Mineralocorticoids are a class of
steroid hormoneSteroid hormones are steroids that act as hormones. Steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestagens...
s characterised by their similarity to
aldosteroneAldosterone is a hormone that increases the reabsorption of sodium and water and the release of potassium in the kidneys. This increases blood volume and, therefore, increases blood pressure. Many drugs, such as spironolactone, lower blood pressure by blocking the aldosterone receptor...
and their influence on salt and water balance.
The name
mineralocorticoid derives from early observations that these hormones were involved in the retention of
sodiumSodium is a metallic element with a symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals within "group 1"...
, a
mineralA mineral is a naturally occurring solid formed through geological processes that has a characteristic chemical composition, a highly ordered atomic structure, and specific physical properties. A rock, by comparison, is an aggregate of minerals and/or mineraloids, and need not have a specific...
. The primary
endogenousThe word endogenous means "proceeding from within", the opposite of exogenous.-Biology:Endogenous substances are those that originate from within an organism, tissue, or cell . Endogenous retrovirus are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
mineralocorticoid is
aldosteroneAldosterone is a hormone that increases the reabsorption of sodium and water and the release of potassium in the kidneys. This increases blood volume and, therefore, increases blood pressure. Many drugs, such as spironolactone, lower blood pressure by blocking the aldosterone receptor...
, although a number of other endogenous hormones (including
progesteroneProgesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
and
deoxycorticosterone11-Deoxycorticosterone is a steroid hormone produced by the adrenal gland that possess mineralocorticoid activity and acts as a precursor to aldosterone. As its names indicate, it can be understood as 21-hydroxy- variant of progesterone or a 11-deoxy- variant of corticosterone. It has no...
) have mineralocorticoid function.
Aldosterone acts on the kidneys to provide active reabsorption of
sodiumSodium is a metallic element with a symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals within "group 1"...
and an associated passive reabsorption of
waterWater is an ubiquitous chemical substance that is composed of hydrogen and oxygen and is essential for all known forms of life.In typical usage, water refers only to its liquid form or state, but the substance also has a solid state, ice, and a gaseous state, water vapor or steam. Water covers 71%...
, as well as the active secretion of
potassiumPotassium is the chemical element with the symbol K , atomic number 19, and atomic mass 39.0983. Potassium was first isolated from potash...
in the principal cells of the cortical collecting tubule and active secretion of
protonThe proton is a subatomic particle with an electric charge of +1 elementary charge. It is found in the nucleus of each atom but is also stable by itself and has a second identity as the hydrogen ion, H
+...
s via proton
ATPaseATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate into adenosine diphosphate and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme harnesses to drive other chemical reactions that would not otherwise occur...
s in the lumenal membrane of the intercalated cells of the collecting tubule.
Mineralocorticoids are a class of
steroid hormoneSteroid hormones are steroids that act as hormones. Steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestagens...
s characterised by their similarity to
aldosteroneAldosterone is a hormone that increases the reabsorption of sodium and water and the release of potassium in the kidneys. This increases blood volume and, therefore, increases blood pressure. Many drugs, such as spironolactone, lower blood pressure by blocking the aldosterone receptor...
and their influence on salt and water balance.
Physiology
The name
mineralocorticoid derives from early observations that these hormones were involved in the retention of
sodiumSodium is a metallic element with a symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals within "group 1"...
, a
mineralA mineral is a naturally occurring solid formed through geological processes that has a characteristic chemical composition, a highly ordered atomic structure, and specific physical properties. A rock, by comparison, is an aggregate of minerals and/or mineraloids, and need not have a specific...
. The primary
endogenousThe word endogenous means "proceeding from within", the opposite of exogenous.-Biology:Endogenous substances are those that originate from within an organism, tissue, or cell . Endogenous retrovirus are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
mineralocorticoid is
aldosteroneAldosterone is a hormone that increases the reabsorption of sodium and water and the release of potassium in the kidneys. This increases blood volume and, therefore, increases blood pressure. Many drugs, such as spironolactone, lower blood pressure by blocking the aldosterone receptor...
