Antidiuretic hormone, ADH or vasopressin
The antidiuretic hormone, ADH, also called vasopressin and arginine-vasopressin, is a nanopeptide (nine amino acids) synthesized in the hypothalamus, transported to and stored in the posterior lobe of the pituitary gland which releases it into the blood circulation. It has antidiuretic and vasopressor actions.
Metabolism of vasopressin
Vasopressin is a nanopeptide with a disulfide bond between two cysteine residues. Its structure resembles that of oxytocin.
Formed in the supra-optic and paraventricular nuclei of the hypothalamus by cleavages of a preprohormone of 168 amino acids and then a prohormone, vasopressin is transported to the posterior lobe of the pituitary gland which stores it.
Its release depends primarily on two factors: hyperosmolality and blood volume and in addition on the effects of certain drugs.
The increase in the osmolality of the blood irrigating the hypothalamic-pituitary complex elicits the secretion of vasopressin. In patients presenting a central diabetes insipidus, there is no response to the increase of osmolality;
- Blood volume:
The decrease in the volume of extracellular liquids and of arterial pressure decreases the stimulation of the baroreceptors located in atria, pulmonary veins, carotid sinus, increasing the secretion of vasopressin, an increase has opposite effects. In addition, angiotensin facilitates ADH secretion;
- Effects of drugs:
Tricyclic antidepressants, fluoxetin and the other inhibitors of serotonin reuptake, nicotine, neuroleptics, carbamazepine can increase the secretion of ADH. When this increase is important, it results in fluid retention, generally detected by a hyponatremia of dilution. This syndrome is named in the literature SIADH or syndrome of inappropriate secretion of antidiuretic hormone.
Other drugs like phenytoine, mineralocorticoids and glucocorticoids can decrease its secretion. Ethanol also reduces it.
Modifications of the effect of the hormone at the renal level can in addition be observed, see below.
In patients with central diabetes insipidus, there is no or an insufficient secretion of ADH. In patients with nephrogenic diabetes insipidus, there is a secretion of ADH but absence of response at the renal level.
The plasma half-life of ADH is about 15 to 30 minutes. It is inactivated by plasma and tissue endopeptidases, particularly in the kidney and liver.
Effects of vasopressin
The effects of vasopressin result from stimulation of V1 and V2 receptors, V1 mainly responsible for vasoconstriction, V2 for the antidiuretic effect
V1 receptors are coupled by G protein to phospholipase C. Its activation elicits the hydrolysis of PIP2 in IP3 and DAG, which induces an increase of intracellular calcium concentration, responsible for the vasoconstriction.
V2 receptors are coupled by G protein to adenylcyclase. Its activation elicits an increase in cAMP which, via protein kinases, induces the activation of aqueous channels called aquaporins of type 2 or AQP2 mainly located in the renal collecting duct. Under the influence of vasopressin AQP2 migrate from the cytoplasm to the apical membrane. In nephrogenic diabetes insipidus there are AQP2 alterations.
- Antidiuretic action (V2):
The ADH increases water permeability of collecting ducts in the cortical and medullary part of the kidney. It induces the incorporation of aquaporins in the apical membrane of collecting ducts and induces their opening, which allows water reabsorption.
A certain number of drugs modify the activity of ADH on the kidney:
Chlorpropamide, acetaminophen, carbamazepine, indomethacine, as well as others nonsteroidal antiinflammatory drugs, can increase the activity of ADH and cause fluid retention.
Chlorpropamide, a hypoglycemic sulphamide, potentiates the action of very low concentrations of vasopressin. When it is used for the treatment of diabetes mellitus, chlorpropamide can elicit, as an adverse effect, an apparent syndrome of inappropriate secretion of ADH. In the treatment of central diabetes insipidus, when it is not possible to use ADH analogues, chlorpropamide is used, alone or sometimes combined with a thiazide diuretic.
Lithium, demeclocycline, méthoxyflurane decrease the renal activity of ADH. The polyuria observed in some patients treated by lithium is explained by this mechanism.
Demeclocycline, is the only tetracyclines with an antagonist effect on ADH in the kidney. It reduces water retention induced by an excessive secretion of antidiuretic hormones, often of neoplastic origin. When used as an antibiotic demeclocycline can cause a r eversible nephrogenic diabetes insipidus with polyuria, polydipsia. Phototoxic reactions can occur in patients treated by demeclocycline and sunlight exposure should be avoided.
