation are the uptake and degradation of storage substances (glycogen, fat), metabolic pathways for biosynthesis and degradation of central metabolites (glucose, fatty acids, etc.), and the supply of metabolic energy.
Digestive processes Digestive processes are usually regulated by locally acting peptides (paracrine), but mediators, biogenic amines, and neuropeptides are also involved.
Maintenance of ion concentrations (homeostasis) Concentrations of Na+, K+, and Cl– in body fluids, and the physiological variables dependent on these (e. g. blood pressure), are subject to strict regulation. The principal site of action of the hormones involved is the kidneys, where hormones increase or reduce the resorption of ions and recovery of water. The concentrations of Ca2+ and phosphate, which form the mineral substance of bone and teeth, are also precisely regulated. Many hormones influence the above processes only indirectly by regulating the synthesis and release of other hormones (hormonal hierarchy).
3. Endocrine, paracrine, and autocrine hormone effects.
http://www.youtube.com/watch?v=3LW7TSBcFjE&feature=related
Hormones transfer signals by migrating from heir site of synthesis to their site of action. They are usually transported in the blood. In this case, they are said to have an endocrine effect (example: insulin). By contrast, tissue hormones, the target cells for which are in the immediate vicinity of the glandular cells that produce them, are said to have a paracrine effect (example: gastrointestinal tract hormones). When signal substances also pass effects back to the cells that synthesize them, they are said to have an autocrine effect (example: prostaglandins). Autocrine effects are often found in tumor cells, which stimulate their own proliferation in this way. Insulin,which is formed in the B cells of the pancreas, has both endocrine and paracrine effects. As a hormone with endocrine effects, it regulates glucose and fat metabolism. Via a paracrinemechanism, it inhibits the synthesis and release of glucagon from the neighboring A cells.
Endocrine glands
The endocrine system is made up of glands that produce and secrete hormones, chemical substances produced in the body that regulate the activity of cells or organs. These hormones regulate the body's growth, metabolism (the physical and chemical processes of the body), and sexual development and function. The hormones are released into the bloodstream and may affect one or several organs throughout the body.
Hormones are chemical messengers created by the body. They transfer information from one set of cells to another to coordinate the functions of different parts of the body.
The major glands of the endocrine system are the hypothalamus, pituitary, thyroid, parathyroids, adrenals, pineal body, and the reproductive organs (ovaries and testes). The pancreas is also a part of this system; it has a role in hormone production as well as in digestion.
The endocrine system is regulated by feedback in much the same way that a thermostat regulates the temperature in a room. For the hormones that are regulated by the pituitary gland, a signal is sent from the hypothalamus to the pituitary gland in the form of a "releasing hormone," which stimulates the pituitary to secrete a "stimulating hormone" into the circulation.
The stimulating hormone then signals the target gland to secrete its hormone. As the level of this hormone rises in the circulation, the hypothalamus and the pituitary gland shut down secretion of the releasing hormone and the stimulating hormone, which in turn slows the secretion by the target gland. This system results in stable blood concentrations of the hormones that are regulated by the pituitary gland.
Classification of hormones.
The animal organism contains more than 100 hormones and hormone-like substances, which can be classified either according to their structure or according to their function. In chemical terms, most hormones are:
Ø hormones of protein structure: all hormones of anterior pituitary (except ACTH), insulin, parathyroid hormone;
Ø hormones of peptide structure: ACTH, calcitonin, glucagon, hormones of posterior pituitary, factors of hypothalamus, thymozin;
Ø steroid hormones: adrenal cortical steroids, sex hormones;
Ø
Ø hormones - derivatives of amino acid: thyroid hormones, adrenal medulla hormones, epiphysis hormones;
Ø
Ø hormones derivatives of unsaturated fatty acid: prostaglandins.
v Lipotrophic
v Hydrophilic
http://www.youtube.com/watch?v=kIPYVV4aThM&feature=related
http://www.youtube.com/watch?v=8fh2HmdxQjQ&feature=related
Mechanism of action
A. Mechanism of action of lipophilic hormones
Lipophilic signaling substances include the steroid hormones, calcitriol, the iodothyronines (T3 and T4), and retinoic acid. These hormones mainly act in the nucleus of the target cells, where they regulate gene transcription in collaboration with their receptors and with the support of additional proteins (known as coactivators and mediators). There are several effects of steroid hormones that are notmediated by transcription control. These alternative pathways for steroid effects have not yet been fully explained. In the blood, there are a number of transport proteins for lipophilic hormones. Only the free hormone is able to penetrate the membrane and enter the cell. The hormone encounters its receptor in the nucleus (and sometimes also in the cytoplasm). The receptors for lipophilic hormones are rare proteins. They occur in small numbers (103–104 molecules per cell) and show marked specificity and high affinity for the hormone (Kd = 10–8–10–10 M). After binding to the hormone, the steroid receptors are able to bind as homodimers or heterodimers to control elements in the promoters of specific genes, from where they can influence the transcription of the affected genes—i. e., they act as transcription factors. The illustration shows the particularly well-investigated mechanism of action for cortisol, which is unusual to the extent that the hormone–receptor complex already arises in the cytoplasm. The free receptor is present in the cytoplasm as a monomer in complex with the chaperone hsp90. Binding of cortisol to the complex leads to an allosteric conformational change in the receptor, which is then released from the hsp90 and becomes capable of DNA binding as a result of dimerization. In the nucleus, the hormone–receptor complex binds to nucleotide sequences known as hormone response elements (HREs). These are short palindromic DNA segments that usually promote transcription as enhancer elements. The illustration shows the HRE for glucocorticoids (GRE; “n” stands for any nucleotide). Each hormone receptor only recognizes its “own” HRE and therefore only influences the transcription of genes containing that HRE. Recognition between the receptor and HRE is based on interaction between the amino acid residues in the DNA-binding domain (B) and the relevant bases in the HRE (emphasized in color in the structure illustrated). As discussed on p. 244, the hormone receptor does not interact directly with the RNA polymerase, but rather—along with other transcription factors—with a coactivator/mediator complex that processes all of the signals and passes them on to the polymerase. In this way, hormonal effects lead within a period of minutes to hours to altered levels ofmRNAs for key proteins in cellular processes (“cellular response”).