, although a number of other endogenous hormones (including
progesteroneProgesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
and
deoxycorticosterone11-Deoxycorticosterone is a steroid hormone produced by the adrenal gland that possess mineralocorticoid activity and acts as a precursor to aldosterone. As its names indicate, it can be understood as 21-hydroxy- variant of progesterone or a 11-deoxy- variant of corticosterone. It has no...
) have mineralocorticoid function.
Aldosterone acts on the kidneys to provide active reabsorption of
sodiumSodium is a metallic element with a symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals within "group 1"...
and an associated passive reabsorption of
waterWater is an ubiquitous chemical substance that is composed of hydrogen and oxygen and is essential for all known forms of life.In typical usage, water refers only to its liquid form or state, but the substance also has a solid state, ice, and a gaseous state, water vapor or steam. Water covers 71%...
, as well as the active secretion of
potassiumPotassium is the chemical element with the symbol K , atomic number 19, and atomic mass 39.0983. Potassium was first isolated from potash...
in the principal cells of the cortical collecting tubule and active secretion of
protonThe proton is a subatomic particle with an electric charge of +1 elementary charge. It is found in the nucleus of each atom but is also stable by itself and has a second identity as the hydrogen ion, H
+...
s via proton
ATPaseATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate into adenosine diphosphate and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme harnesses to drive other chemical reactions that would not otherwise occur...
s in the lumenal membrane of the intercalated cells of the collecting tubule. This in turn results in an increase of
blood pressureBlood pressure is the pressure exerted by circulating blood on the walls of blood vessels, and is one of the principal vital signs. During each heartbeat, BP varies between a maximum and a minimum pressure...
and
blood volumeBlood volume is the volume of blood in a person's circulatory system. A typical adult has a blood volume of approximately between 4.7 and 5 litres, with females generally having less blood volume than males....
.
Aldosterone is produced in the cortex of the
adrenal glandIn mammals, the adrenal glands are the star-shaped endocrine glands that sit on top of the kidneys; their name indicates that position...
and its secretion is mediated principally by angiotensin II, but also by adrenocorticotrophic hormone (ACTH) and local
potassiumPotassium is the chemical element with the symbol K , atomic number 19, and atomic mass 39.0983. Potassium was first isolated from potash...
levels.
Mode of Action
The effects of mineralocorticoids are mediated by slow genomic mechanisms through
nuclear receptorIn the field of molecular biology, nuclear receptors are a class of proteins found within the interior of cells that are responsible for sensing the presence of steroid and thyroid hormones and certain other molecules...
s as well as by fast nongenomic mechanisms through membrane-associated receptors and signaling cascades.
Genomic mechanisms
Mineralocorticoids bind to the cytosolic
mineralocorticoid receptorThe mineralocorticoid receptor , also called aldosterone receptor, is officially labelled nuclear receptor subfamily 3, group C, member 2, and is a receptor with high affinity for mineralocorticoids...
. This type of
receptorIn biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling molecule may attach...
gets activated upon
ligandIn chemistry, a ligand is either an atom, ion, or molecule that binds to a central metal-atom to produce a coordination complex. The bonding between the metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The metal-ligand bonding ranges from covalent...
binding. After a hormone binds to the corresponding receptor, the newly formed receptor-ligand complex test itself into the
cell nucleusIn cell biology, the nucleus , also sometimes referred to as the "control center", is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as...
, where it binds to many hormone response elements (
HREA hormone response element is a response element for hormones, a short sequence of DNA within the promoter of a gene that is able to bind a specific hormone receptor complex and therefore regulate transcription...
) in the
promoterIn genetics, a promoter is a region of DNA that facilitates the transcription of a particular gene. Promoters are typically located near the genes they regulate, on the same strand and upstream .-Overview:...
region of the target
geneA gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain their cells and pass genetic traits to offspring...
s in the
DNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms and some viruses. The main role of DNA molecules is the long-term storage of information...
.
The opposite mechanism is called
transrepressionIn the field of molecular biology, transrepression is a process whereby one protein represses the activity of a second protein through a protein-protein interaction...