In addition, thiazide diuretics have, in patients with nephrogenic diabetes insipidus, a paradoxical antidiuretic effect, probably by depletion of sodium in the tubular fluid. They are the main treatment, often combined with amiloride, of the nephrogenic diabetes insipidus.
- Vasoconstrictive effect (V1):
With doses higher than those which are necessary to induce water retention, ADH induces vasoconstriction. The plasma concentration of vasopressin can be sufficient to increase peripheral resistance and arterial pressure. The decrease in cutaneous blood flux seen in smokers could be the consequence of an increase in the secretion of vasopressin under the influence of nicotine.
The development of specific antagonists of V1 type would make it possible to better specify the role of vasopressin in physiology and pathology, and probably to find therapeutic applications.
- Role in hemostasis:
ADH has a platelet aggregating effect under conditions of stress where its secretion is highly increased.
It has a favorable action in patients with hemophilia or von Willebrand disease by increasing the secretion of Factor VIII and the Factor von Willebrand. The product usually used in these indications is desmopressin which decreases the bleeding time.
- Other effects:
ADH stimulates ACTH secretion.
Experimental studies showed that ADH facilitates memorizing whereas oxytocin could have an inverse effect.
In addition, vasopressin by activating receptors present in the brain is involved in sexual behavior, at least in certain animal species.
Structural analogues of vassopressin
The vasopressor effect being seldomdesirable, vasopressin analogues such as desmopressin with strong antidiuretic activity and low vasopressor activity have been obtained. The following table compares the effects of vasopressin and desmopressin.
Desmopressin differs from vasopressin, by the loss of the amine group on cysteine, which increases its antidiuretic activity and prolongs its action, and by the replacement of L-arginine by D-arginine, which decreases considerably its affinity for V1 receptors and its vasopressor effect.
The principal therapeutic use of vasopressin structural analogues with little vasoconstrictive effect is the treatment of central diabetes insipidus, i.e. by insufficient hormonal secretion. The analogue used for its antidiuretic effect is desmopressin. Being a polypeptide, desmopressin is poorly absorbed by the digestive tract and partially inactivated by the enzymes of the digestive tract. It is administered by injection, nasal spray, and even by oral route but in this last case a very high dose is given to compensate for its low bioavailability.
In addition to its use in diabetes insipidus, desmopressin is used in the treatment of enuresis (child > 5 years), hemorrhages by defect of factor VIII (hemophilia A) or of von Willebrand Factor. It is also used in functional exploration to test the power of concentration of the kidney.
During its use as antihemorrhagic, desmopressin can induce fluid retention with dilutional hyponatremia.
Terlipressine, an inactive prodrug which in the body is progressively converted to lypressin, is not used in the treatment of diabetes insipidus but in that of digestive hemorrhages by rupture of esophageal varices because of its vasoconstrictive effect on the portal circulation. Terlipressine can induce adversely a hypertensive peak.
Vasopressin itself, according to recent studies, is as effective as adrenaline in the treatment of cardiac arrests and certain shocks with excessive vasodilation. In these indications it could be used as an alternative to adrenaline.
Vasopressin receptor antagonists
Vasopressine receptor antagonists can reduce vasoconstriction by inhibiting V1 receptors and increase aquaresis by inhibiting V2 receptors.
Conivaptan is a non-peptide antagonist of vasopressin receptors V1A and V2. The main pharmacological effect of conivaptan is to induce an aquaresis (enhanced excretion of free water) with as a consequence an increase of sodium concentration in the plasma. It is marketed as Vaprisol* and used for the treatment of hyponatremia of the syndrome of inappropiate secretion of antidiuretic hormone.
The generic names of drugs having V2 vasopressin antagonist effects are terminated by “vaptan”. Other vaptans under investigation are tolvaptan, lixivaptan, satavaptan... Their indications are the hyponatremia of the syndrome of inappropriate secretion of antidiuretic hormone and perhaps, in some circumstances, congestive heart failure and cirrhosis.
Apelin is a peptide which exists in three isoforms of 13, 17 and 36 amino acids, coming from a common precursor of 77 amino acids. Apelin is present in the brain, the digestive tract, adipocytes…Apelin is the ligand of G-protein coupled receptor APJ. In the hypothalamus, apelin inhibits the secretion of vasopressin which results in an aquaretic effect (free water elimination). Apelin decreases arterial blood pressure via nitric oxide release. It has also a positive inotropic effect. It could be implicated in HIV penetration in target cells. Pharmacological modulation of metabolism and effects of apelin can have therapeutic applications.