B. Mechanism of action of hydrophilic hormones
The messages transmitted by hydrophilic signaling substances are sent to the interior of the cell by membrane receptors. These bind the hormone on the outside of the cell and trigger a new second signal on the inside by altering their conformation. In the interior of the cell, this secondary signal influences the activity of enzymes or ion channels. Via further steps, switching of the metabolism, changes in the cytoskeleton, and activation or inhibition of transcription factors can occur (“signal transduction”) can occur.
http://www.youtube.com/watch?v=oOj04WsU9ko
Examples of peptide hormones
Hormones of hypothalamus (releasing and inhibitory factors), structure, mechanism of action.
Hypothalamus has the wide anatomic links with other parts of the brain. Therefore in different mental disorders there is the change of secretion of hypothalamus hormones.
http://www.youtube.com/watch?v=hLeBNyB1qKU&feature=related
Two groups of hormones are produced by hypothalamus corresponding to the anterior and posterior pituitary.
Hypothalamus and posterior pituitary. 3 peptides are synthesized in the hypothalamus that pass to the posterior pituitary along axons where they are accumulated: oxytocin, vasopressin (antidiuretic hormone) and neurophysin. The later binds the oxytocin and vasopressin and promotes their transportation to the pituitary.
Hypothalamus and anterior pituitary. Hypothalamus is connected with the anterior pituitary by the net of blood capillaries, so called hypothalamic portal system. Hypothalamus produces very active peptide compounds that pass via this portal system to anterior pituitary and stimulate or oppress the secretion of tropic hormones. Compounds stimulating the secretion are called releasing factors. 7 releasing factors are known according to the amount of tropic hormones of anterior pituitary:
- corticotropin-releasing factor
- thyrotropin-releasing factors
- somatotropin-releasing factors
- follicletropin-releasing factor
- luteotropin-releasing factor
- prolactotropin-releasing factor
- melanotropin-releasing factor.
Hypothalamus also secretes substances called inhibitory factors or statins, which can inhibit release of the some pituitary hormones. 3 inhibitory factors are known today:
- somatostatin
- prolactostatin
- melanostatin.
Releasing and inhibitory factors are produced in only minute amounts.
http://www.youtube.com/watch?v=-UaSfYKsFh0
Hormones of pituitury, structure, mechanism of action.
Tropic hormones are produced by the anterior pituitary. Usually tropic hormones not directly regulate the metabolism but act on the peripheral endocrine glands.
Somatotropic hormone (STH, growth hormone)
Chemical structure: simple protein
The intensity of secretion is regulated by the relationship between the somatotropic-releasing factor and somatostatin.
The main function of somatotropic hormone - stimulation of growth. Hormone is necessary for the bone tissue formation, for the muscle tissue growth, for the formation of peculiarities of men and women body.
Somatotropic hormone can act both directly on the metabolism and indirectly stimulating the synthesis of somatomedines (specific protein growth factors which are synthesized in liver).
The effect of somatotropic hormone on:
- protein metabolism: stimulates the passing of amino acids into the cells;
activates the synthesis of proteins, DNA, RNA.
- carbohydrate metabolism: activates the insulinase of liver;
inhibits the conversion of lipids to carbohydrates;
activates the exit of glucose from liver;
inhibits the entry of glucose into the cells.
- lipid metabolism: stimulates lipolisis;
stimulates the oxidation of fatty acids.
The deficiency of somatotropic hormone in children age causes nanism. Nanism - proportional underdevelopment of all body.
The deficiency of somatotropic hormone in adult persons hasn’t clinical symptoms.
The excess of somatotropic hormone in children age causes gigantism.
The excess of somatotropic hormone in adult persons causes acromegalia (disproportional development of the separate body parts).
http://www.youtube.com/watch?v=VX2wgM4kUfM
Thyrotropic hormone (TTH).
Chemical structure: glicoprotein.
This hormone is necessary for the normal functions of thyroid glands.
Thyrotropic hormone promotes:
- accumulation of iodine in thyroid;
- including of iodine into the tyrosine;
- synthesis of thyroxine and triiodothyronine.
Adrenocorticotropic hormone (ACTH).
Chemical structure: polipeptide.
This hormone is necessary for the normal functions of adrenal cortex. It enhances the formation of steroid hormones and their secretion into the blood.
ACTH has also the melanocyte-stimulating activity.
Excessive secretion of ACTH causes the Icenko-Kushing disease (symptoms of hypercorticism, hyperpigmentation).
As you know, Cushing’s is a rarely diagnosed endocrine disorder characterized by hypercortisolism. Cortisol is a hormone produced by the adrenal glands and is vital to regulate the body’s cardivoascular functions and metabolism, to boost the immune system and to fight inflammation. But its most important job is to help the body to respond to stress.
The adrenal glands release cortisol in response to stress, so atheletes, women experiencing pregnancy, and those suffering from alcoholism, panic disorders and malnutrition naturally have higher-than-normal levels of cortisol.
People with Cushing’s Syndrome live life with too much cortisol for their bodies as a result of a hormone-secreting tumor. Mine is located in the pituitary gland. Endogenous hypercortisolism leaves the body in a constant state of “fight or flight,” which ravages the body and tears down the body’s major systems including cardivascular, musculo-skeletal, endocrine, etc.
Symptoms vary, but the most common symptoms include rapid, unexplained weight gain in the upper body with increased fat around the neck and face (“moon facies”); buffalo hump; facial flushing/plethora; muscle wasting in the arms and legs; purplish striae (stretch marks) on the abdomen, thighs, buttocks, arms and breasts; poor wound healing and bruising; severe fatigue; depression, anxiety disorders and emotional lability; cognitive difficulties; sleep disorders due to abnormally high nighttime cortisol production; high blood pressure and high blood sugar/diabetes; edema; vision problems; premature osteoperosis; and, in women, signs of hyperandrogenism such as menstrual irregularities, infertility, hirsutism, male-patterned balding and steroid-induced acne.