. The
hormone receptorA hormone receptor is a receptor protein on the surface of a cell or in its interior that binds to a specific hormone. The hormone causes many changes to take place in the cell....
without ligand binding interacts with
heat shock proteinHeat shock proteins are a class of functionally related proteins whose expression is increased when cells are exposed to elevated temperatures or other stress. This increase in expression is transcriptionally regulated. The dramatic upregulation of the heat shock proteins is a key part of the...
s and prevents the
transcriptionTranscription, or RNA synthesis, is the process of creating an equivalent RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA in the presence of the correct enzymes...
of targeted genes.
Aldosterone and
cortisolCortisol is a corticosteroid hormone or glucocorticoid produced by the adrenal cortex, that is part of the adrenal gland . It is usually referred to as the "stress hormone" as it is involved in response to stress and anxiety, controlled by CRH...
have similar affinity for the mineralocorticoid receptor however, glucocorticoids circulate at roughly 100 times the level of mineralocorticoids. An enzyme exists in mineralocorticoid target tissues to prevent overstimulation by glucocorticoids. This enzyme, 11-beta hydroxysteroid dehydrogenase type II (
Protein:HSD11B2Hydroxysteroid dehydrogenase 2, also known as HSD11B2, isa human gene. It encodes an NAD+-dependent enzyme expressed in aldosterone-selective epithelial tissues such as the kidney, colon, salivary and sweat glands...
), catalyzes the deactivation of glucocorticoids to 11-dehydro metabolites. Licorice is known to be an inhibitor of this enzyme and chronic consumption can result in a condition known as
pseudohyperaldosteronismPseudohyperaldosteronism is a medical condition that mimics hyperaldosteronism. Like hyperaldosteronism, it produces hypertension associated with low plasma renin activity, and metabolic alkalosis associated with hypokalemia...
.
18 hydroxy 11 deoxycorticosterone (also designated 18OH-DOC) is a steroid hormone probably used to conserve
sodiumSodium is a metallic element with a symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals within "group 1"...
and stimulate
hydrogen ionHydrogen ion is recommended by IUPAC as a general term for all ions of hydrogen and its isotopes. Depending on the charge of the ion, two different classes can be distinguished:-Cation :...
(or acid) excretion. 18OH-DOC lowers urine pH but has no affect on
potassiumPotassium is the chemical element with the symbol K , atomic number 19, and atomic mass 39.0983. Potassium was first isolated from potash...
excretion. This would seem to indicate that 18OH-DOC's primary purpose is to stimulate hydrogen ion or
ammoniumThe ammonium cation is a positively charged polyatomic cation of the chemical formula NH. It has a formula weight of 18.05 and is formed by the protonation of ammonia...
excretion. Under low sodium intake 18 OH DOC is increased in serum. There is a marked increase in serum 18OH DOC after injection of insulin and this may be due to the hypokalemic (low serum potassium) tendency after a rise in insulin which in turn would make the serum more acidic. Since 18OH-DOC lowers urine pH (increases acidity) but has no affect on potassium excretion, this would seem to indicate that 18OH-DOC's primary purpose is to stimulate hydrogen ion or ammonium excretion. Its use by the body to conserve potassium would be indirect by virtue of hydrogen ion's interference with potassium excretion. This interference is further indicated because injecting sodium bicarbonate or even hyperventilating (breathing rapidly beyond need) can triple potassium excretion. The daily rhythm for potassium and hydrogen ion excretion show a rather close inverse relationship, which gives additional circumstantial support to the supposition that they compete at a common site. 18OH-DOC is strongly dependent on the potassium cell or plasma content, because in potassium deficient rats markedly less 18OH-DOC is converted to 18OH-corticosterone and less yet if sodium is deficient.
ACTH (a peptide hormone) has a large affect on 18OH DOC, causing 18OH DOC to go down to zero when ACTH does. This could be for the primary purpose of keeping serum immune enzymes and cell fluids at a high
pHpH is a measure of the acidity or basicity of a solution. It is defined as the cologarithm of the activity of dissolved hydrogen ions . Hydrogen ion activity coefficients cannot be measured experimentally, so they are based on theoretical calculations...
