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ANTIDIURETIC HORMONE

 

TABLE OF CONTENTS

Antidiuretic Hormone
Diabetes Insipidus
Syndrome of Inappropriate ADH

ANTIDIURETIC HORMONE

Antidiuretic hormone (ADH) or Arginine Vasopressin (AVP) is synthesized in the hypothalamus mostly by the supraoptic nuclei. It is then packaged into transport vesicles in the cell body and transported via fast vesicular transport through the axon of the neurons. The axons pass through the pituitary stalk or infundibulum and synapse with specialized cells called pituicytes, which are neuroglia cells in the posterior pituitary. ADH is produced as a large prohormone peptide. About 10 amino acids from the amino terminus is cleaved to yield ADH as well as Oxytocin. A longer peptide chain from the middle is also cleaved which yields a protein called neurophysin. It is thought that neurophysin binds to ADH and Oxytocin to increase the half life of the hormones when they circulate in blood. The last part of the prohormone at the carboxyl terminus is a glycoprotein, which has an unknown function.

ADH, also known as Vasopressin, is a hormone that decreases the amount of water lost by sweating and excreting with urine. ADH is released when the blood osmolarity increases (blood becomes less dilute), blood volume decreases, or when the blood pressure decreases. Nicotine, acetylcholine, morphine, some anesthetics, and tranquilizers have also been known to increase ADH release, whereas ethanol has been know to decrease ADH release. ADH acts on two types of receptors, V1 and V2. Both of these receptors are seven-transmembrane receptors found on the plasma membrane. V1 is found on cells of blood vessels. It acts through a Gp mediated action, which increases the cytosolic Ca2+ concentration. This leads to and increase in prostaglandins, PGs to be exact, and with the high calcium concentration, cause the smooth muscle of the blood vessels to contract, causing vasoconstriction. V2 acts on the cells of the collecting duct through a Gs coupled hormone action, leading to an increased water permeability of the collecting ducts of the kidneys. After an ADH molecule binds to a V2 receptor, Gs is activated on the cytosolic side, which in turn binds to a membrane bound adenylate cyclase (AC) and activates it. AC converts ATP to cAMP, which binds to a serine kinase. The activated serine kinase uses ATP to start a phosphorylation cascade. This causes vesicles with many aquapores in their membranes to fuse with the plasma membrane and increase water permeability. Since the surrounding tissue (renal medulla) of the collecting duct has a very high salt concentration, water rushes out of the collecting ducts and ultimately ends up in the blood capillaries in the kidneys. Sweat glands in the skin are also targets for ADH. When stimulated by ADH, sweat gland excretions are more concentrated. ADH also increases thirst, as well as adrenocorticotropic hormone (ACTH). ADH release is controlled by osmoreceptors in the hypothalamus and barroreceptors in the blood vessels.

 

PROBLEMS WITH ADH

One of the most common clinical problems with ADH is Diabetes Insipidus (DI). Some of the symptoms of DI are: excretion of large volumes of urine, extreme thirst, bedwetting and others. In persons with severe DI, the water loss can be so extreme that the person may die due to dehydration if deprived from water for a day. People with untreated DI usually drink 3-5 times more water a day than normal people. DI can be characterized as central neurogenic DI or nephrogenic DI. Central neurogenic DI is usually caused by damage to the hypothalamus, pituitary stalk, or the posterior pituitary lobe due to head trauma, brain surgery, or brain tumor. In neurogenic DI, ADH is either not produced at all, or it is produced but not released. Nephrogenic DI is caused by problems in the kidney. These can range from kidney damage, nonfunctional ADH receptors, or problems in the signal transduction pathway. In nephrogenic DI, ADH is produced and released by the brain, but the kidneys do not respond to it. Neurogenic DI is much easier to treat than nephrogenic DI. Patients with neurogenic DI are treated by hormone replacement. A subcutaneous injection or a nasal spray is used to deliver ADH analogs, such as Desmopressin® or Lypressin®. Nephrogenic DI is treated by restriction of salt in the diet and use of some diuretic drugs. Prostaglandin synthesis inhibitors may also be helpful. This is a more difficult and complex treatment and does not have great results.

Another ADH disorder is Syndrome of Inappropriate ADH or SIADH. In patients with SIADH, the blood osmolarity is very low and the ADH concentration is inappropriately high. Retention of water and normal water intake leads to hyponatremia and hypo-osmolarity. The urine is very concentrated in these patients. Common causes of SIADH are malignant neoplasms that are associated with ectopic vasopressin production. Bronchiogenic carcinomas and some cancers of the pancreas, duodenum, brain, prostate and thymus tend to produce ADH. Other nonmalignant diseases such as tuberculosis and pneumonias have also been noted to increase blood ADH concentrations. There are many central nervous system trauma and infections that can cause SIADH. Some endocrine diseases such as adrenal insufficiency, myxedema and anterior pituitary insufficiency can lead to increased production of ADH. Chemotheraputic drugs such as vincristine anc cyclophosphamide can cause SIADH. Treatment of SIADH depends on the underlying cause. Fluid restriction and administration of diuretics can be the first steps in the treatment process. In severe cases of SIADH, hypertonic saline may be administered to increase plasma sodium concentration. Patients with drug induced SIADH can be treated by withholding the drug.


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