Most people with Cushing’s long for the ability to do simple things, like walk a flight of stairs without having to sit for half an hour afterwards, or vacuum the house or even unload a dishwasher.
One of the worst parts about this disease is the crushing fatigue and muscle wasting/weakness, which accompanies hypercortisolism. Not only do we become socially isolated because of the virilzing effects of an endocrine tumor, which drastically alters our appearance, but we no longer feel like ourselves with regard to energy. We would love to take a long bike ride, run three miles or go shopping like we used to — activities, which we took for granted before the disease struck. Those activities are sadly impossible at times for those with advanced stages of the disease.
Gonadotropic hormones.
Follicle stimulating hormone (FSH).
Chemical structure: glycoprotein.
Function: stimulates the function of follicles (oogenesis) in women and spermatogenesis in men.
FSH (follicle stimulating hormone) regulates the
development, growth, pubertal maturation, and reproductive processes of the
body
In both males and females, FSH stimulates the maturation of germ cells.
In males, FSH induces sertoli cells to secrete inhibin and stimulates the
formation of sertoli-sertoli tight junctions (zonula occludens).
In females, FSH initiates follicular growth, specifically affecting granulosa
cells. With the concomitant rise in inhibin B, FSH levels then decline in the
late follicular phase. This seems to be critical in selecting only the most
advanced follicle to proceed to ovulation. At the end of the luteal phase,
there is a slight rise in FSH that seems to be of importance to start the next
ovulatory cycle.
Luteinizing hormone (LH).
Chemical structure: glycoprotein.
Function: stimulates the formation of yellow body in women and testosterone secretion in men.
In both males and females, (LH) Luteinising hormone is
essential for reproduction.
In females, at the time of menstruation, FSH initiates follicular growth,
specifically affecting granulosa cells. With the rise in estrogens, LH
receptors are also expressed on the maturing follicle that produces an
increasing amount of estradiol. Eventually at the time of the maturation of the
follicle, the estrogen rise leads via the hypothalamic interface to the
“positive feed-back” effect, a release of LH over a 24-48 hour period. This 'LH
surge' triggers ovulation thereby not only releasing the egg, but also
initiating the conversion of the residual follicle into a corpus luteum that,
in turn, produces progesterone to prepare the endometrium for a possible
implantation. LH is necessary to maintain luteal function for the first two
weeks. In case of a pregnancy luteal function will be further maintained by the
action of hCG (a hormone very similar to LH) from the newly established pregnancy.
LH supports thecal cells in the ovary that provide androgens and hormonal
precursors for estradiol production.
In the male, LH acts upon the Leydig cells of the testis and is
responsible for the production of testosterone, an androgen that exerts both
endocrine activity and intratesticular activity on spermatogenesis.
Prolactin (PRL).
When the baby beings to suck, some nerve cells in the mother's breast send a message to the hypothalamus. 2) On receiving the message, the hypothalamus removes the brake from the prolactin. 3-4) In order to begin the production of mother's milk, the prolactin secreted by the pituitary gland stimulates the milk glands in the mother's breast.
Chemical structure: protein.
Functions: - stimulates lactation;
- stimulates function of yellow body (secretion of progesterone);
- promotes formation of mother instinct;
- stimulates the formation of prostate glandular tissue in men.
Lipotropic hormone.
Chemical structure: protein.
Functions: - stimulates the mobilization of lipids from depot;
- decreases the Ca amount in blood;
- has the melanocyte-stimulating activity.
Posterior pituitary.
Vasopressin (Antidiuretic Hormone)
Chemical structure: peptide.
Functions: - activates the hyaluronidase. This enzyme splits the hyaluronic acid. The permeability of membranes is increased and reabsorption of water in kidneys is increased too. As result the day diuresis is decreased;
- narrows arterioles and capillaries and increases the blood pressure.
AVP has two principle sites of action: the kidney and blood vessels.
- The primary function of AVP in the body is to regulate extracellular fluid volume by affecting renal handling of water, although it is also a vasoconstrictor and pressor agent (hence, the name "vasopressin"). AVP acts on renal collecting ducts via V2 receptors to increase water permeability (cAMP-dependent mechanism), which leads to decreased urine formation (hence, the antidiuretic action of "antidiuretic hormone"). This increases blood volume, cardiac output and arterial pressure.
- A secondary function of AVP is vasoconstriction. AVP binds to V1 receptors on vascular smooth muscle to cause vasoconstriction via the IP3 signal transduction pathway, which increases arterial pressure; however, the normal physiological concentrations of AVP are below its vasoactive range. Studies have shown, nevertheless, that in severe hypovolemic shock, when AVP release is very high, AVP does contribute to the compensatory increase in systemic vascular resistance.
-
The deficiency of vasopressin in organism causes diabetes insipidus. Clinical symptoms - poliuria, dehydration of the organism, low density of the urine.
Diabetes insipidus results in excessive thirst and urination. The reason is problems with a particular hormone or its receptor. Diabetes insipidus increases the risk for dehydration.
What Is Diabetes Insipidus?
Diabetes insipidus is caused by problems related to a hormone called antidiuretic hormone or its receptor. Antidiuretic hormone (ADH) is produced in a part of the brain called the hypothalamus. It's stored in the brain's pituitary gland. Release of ADH causes the kidneys to hold onto water, which makes urine more concentrated.
Normally, if we are thirsty or slightly dehydrated, ADH levels rise. The kidneys reabsorb more water and excrete concentrated urine. If, on the other hand, we chugged a half-gallon of water (don't try this at home), ADH levels would fall. Clear, dilute urine would pass. Diabetes insipidus can be caused by either of two problems with ADH. One is too little ADH is produced. When that's the case, the condition is called central diabetes insipidus. The other is there's enough ADH produced, but the kidneys can't respond to it. That condition is known as nephrogenic diabetes insipidus.
In either form of diabetes insipidus, the result is the same. The kidneys can't do their job of conserving water. Even when a person with diabetes insipidus is dehydrated, the kidneys will excrete abundant, dilute urine. This inability of the kidneys to conserve water leads to the symptoms of diabetes insipidus:
· Excessive thirst
· Excessive urine production (polyuria)
In some people, these symptoms can become extreme, causing dehydration.
