Antidiuretic hormone activity

Carbamazepine stimulates antidiuretic hormone activity and has been used for the treatment of neurohypophyseal diabetes insipidus. Carbamazepine induces microsomal enzymes and its metabolism is subject to auto-induction. Frequently occurring adverse effects are sedation, dry mouth, dizziness and gastrointestinal disturbances. Photosensitivity reactions, urticaria and Stevens-Johnson syndrome have been described. The elderly are more prone to mental confusion, cardiac abnormalities and problems due to inappropriate ADH secretion. 

The term diabetes from the Greek dia, through, and bainen, to go, means passing through or siphon and describes the excessive production of urine (polyuria) in this condition. Diabetes mellitus mellitus, honey) refers to the sweet taste of the urine, while in diabetes insipidus the urine is insipid (i.e. tasteless). (Don t worry, you don t have to taste the urine nowadays ) Diabetes is caused by lack of insulin activity while diabetes insipidus is caused by insufficient vasopressin (antidiuretic hormone) activity. 

Several human receptors for the neurohypophyseal hormones have been cloned and the sequences elucidated. The human V2 receptor for antidiuretic hormone presumably contains 371 amino acids and seven transmembrane segments and activates cycHc AMP (76). The oxytocin receptor is a classic G-protein-coupled type of receptor with a proposed membrane topography also involving seven transmembrane components (84). A schematic representation of the oxytocin receptor stmcture within the membrane is shown in Eigure 4 (85). 

Fig. 2. Schematic representation of relevant electrolyte transport through the renal tubule, depicting the osmolar gradient ia medullary iaterstitial fluid ia ywOj yW where represents active transport, —passive transport, hoth active and passive transport, and passive transport of H2O ia the presence of ADH, ia A, the cortex, and B, the medulla. An osmole equals a mole of solute divided by the number of ions formed per molecule of the solute. Thus one mole of sodium chloride is equivalent to two osmoles, ie, lAfNaCl = 2 Osm NaCl. ADH = antidiuretic hormone.

Vasopressin (antidiuretic hormone) is a peptide synthesized in the hypothalamus and secreted from the neurohypophysis of the pituitary gland. This substance plays an important role in the long-term regulation of blood pressure through its action on the kidney to increase reabsorption of water. The major stimulus for release of vasopressin is an increase in plasma osmolarity. The resulting reabsorption of water dilutes the plasma toward its normal value of 290 mOsM. This activity is discussed in more detail in Chapter 10 (the endocrine system) and Chapter 19 (the renal system). 

Li+ also inhibits several hormone-stimulated adenylate cyclases which, in some cases, appear to be related to side effects of Li+ therapy. For instance, Li+ inhibits the hydro-osmotic action of vasopressin, the antidiuretic hormone which increases water resorption in the kidney [136]. This effect is associated with polyuria, a relatively harmless side effect sometimes experienced with Li+ treatment, which arises from the inability of the kidney to concentrate urine. Li+ has been shown to inhibit vasopressin-stimulated adenylate cyclase activity in renal epithelial cells. Additionally, Li+ is reported to enhance the vasopressin-induced synthesis of prostaglandin E2 (PGE2) in vitro in kidney. PGE2 inhibits adenylate cyclase activity by stimulation of Gj, and, therefore, this effect may contribute to the Li+-induced polyuria. 

SYMPATHETIC NERVOUS SYSTEM ACTIVITY + ANTIDIURETIC HORMONE (ADH), Water retention + Blood pressure increase... 

Many of the adverse effects of lithium can be ascribed to the action of lithium on adenylate cyclase, the key enz)nne that links many hormones and neurotransmitters with their intracellular actions. Thus antidiuretic hormone and thyroid-stimulating-hormone-sensitive adenylate cyclases are inhibited by therapeutic concentrations of the drug, which frequently leads to enhanced diuresis, h)rpoth)n oidism and even goitre. Aldosterone synthesis is increased following chronic lithium treatment and is probably a secondary consequence of the enhanced diuresis caused by the inhibition of antidiuretic-hormone-sensitive adenylate cyclase in the kidney. There is also evidence that chronic lithium treatment causes an increase in serum parathyroid hormone levels and, with this, a rise in calcium and magnesium concentrations. A decrease in plasma phosphate and in bone mineralization can also be attributed to the effects of the drug on parathyroid activity. Whether these changes are of any clinical consequence is unclear. 

