A 23-year-old woman was referred to the Endocrine Clinic complaining of increasing thirst and passing large volumes of urine. She was drinking up to three 2 L bottles of water each day, in addition to tea and coffee. Over the previous 6 months she had started waking at night needing to pass urine and to drink. There was no history of headache, visual impairment, or psychiatric disturbance, no history to suggest pituitary dysfunction and no family history of note. She was taking no medication. Blood tests showed normal glucose, potassium and calcium levels. Further investigations showed her to have 24-hour urine volume of 4.3 L and serum osmolality of 302 mOsmol/kg with a simultaneous urine osmolality of 276 mOsmol/kg. During a formal water deprivation test, serum osmolality rose with an impaired response of urine osmolality. After intramuscular administration of des-amino-des-aspartate-arginine vasopressin (DDAVP, a long-acting analogue of antidiuretic hormone) her urine promptly concentrated, confirming a diagnosis of cranial diabetes insipidus (DI). She was initially treated with intranasal DDAVP, subsequently converting to oral therapy. Endocrine and radiological investigations of the hypothalamus and pitui- tary revealed no evidence of a space occupying lesion.
Thirst and polyuria are important clinical symptoms. In the absence of hyperglycaemia, hypercalcaemia and hypokalaemia (all of which produce a secondary nephrogenic DI; Table 35.1) it is important to distinguish between cranial DI, nephrogenic DI and primary (psychogenic) polydipsia.
Vasopressin is a nonapeptide, synthesized mainly in nerve terminals in the magnocellular paraventricular and supraoptic neurones of the hypothalamus (Fig. 35a). It is also synthesized in other brain areas. Axons of vasopressin cell bodies project not only to the posterior pituitary, but some also make contact with the fenestrated capillaries of the median eminence portal system, while others project to the spinal cord and other brain centres. Vasopressin biosynthesis is very similar in principle to that of oxytocin, in that it is packaged together with a neurophysin, neurophysin II. The importance of the neurophysins is highlighted by the discovery that in a mutant strain of rats, the ‘Brattleboro’ rat, a single nucleotide deletion in the second exon of the gene encoding a very highly conserved region of neurophysin II prevents the translation of vasopressin mRNA. These rats suffer from the equivalent of human diabetes insipidus.
Mechanism of action of vasopressin Vasopressin acts through specific G-protein-coupled receptors on the plasma membrane of the target cell (Fig. 35a). These have been discovered in many organs,including kidney, pituitary, brain, blood vessels, platelets, liver, the gonads and on tumour cells.
Vasopressin receptors. Three subtypes of vasopressin receptors have been discovered V1A, V1B and V2. The vasopressin V1A receptor mediates glycogenolysis, platelet aggregation, cell proliferation and contraction and release of coagulation factor. Vasopressin receptor V1B is expressed predominantly in the anterior pituitary gland and mediates the release of ACTH, β-endorphin, and prolactin. The vasopressin V2 receptor is exclusively expressed in the kidney, and defects in this receptor result in nephrogenic diabetes insipidus. V1 actions are mediated through the IP3 system, whereas V2 are through cyclic AMP (Fig. 35a).
Physiological actions of vasopressin Kidney. Vasopressin affects the ability of the renal tubules to reabsorb water (Fig. 35b). The receptors for vasopressin occur principally in the ascending loop of Henle and the collecting ducts, with some in the mesangium (periphery) of the glomerulus. Solutes are powerfully reabsorbed from the loop of Henle, while the walls of the collecting ducts have a variable permeability to water. In the absence of vasopressin, the collecting ducts are impermeable to water, and hypo-osmotic urine is voided. In the chronic state, this is diabetes insipidus. When the plasma concentration of vasopressin is high, for example during dehydration or haemorrhage, the collecting ducts become permeable to water, and hyperosmotic urine is voided, resulting in a concentration of solutes in plasma. In the healthy individual, vasopressin regulates the development of the osmotic gradient as the tubular filtrate passes through the tubules, and ensures the conservation of water by the body. Vasopressin release from the posterior pituitary is determined principally by blood volume. In the hypothalamus, anatomically near to the paraventricular and supraoptic nuclei, there are osmoreceptors, selectively sensitive to sucrose or sodium ions, which are trig-gered by a rise in the osmolarity of blood. Vasopressin is released and blood volume rises, which switches off osmoreceptor activity.
Blood pressure. Vasopressin is involved in the regulation of blood pressure through its effects on blood volume (Fig. 35c). When this rises, it activates pressure-sensitive receptors in the carotid sinus, the aortic arch and the left atrium, sending afferent messages to the brain stem via the vagus and glossopharangeal nerves, and vasopressin release is inhibited. Vasopressin itself, within physiological ranges of concentration in the bloodstream, does not alter blood pressure.
Adrenocorticotrophic hormone (ACTH) and thyroid-stimulatinghormone(TSH) secretion areaffectedbyvasopressin, whichreachestheanteriorpituitarycorticotrophviatheportal system. It causes ACTH secretion in its own right as a releasing hormone, and also potentiates the action of corticotrophinreleasing factor (see Chapter 18). It is not known, however, how important this effect of vasopressin is in the control of ACTH release. Vasopressin, in physiological concentrations, stimulates the release of TSH from the anterior pituitary thyrotroph, and is equipotent with thyrotrophin-releasing hormone (TRH) in this respect. It has also been discovered that vasopressin actually inhibits TRH release, and it has been suggested that centrally released vasopressin may function in the hypothalamus as part of a ‘short-loop’ negative-feedback regulator of TSH release.
Liver. Vasopressin has a glycogenolytic action in the liver, where it increases the intracellular concentration of Ca2+ in hepatocytes. Vasopressin activates the calcium-dependent phosphorylation of the phosphorylase enzyme that catalyses the conversion of glycogen to glucose phosphate.
Brain. Vasopressin may be involved in memory and male social behaviour.