Excessive fluid losses can also cause electrolyte imbalances. Possible symptoms include:
· Unexplained weakness
· Lethargy
· Muscle pains
· Irritability
But why "insipidus?" People with diabetes insipidus aren't insipid, but their urine is. Insipid can mean dull or lacking flavor. Believe it or not, doctors long ago would taste urine to detect illness. Unlike diabetes mellitus, which results in sweet tasting urine, diabetes insipidus creates watery, flavor-free urine.
Oxytocin.
Chemical structure: peptide.
Functions: stimulates the contraction of smooth muscles, especially the muscles of uterus and muscle fibres of alveoluses of mammas.
Oxytocin is used for delivery stimulation, for stop of bleeding after delivery, for stimulation of lactation.
Numerically the largest group of signaling substances, these arise by protein biosynthesis. The smallest peptide hormone, thyroliberin (362 Da), is a tripeptide. Proteohormones can reach masses of more than 20 kDa—e. g., thyrotropin (28 kDa). Similarities in the primary structures of many peptide hormones and proteohormones show that they are related to one another. They probably arose from common predecessors in the course of evolution. Thyroliberin (thyrotropin-releasing hormone, TRH) is one of the neurohormones of the hypothalamus. It stimulates pituitary gland cells to secrete thyrotropin (TSH). TRH consists of three amino acids, which are modified in characteristic ways.
Thyrotropin (thyroid-stimulating hormone, TSH) and the related hormones lutropin (luteinizing hormone, LH) and follitropin (follicle-stimulating hormone, FSH) originate in the adenohypophysis. They are all dimeric glycoproteins with masses of around 28 kDa. Thyrotropin stimulates the synthesis and secretion of thyroxin by the thyroid gland.
Hormones of pancreas, structure, mechanism of action
Insulin is produced and released by the B cells of the pancreas and is released when the glucose level rises. Insulin reduces the blood sugar level by promoting processes that consume glucose— e. g., glycolysis, glycogen synthesis, and conversion of glucose into fatty acids. By contrast, it inhibits gluconeogenesis and glycogen degradation. Insulin causes cells in the liver, skeletal muscles, and fat tissue to absorb glucose from the blood. In the liver and skeletal muscles, glucose is stored as glycogen, and in fat cells (adipocytes) it is stored as triglycerides.
Insulin stops the use of fat as an energy source by inhibiting the release of glucagon. With the exception of the metabolic disorder diabetes mellitus and metabolic syndrome, insulin is provided within the body in a constant proportion to remove excess glucose from the blood, which otherwise would be toxic. When blood glucose levels fall below a certain level, the body begins to use stored sugar as an energy source through glycogenolysis, which breaks down the glycogen stored in the liver and muscles into glucose, which can then be utilized as an energy source. As a central metabolic control mechanism, its status is also used as a control signal to other body systems (such as amino acid uptake by body cells). In addition, it has several other anabolic effects throughout the body.
When control of insulin levels fails, diabetes mellitus can result. As a consequence, insulin is used medically to treat some forms of diabetes mellitus. Patients with type 1 diabetes depend on external insulin (most commonly injected subcutaneously) for their survival because the hormone is no longer produced internally.[2] Patients with type 2 diabetes are often insulin resistant and, because of such resistance, may suffer from a "relative" insulin deficiency. Some patients with type 2 diabetes may eventually require insulin if other medications fail to control blood glucose levels adequately. Over 40% of those with Type 2 diabetes require insulin as part of their diabetes management plan.
The human insulin protein is composed of 51 amino acids, and has a molecular weight of 5808 Da. It is a dimer of an A-chain and a B-chain, which are linked together by disulfide bonds.
http://www.youtube.com/watch?v=V1LjRi8Nvv4
http://www.youtube.com/watch?v=VLiTbb6MaEU&NR=1
http://www.youtube.com/watch?v=ZsTSoLhl3Y4&feature=related
http://www.youtube.com/watch?v=nBJN7DH83HA&feature=related
Glucagon, a
peptide of 29 amino acids, is a product of the A cells of the pancreas. It is
the antagonist of insulin and, like insulin, mainly influences carbohydrate and
lipid metabolism. Its effects are each opposite to those of insulin. Glucagon
mainly acts via the second messenger
Glucagon is a linear peptide of 29 amino acids. Its primary sequence is almost perfectly conserved among vertebrates, and it is structurally related to the secretin family of peptide hormones. Glucagon is synthesized as proglucagon and proteolytically processed to yield glucagon within alpha cells of the pancreatic islets. Proglucagon is also expressed within the intestinal tract, where it is processed not into glucagon, but to a family of glucagon-like peptides (enteroglucagon).
Physiologic Effects of Glucagon
The major effect of glucagon is to stimulate an increase in blood concentration of glucose. As discussed previously, the brain in particular has an absolute dependence on glucose as a fuel, because neurons cannot utilize alternative energy sources like fatty acids to any significant extent. When blood levels of glucose begin to fall below the normal range, it is imperative to find and pump additional glucose into blood. Glucagon exerts control over two pivotal metabolic pathways within the liver, leading that organ to dispense glucose to the rest of the body:
·
Glucagon
stimulates breakdown of glycogen stored in the liver.
When blood glucose levels are high, large amounts of glucose are taken up by
the liver. Under the influence of insulin, much of this glucose is stored in
the form of glycogen. Later, when blood glucose levels begin to fall, glucagon
is secreted and acts on hepatocytes to activate the enzymes that depolymerize
glycogen and release glucose.
· Glucagon activates hepatic gluconeogenesis. Gluconeogenesis is the pathway by which non-hexose substrates such as amino acids are converted to glucose. As such, it provides another source of glucose for blood. This is especially important in animals like cats and sheep that don't absorb much if any glucose from the intestine - in these species, activation of gluconeogenic enzymes is the chief mechanism by which glucagon does its job.
Glucagon also appears to have a minor effect of enhancing lipolysis of triglyceride in adipose tissue, which could be viewed as an addition means of conserving blood glucose by providing fatty acid fuel to most cells.