Water. Water resorption in the proximal tubule is a passive process in which water follows the osmotically active particles, particularly the Na" ions. Fine regulation of water excretion (diuresis) takes place in the collecting ducts, where the peptide hormone vasopressin (antidiuretic hormone, ADH) operates. This promotes recovery of water by stimulating the transfer of aquaporins (see p. 220) into the plasma membrane of the tubule cells via V2 receptors. A lack of ADH leads to the disease picture of diabetes insipidus, in which up to 30 L of final urine is produced per day. 

Arachidonic acid is not present in significant amounts in tissues as the free acid but is stored as a fatty acid at the sn-2 position of phospholipids. Prostaglandin biosynthesis is initiated by the interaction of a stimulus with the cell surface. Depending on the cell type, the stimulus can take the form of a hormone, such as angiotensin II or antidiuretic hormone, or a protease such as thrombin (involved in blood clotting), or both hormone and protease. These agents bind to a specific receptor that activates a phospholipase A2 that specifically releases the arachidonic acid from a phospholipid such as phosphatidylcholine. The release of arachidonic acid by phospholipase A2 is believed to be the rate-limiting step for the biosynthesis of eicosanoids. 

Many hormonal secretion processes also exhibit strong circadian components. This is true, for instance, for cortisol, antidiuretic hormone, and growth hormone. The secretion of growth hormone is markedly increased during the early periods of sleep, and the secretion of antidiuretic hormone also reflects the sleep-wake cycle. The mechanisms underlying these oscillations can often be traced back to cyclical variations in the activity of the central nervous system. At the same time, the circadian rhythm modulates the above-mentioned ultradian oscillations. 

Chlorpropamide 60 Metabolized by liver (-70%) to less active metabolites and excreted intact (-30%) by kidneys can potentiate antidiuretic hormone action taken once a day... 

Figure 29.5. Schematic illustration of passive and active movement of electrolytes and water following glomerular filtration. Concentrations of tubular urine and peritubular fluid are given in milliosmoles per liter. Horizontal lines represent areas of increasing interstitial osmolarity. Tubule segments edged with thick black lines are either impermeable to water (loop of Henle) or display antidiuretic hormone-dependent water permeability (collecting duct).

Antidiuretic hormone is a posterior pituitary peptide hormone that binds to vasoconstrictive Via receptors (via Gaq to activate PLC and thence increase cytsosolic Ca2+), to V2 receptors (causing kidney water reabsorption via Gas and increased cAMP) and to corticotropin secretion-regulating Vlb (V3) receptors (mediated by Gaq to activate PLC and thence increase cytosolic Ca2+). For bioactive-G protein interactions see Table 5.9. 

Re-absorption is a two-step process beginning with the active or passive extraction of substances from the mbule fluid into the renal interstitium (the connective tissue that surrounds the nephrons), followed by their transport from the interstitium into the bloodstream. These transport processes are driven by hydrostatic, oncotic, diffusion and active transport. Some key regulatory hormones for re-absorption include aldosterone, which stimulates active sodium re-absorption (and water as a result), and antidiuretic hormone, which stimulates passive water re-absorption. Both hormones exert their effects principally on the collecting ducts. 

About 50% of patients with cirrhosis develop ascites within 10 years of diagnosis and 50% of these will die within 2 years. The process by which ascites forms in cirrhosis is not fully understood but appears to involve the accumulation of vasodilator substances, activation of the renin-angiotensin-aldosterone system (causing renal retention of sodium and water), and the production of antidiuretic hormone (causing hyponatraemia due to dilution, not deficiency, of plasma sodium). 

Antidiuretic hormone (ADH) In cirrhotic and ascitic patients, the ADH level is usually elevated, (s. tab. 16.5) With a reduced effective plasma volume, ADH is released by non-osmotic stimulation in the neurohypophysis and possibly broken down in the liver at a reduced rate as well. The plasma activity of ADH largely... 

Fig. 19 (A) Cross-sectional view of the Alzet osmotic pump, an osmotic pressure-activated drug-delivery system. (B) The effect of 7 days of subcutaneous delivery of antidiuretic hormone (vasopressin) on the daily volume of urinary excretion and urine osmolality in the Brattleboro rats with diabetes insipidus.

Many of the NSAIDs are associated with renal disorders arising de novo or by aggravation of existent renal dysfunction. Inhibition of PGE-1 synthesis intrarenally leads to a reduction in the vasodilator activity of this prostaglandin, which normally contributes to maintenance of renal functional balance and protection against the vasoconstrictor effects of noradrenaline and angiotensin-II and the action of antidiuretic hormone. 

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