(alkaline) during internal infection, but not doing so during the intestinal infection of diarrhea, during which disease the resulting dehydration forces ACTH to decline. It probably is important normally to keep the vacuoles where pathogens are digested at a high pH because if the pH or alkalinity is not high enough, the pathogens inside the immune cells are not digested and thus released intact. So when an intestinal disease is not calling for ACTH to decline, the indirect potassium conserving attribute of 18OH-DOC by virtue of stimulating acid excretion would be valuable, as would also increased acid excretion during internal disease be valuable.
18OH DOC may act primarily by blocking aldosterone's effect on potassium, and must have
aldosteroneAldosterone is a hormone that increases the reabsorption of sodium and water and the release of potassium in the kidneys. This increases blood volume and, therefore, increases blood pressure. Many drugs, such as spironolactone, lower blood pressure by blocking the aldosterone receptor...
to assist it with sodium. Nichols, et al., have been able to show that injection of 18OH-DOC, which raised blood levels of this hormone ten times, were more retentive of sodium than a similar amount of aldosterone. So there must be a synergism involved. At the same time, the ratio of sodium to potassium excretion declined very little for 18OH-DOC, while for aldosterone, the ratio fell to as little as 1/3 that of control men. This implies a considerable sparing of potassium by 18OH-DOC. Urine potassium excretion is not altered by 18OH-DOC injection.
Angiotensin II has very little effect on 18OH-DOC and is ambiguous nor does serum potassium above 4.8 mEq/litter (187 mg). This last is not surprising since 18OH-DOC should not be used by the body at high serum potassium. Under low sodium intake, 18OH-DOC rises in the serum. ACTH causes a marked increase in 18OH-DOC, probably by a generalized affect on the
zona fasciculataThe zona fasciculata constitutes the middle zone of the adrenal cortex, sitting directly beneath the zona glomerulosa. Constituent cells are organized into bundles or "fascicles"....
of the
adrenal cortexSituated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis.-Layers:The cortex can be divided...
where 18OH-DOC is synthesized. So when it is necessary for sodium to be unloaded during the dehydration induced decline of ACTH during diarrhea in order to preserve osmotic pressure, the resulting 18OH-DOC decline would assist in this.
18OH-DOC is deeply involved in one of the three forms (at least) of
hypertensionHypertension is a chronic medical condition in which the blood pressure is elevated. It is also referred to as high blood pressure or shortened to HT, HTN or HPN. The word "hypertension", by itself, normally refers to systemic, arterial hypertension.Hypertension can be classified as either...
(high blood pressure).
Pathophysiology
HyperaldosteronismHyperaldosteronism, also aldosteronism, is a medical condition where too much aldosterone is produced by the adrenal glands, which can lead to lowered levels of potassium in the blood.-Types:...
(the syndrome caused by elevated aldosterone) generally results from adrenal neoplasms. The two main resulting problems:
- Hypertension
Hypertension is a chronic medical condition in which the blood pressure is elevated. It is also referred to as high blood pressure or shortened to HT, HTN or HPN. The word "hypertension", by itself, normally refers to systemic, arterial hypertension.Hypertension can be classified as either...
and edemaEdema or oedema , formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin, or in one or more cavities of the body...
due to excessive Na+ and water retention.
- Accelerated excretion of potassium ions
Potassium is the chemical element with the symbol K , atomic number 19, and atomic mass 39.0983. Potassium was first isolated from potash...
. With extreme K+ loss there is muscle weakness and eventually paralysis.
Underproduction, or hypoaldosteronism, leads to the salt-wasting state associated with
Addison's diseaseAddison's disease is a rare endocrine disorder in which the adrenal glands do not produce enough steroid hormones...
, although classical
congenital adrenal hyperplasiaCongenital adrenal hyperplasia refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands ....
and other disease states may also cause this situation.
Pharmacology
An example of synthetic mineralocorticoids is
fludrocortisoneFludrocortisone is a synthetic corticosteroid with moderate glucocorticoid potency and much greater mineralocorticoid potency.The brand name in the U.S...
(Florinef). Important mineralocorticoid inhibitors are
spironolactoneSpironolactone is a diuretic and is used as an antiandrogen....
and
eplerenoneEplerenone is an aldosterone antagonist used as an adjunct in the management of chronic heart failure. It is similar to spironolactone, though it may be more specific for the mineralocorticoid receptor and is specifically marketed for reducing cardiovascular risk in patients following myocardial...
.