Control of Glucagon Secretion
Knowing that glucagon's major effect is to increase blood glucose levels, it makes sense that glucagon is secreted in response to hypoglycemia or low blood concentrations of glucose.
Two other conditions are known to trigger glucagon secretion:
· Elevated blood levels of amino acids, as would be seen after consumption of a protein-rich meal: In this situation, glucagon would foster conversion of excess amino acids to glucose by enhancing gluconeogenesis. Since high blood levels of amino acids also stimulate insulin release, this would be a situation in which both insulin and glucagon are active.
· Exercise: In this case, it is not clear whether the actual stimulus is exercise per se, or the accompanying exercise-induced depletion of glucose.
In terms of negative control, glucagon secretion is inhibited by high levels of blood glucose. It is not clear whether this reflects a direct effect of glucose on the alpha cell, or perhaps an effect of insulin, which is known to dampen glucagon release. Another hormone well known to inhibit glucagon secretion is somatostatin.
Disease States
Diseases associated with excessively high or low secretion of glucagon are rare. Cancers of alpha cells (glucagonomas) are one situation known to cause excessive glucagon secretion. These tumors typically lead to a wasting syndrome and, interestingly, rash and other skin lesions.
Although insulin deficiency is clearly the major defect in type 1 diabetes mellitus, there is considerable evidence that aberrant secretion of glucagon contributes to the metabolic derangements seen in this important disease. For example, many diabetic patients with hyperglycemia also have elevated blood concentrations of glucagon, but glucagon secretion is normally suppressed by elevated levels of blood glucose.
What is diabetes mellitus?
Diabetes is a disease of the pancreas, an organ behind your stomach that produces the hormone insulin. Insulin helps the body use food(glucose) for energy. When a person has diabetes, the pancreas either cannot produce enough insulin, or the body uses the insulin incorrectly, or both. Insulin works together with glucose in the bloodstream to help it enter the body’s cells to be burned for energy. If the insulin isn’t functioning properly, glucose cannot enter the cells. This causes glucose levels in the blood to rise, creating a condition of high blood sugar or hyperglycaemia which is the hallmark of diabetes, and leaving the cells without fuel. When blood glucose rises above a certain level, it spills over into the urine.
What are the common types of diabetes?
There are two common forms of diabetes: type 1 and type 2.
· Type 1(Insulin dependent): Type 1 diabetes occurs because the insulin-producing cells of the pancreas are damaged. In type 1 diabetes, the pancreas makes little or no insulin, so sugar cannot get into the body’s cells for use as energy. People with type 1 diabetes must use insulin injections to control their blood glucose. Type 1 is the most common form of diabetes in people under age 20, but it can occur at any age. Ten percent of people with diabetes are diagnosed with type 1.
· Type 2(Non-insulin dependent): In type 2 diabetes, the pancreas makes insulin, but it either doesn’t produce enough insulin or the insulin does not work properly. Type 2 diabetes may sometimes be controlled with a combination of diet, weight management and exercise. However, treatment also may include oral glucose-lowering medications or insulin injections.
Generally, type 2 diabetes is more common in people over age 40 who are overweight. However, the increased prevalence of obesity has increased the number of people under age 40 who are diagnosed with type 2 diabetes. Nine out of 10 people with diabetes have type 2.
What causes Diabetes Mellitus?
The following factors may increase your chance of getting diabetes:
· Family history of diabetes or inherited tendency
· African-American, Hispanic or Native American race or ethnic background
· Obesity (being 20 percent or more over your desired body weight)
· Physical stress (such as surgery or illness)
· Use of certain medications
· Injury to pancreas (such as infection, tumor, surgery or accident)
· Autoimmune disease
· Hypertension
· Abnormal blood cholesterol or triglyceride levels
· Age (risk increases with age)
· Alcohol (risk increases with years of heavy alcohol use)
· Smoking
· Pregnancy (Pregnancy puts extra stress on a woman’s body which causes some women to develop diabetes. Blood sugar levels often return to normal after childbirth. Yet, women who develop diabetes during pregnancy have an increased chance of developing diabetes later in life.)
How is diabetes diagnosed?
The preferred method of diagnosing diabetes is the fasting blood sugar test (FBS). The FBS measures your blood glucose level after you have fasted (not eaten anything) for 10 to 12 hours.
Normal fasting blood glucose is between 70 and 100 mg/dl for people who do not have diabetes. The standard diagnosis of diabetes is made when:
· A patient has a fasting blood glucose level of 126 mg/dl or higher on two separate occasions; or
· A patient has a random blood glucose level of 200 mg/dl or greater and has common symptoms of diabetes, such as:
· – Increased thirst
· –Frequent urination
· –Increased hunger
·
–Fatigue
–Blurred vision
· –Weight loss
· On occasion, an oral glucose tolerance test may aid in the diagnosis of diabetes or an earlier abnormality that may become diabetes – called impaired glucose tolerance.
Other symptoms may include:
· Slow healing sores or cuts
· Itchy skin (usually in the vaginal or groin area); yeast infections
· Dry mouth
What are some of the long-term complications of diabetes?
Retinopathy (eye disease): All patients with diabetes should see an ophthalmologist (eye specialist) yearly for a dilated eye examination. Patients with known eye disease, symptoms of blurred vision in one eye or who have blind spots may need to see their ophthalmologist more frequently.
Nephropathy (kidney disease): Urine testing should be performed yearly. Regular blood pressure checks also are important because control of hypertension (high blood pressure) is essential in slowing kidney disease. Generally, blood pressure should be maintained less than 130/80 in adults. Persistent leg or feet swelling also may be a symptom of kidney disease and should be reported to your doctor.
Neuropathy (nerve disease): Numbness or tingling in your feet should be reported to your doctor at your regular visits. You should check your feet daily for redness, calluses, cracks or breakdown in skin tissue. If you notice these symptoms before scheduled visits, notify your doctor immediately.
Other long-term may complications include:
· Eye problems, such as glaucoma and cataracts
· Dental problems
· High blood pressure
· Heart disease
·
PREVENTION
Because of the link between obesity and type 2 diabetes, you can do a great deal to reduce your chance of developing the disease by slimming down if you are overweight. This is especially true if diabetes runs in your family.
In fact, studies have shown that exercise and a
healthy diet can prevent the development of type 2 diabetes in people with
impaired glucose tolerance — a condition that often develops prior to
full-blown type 2 diabetes. Medications have also been shown to provide similar
benefit. Both diabetes drugs metformin and Precose have been shown to prevent
the onset of type 2 diabetes in people with this pre-diabetes condition.
In someone who already has diabetes, exercise and a nutritionally balanced diet
can greatly limit the effects of both types 1 and 2 diabetes on your body. In
diabetics, stopping smoking is one of the best ways to help prevent the
damaging effects of diabetes. If you smoke, quit; smoking dramatically
increases the risk of heart disease, particularly for people with diabetes.
http://www.youtube.com/watch?v=FEsTIOIufiQ
Hormones of adrenal glands.
Adrenal glands consist of two parts: external - cortex, internal - medulla.
http://www.youtube.com/watch?v=06jbq3bxKE0&feature=related
Epinephrine is a hormone synthesized in the adrenal glands from tyrosine. Its release is subject to neuronal control.This “emergency hormone” mainly acts on the blood vessels, heart, andmetabolism. It constricts the blood vessels and thereby increases blood pressure; it increases cardiac function; it promotes the degradation of glycogen into glucose in the liver and muscles; and it dilates the bronchia.
Each part secrets specific hormones.
Hormones of adrenal medulla – catecholamines (epinephrine, norepinephrine, dopamine).
Chemical structure - these hormones are derivatives of amino acid tyrosine.
Epinephrine, norepinephrine,
dopamine exist in blood in
Functions: causes very potent contraction of vessels and increase the blood pressure, increase a pulse rate. Epinephrine relaxes the smooth muscles of bronchi, intestine, promote the contraction of uterus smooth muscle. Epinephrine play a great role in stress reactions.
catecholamine, any of various naturally occurring amines that function as neurotransmitters and hormones within the body. Catecholamines are characterized by a catechol group (a benzene ring with two hydroxyl groups) to which is attached an amine (nitrogen-containing) group. Among the catecholamines are dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline).
All catecholamines are synthesized from the amino acid l-tyrosine according to the following sequence: tyrosine → dopa (dihydroxyphenylalanine) → dopamine → norepinephrine (noradrenaline) → epinephrine (adrenaline).
Catecholamines are synthesized in the brain, in the adrenal medulla, and by some sympathetic nerve fibres. The particular catecholamine that is synthesized by a nerve cell, or neuron, depends on which enzymes are present in that cell. For example, a neuron that has only the first two enzymes (tyrosine hydroxylase and dopa decarboxylase) used in the sequence will stop at the production of dopamine and is called a dopaminergic neuron (i.e., upon stimulation, it releases dopamine into the synapse). In the adrenal medulla the enzyme that catalyzes the transformation of norepinephrine to epinephrine is formed only in the presence of high local concentrations of glucocorticoids from the adjacent adrenal cortex; chromaffin cells in tissues outside the adrenal medulla are incapable of synthesizing epinephrine.
l-Dopa is well known for its role in the treatment of parkinsonism, but its biological importance lies in the fact that it is a precursor of dopamine, a neurotransmitter widely distributed in the central nervous system, including the basal ganglia of the brain (groups of nuclei within the cerebral hemispheres that collectively control muscle tone, inhibit movement, and control tremour). A deficiency of dopamine in these ganglia leads to parkinsonism, and this deficiency is at least partially alleviated by the administration of l-dopa.
Under ordinary circumstances, more epinephrine than norepinephrine is released from the adrenal medulla. In contrast, more norepinephrine is released from the sympathetic nervous system elsewhere in the body. In physiological terms, a major action of the hormones of the adrenal medulla and the sympathetic nervous system is to initiate a rapid, generalized fight-or-flight response. This response, which may be triggered by a fall in blood pressure or by pain, physical injury, abrupt emotional upset, or hypoglycemia, is characterized by an increased heart rate (tachycardia), anxiety, increased perspiration, tremour, and increased blood glucose concentrations (due to glycogenolysis, or breakdown of liver glycogen). These actions of catecholamines occur in concert with other neural or hormonal responses to stress, such as increases in adrenocorticotropic hormone (ACTH) and cortisol secretion.
Furthermore, the tissue responses to different catecholamines depend on the fact that there are two major types of adrenergic receptors (adrenoceptors) on the surface of target organs and tissues. The receptors are known as alpha-adrenergic and beta-adrenergic receptors, or alpha receptors and beta receptors, respectively. In general, activation of alpha-adrenergic receptors results in the constriction of blood vessels, contraction of uterine muscles, relaxation of intestinal muscles, and dilation of the pupils. Activation of beta-adrenergic receptors increases heart rate and stimulates cardiac contraction (thereby increasing cardiac output), dilates the bronchi (thereby increasing air flow into and out of the lungs), dilates the blood vessels, and relaxes the uterus. Drugs that block the activation of beta receptors (beta blockers), such as propranolol, are often given to patients with tachycardia, high blood pressure, or chest pain (angina pectoris). These drugs are contraindicated in patients with asthma because they worsen bronchial constriction.
Catecholamines play a key role in nutrient metabolism and the generation of body heat (thermogenesis). They stimulate not only oxygen consumption but also consumption of fuels, such as glucose and free fatty acids, thereby generating heat. They stimulate glycogenolysis and the breakdown of triglycerides, the stored form of fat, to free fatty acids (lipolysis). They also have a role in the regulation of secretion of multiple hormones. For example, dopamine inhibits prolactin secretion, norepinephrine stimulates gonadotropin-releasing hormone secretion, and epinephrine inhibits insulin secretion by the beta cells of the islets of Langerhans of the pancreas.
The effect of epinephrine on carbohydrate metabolism:
- activates the decomposition of glycogen in liver and muscles;
- activates the glycolysis, Krebs cycle and tissue respiration;
- causes the hyperglycemia.
The effect of epinephrine on protein metabolism:
- activates the protein decomposition.
The effect of epinephrine on lipid metabolism:
- activates the tissue lipase, mobilization of lipids and oxidation of fatty acids.
- Norepinephrine (NE) and epinephrine (E) are both sympathomimetic catecholamines that are synthesized in the adrenal medulla and terminals of sympathetic neurons. Along the metabolic pathway, NE is synthesized first -- and when an enzyme adds a methyl group, you have epinephrine. NE is the main catecholamine in peripheral tissue and sympathetic neurons. E is mostly made in the adrenal medulla.
-
http://www.youtube.com/watch?v=4g25d7_Afmc
Tissue hormones
Hormonoids (tissue hormones, histohormones) - organic trace substances produced by different cells of different tissues (not by specific glands) that regulate metabolism on the local level (some hormonoids are produced in the blood too (serotonin, acetylcholine).
In the organs, the hormones carry out physiological and biochemical regulatory functions. In contrast to endocrine hormones, tissue hormones are only active in the immediate vicinity of the cells that secrete them. The distinctions between hormones and other signaling substances (mediators, neurotransmitters, and growth factors) are fluid. Mediators is the term used for signaling substances that do not derive from special hormone- forming cells, but are formbymany cell types. Acetylcholine is a neurotransmitter. What that does is it releases chemicals into the brain and plays a role in normal brain functions such as sleep. Also, it deals with attention, learning, and memory skills. The mechanisms that the transmitter controls was a mystery until now. Scientist now know that acetycholine deals with communication between neurons. Located in the prefrontal cortex. This is the formula for acetylcholine.
When acetylcholine is released it binds to a specific reactor. Next it begins to start a molecule cascade. Which then triggers physiological alterations. Which deals with how prefrontal cortical neurons are “wired” together. This explains how acethlcholine is released into the brain. (Biology News)
This process may actually have an effect in the formation of new associative memories. Most of this information can be found in the artical on acetylchonline. The Professor of Cellular Neuroscience, Zafar Bashir was the one who demonstrated how electron stimulation of the prefrontal cortex leads to the release of acetylcholine. Then Dr. Douglas Caruana carried out another experiment. He also found that acetylchonline when released into the prefrontal cortex it helps you remember things. But when to much has been released those memories start to be forgotten.
Just like the article said in the Journal of Neuroscience. Acetylcholine is a neurotransmitter which plays key roles in sleep and other normal functions. This is basically what acetylcholine does before of course we found out that to much of it is dangerous.
Gastrin is released in response to certain stimuli. These include:
· stomach distension
· vagal stimulation (mediated by the neurocrine bombesin, or GRP in humans)
· the presence of partially digested proteins especially amino acids
Gastrin release is inhibited by:
· The presence of acid (primarily the secreted HCl) in the stomach (a case of negative feedback).
· Somatostatin also inhibits the release of gastrin, along with secretin, GIP (gastroinhibitory peptide), VIP (vasoactive intestinal peptide), glucagon and calcitonin.
Function
The presence of gastrin stimulates parietal cells of the stomach to secrete hydrochloric acid (HCl)/gastric acid. This is done both directly on the parietal cell and indirectly via binding onto CCK2/gastrin receptors on ECL cells in the stomach, which then responds by releasing histamine, which in turn acts in a paracrine manner on parietal cells stimulating them to secrete H+ ions. This is the major stimulus for acid secretion by parietal cells.
Along with the above mentioned function, gastrin has been shown to have additional functions as well:
· Stimulates parietal cell maturation and fundal growth.
· Causes chief cells to secrete pepsinogen, the zymogen (inactive) form of the digestive enzyme pepsin.
· Increases antral muscle mobility and promotes stomach contractions.
· Strengthens antral contractions against the pylorus, and relaxes the pyloric sphincter, which stimulates gastric emptying.
· Plays a role in the relaxation of the ileocecal valve.[8]
· Induces pancreatic secretions and gallbladder emptying.[9]
· Impacts lower esophageal sphincter (LES) tone, causing it to contract.[10]
·
Heparin, a highly-sulfated glycosaminoglycan, is widely used as an injectable anticoagulant and has the highest negative charge density of any known biological molecule; it consists of a variably-sulfated repeating disaccharide unit: The most common disaccharide unit is composed of a 2-O-sulfated iduronic acid and 6-O-sulfated, N-sulfated glucosamine, IdoA-GlcN
Heparin is a naturally-occurring anticoagulant
produced by basophils and mast cells; pharmaceutical grade heparin is derived
from mucosal tissues of slaughtered meat animals such as porcine intestine or
bovine lung. Heparin allows the body's natural clot lysis mechanisms to work
normally to break down clots that have already formed.
Heparin binds to the enzyme inhibitor antithrombin (AT) causing
a conformational change that results in its activation through an increase in
the flexibility of its reactive site loop. The activated AT then inactivates thrombin
and other proteases involved in blood clotting, most notably factor
Xa. The rate of inactivation of these proteases by AT
can increase by up to 1000-fold due to the binding of heparin.
The conformational change inAT on
heparin-binding mediates its inhibition of factor Xa. For thrombin inhibition
however, thrombin must also bind to the heparin polymer at a site proximal to
the pentasaccharide. The highly-negative charge density of heparin contributes
to its very strong electrostatic interaction with thrombin The formation of a
ternary complex between AT, thrombin, and heparin
results in the inactivation of thrombin. For this reason heparin's activity
against thrombin is size-dependent, the ternary complex requiring at least 18
saccharide units for efficient formation. In contrast anti factor Xa activity
only requires the pentasaccharide binding site
This size difference has led to the development of low-molecular-weight heparins
and more recently to fondaparinux as
pharmaceutical anticoagulants. Low-molecular-weight heparins and fondaparinux
target anti-factor Xa activity rather than anti-thrombin (IIa) activity, with
the aim of facilitating a more subtle regulation of coagulation and an improved
therapeutic index
Secretin hormone production is stimulated by acid chyme entering the duodenum. This hormone stimulates the pancreas to release bicarbonate to neutralize the acid.
Secretin is a hormone that both controls the environment in the duodenum by regulating secretions of the stomach and pancreas, and regulates water homeostasis throughout the body. It is produced in the S cells of the duodenum, which are located in the crypts of Lieberkühn. In humans, the secretin peptide is encoded by the SCT gene. Secretin was also the first hormone to be identified.
Secretin regulates the pH within the duodenum by inhibiting gastric acid secretion by the parietal cells of the stomach, and by stimulating bicarbonate production by the centroacinar cells and intercalated ducts of the pancreas.
In 2007, secretin was discovered to play a role in osmoregulation by acting on the hypothalamus, pituitary, and kidney.
Secretin increases watery bicarbonate solution from pancreatic and bile duct epithelium. Pancreatic centroacinar cells have secretin receptors in their plasma membrane. As secretin binds to these receptors, it stimulates adenylate cyclase activity and converts ATP to cyclic AMP. Cyclic AMP acts as second messenger in intracellular signal transduction and leads to increase in release of watery carbonate. It is known to promote the normal growth and maintenance of the pancreas.
Secretin increases water and bicarbonate secretion from duodenal Brunner's glands to buffer the incoming protons of the acidic chyme. It also enhances the effects of cholecystokinin to induce the secretion of digestive enzymes and bile from pancreas and gallbladder, respectively.
It counteracts blood glucose concentration spikes by triggering increased insulin release from pancreas, following oral glucose intake.
Although secretin releases gastrin from gastrinomas, it inhibits gastrin release from the normal stomach. It reduces acid secretion from the stomach by inhibiting gastrin release from G cells. This helps neutralize the pH of the digestive products entering the duodenum from the stomach, as digestive enzymes from the pancreas (e.g., pancreatic amylase and pancreatic lipase) function optimally at slightly basic pH.
In addition, secretin stimulates pepsin secretion from chief cells, which can help break down proteins in food digestion. It stimulates release of glucagon, pancreatic polypeptide and somatostatin.
Histamine, an important mediator (local signaling substance) and neurotransmitter, is mainly stored in tissue mast cells and basophilic granulocytes in the blood. It is involved in inflammatory and allergic reactions. “Histamine liberators” such as tissue hormones, type E immunoglobulins (see p. 300), and drugs can release it. Histamine acts via various types of receptor. Binding to H1 receptors promotes contraction of smoothmuscle in the bronchia, and dilates the capillary vessels and increases their permeability. Via H2 receptors, histamine slows down the heart rate and promotes the formation of HCl in the gastric mucosa. In the brain, histamine acts as a neurotransmitter.
They have hormone-like effects in their immediate surroundings. Histamine and prostaglandins are important examples of these substances. Histamine is found in plant and animal tissue and is released from mast cells as part of an allergic reaction in humans. Release of histamine stimulates gastric secretion and causes dilation of capillaries, constriction of bronchial smooth muscle, and decreases blood pressure.
Histamines are released from mast cells as an allergic response to abnormal proteins found in the blood. The mast cells are found in connective tissue that contains numerous basophilic granules and releases substances such as heparin and histamine in response to injury or inflammation of body tissues.
How severe can histamine reactions be?
It has recently been discovered that histamines may play a much larger roll in human disease than once thought. In the past, histamine production was blamed on some very common allergic reactions such as hay fever, bee sting reactions, and anaphylactic shock.
In recent studies, histamine involvement in chronic inflammatory and degenerative diseases such as Lupus, Arthritis, Gulf War Syndrome, Fibromyalgia, Leaky Gut Syndrome, and some skin disorders like Psoriasis and obscure Rashes, has come to light as causes of chronic inflammatory responses to abnormal proteins in the blood of chronically ill patients!
Histamine is a biogenic amine involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and other proteins, in order to allow them to engage foreign invaders in the affected tissues. It is found in virtually all animal body cells.
Histamine forms colorless hygroscopic crystals
that melt at
Histamine has two basic centres, namely the aliphatic amino group and whichever nitrogen atom of the imidazole ring does not already have a proton. Under physiological conditions, the aliphatic amino group (having a pKa around 9.4) will be protonated, whereas the second nitrogen of the imidazole ring (pKa ≈ 5.8) will not be protonated. Thus, histamine is normally protonated to a singly-charged cation. Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase. It is a hydrophilic vasoactive amine.
Once formed, histamine is either stored or rapidly inactivated. Histamine released into the synapses is broken down by acetaldehyde dehydrogenase. It is the deficiency of this enzyme that triggers an allergic reaction as histamines pool in the synapses. Histamine is broken down by histamine-N-methyltransferase and diamine oxidase. Some forms of foodborne disease, so-called "food poisonings," are due to conversion of histidine into histamine in spoiled food, such as fish.
Serotonin is a neurotransmitter
= Neurotransmitters are chemicals that are used to relay, amplify and modulate signals between a neuron and another cell - cell to cell communicators
= Serotonin is produced in the body from amino acids
= Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system because it does not cross the blood-brain barrier. However, tryptophan and its metabolite 5-hydroxytryptophan (5-HTP), from which serotonin is synthesized, can and does cross the blood-brain barrier. These agents are available as dietary supplements and may be effective serotonergic agents
= Drugs may hinder the natural use/loss of serotonin but Drugs do not incease the supply of serotonin.
Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal (GI) tract, platelets, and in the central nervous system (CNS) of animals including humans. It is popularly thought to be a contributor to feelings of well-being and happiness.
Approximately 90% of the human body's total serotonin is located in the enterochromaffin cells in the alimentary canal (gut), where it is used to regulate intestinal movements. The remainder is synthesized in serotonergic neurons of the CNS, where it has various functions. These include the regulation of mood, appetite, and sleep. Serotonin also has some cognitive functions, including memory and learning. Modulation of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants.
Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood platelets, which store it. When the platelets bind to a clot, they disgorge serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting. Serotonin also is a growth factor for some types of cells, which may give it a role in wound healing.
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 Receptors and Mechanism of Action
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.[8] 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.
Structure of Intracellular Receptors
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.
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.
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
hypercholesterolemia
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 (): 6-28 mg/dL; adults (): 2-12 mg/dL
· child one to six years (): 3-21 mg/dL; child one to six years (): 3-10 mg/dL
· 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.
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.
See the following chime tutorial for the detailed molecular basis for the inhibition of the COX enzyme by aspirin.
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.