Chapter 3

Maintenance of the tonicity of extracellular fluids within a very narrow range is crucial for proper cell function, because extracellular osmolality regulates cell shape, as well as intracellular concentrations of ions and other osmolytes.1,2 Furthermore, proper extracellular ionic concentrations are necessary for the correct function of ion channels, action potentials, and other modes of intercellular communication. Normal blood tonicity is maintained over a tenfold variation in water intake by a coordinated interaction among the vasopressin, thirst, and renal systems. Dysfunction in any of these systems can result in abnormal regulation of blood osmolality, which if not properly recognized and treated, may cause life-threatening hyperosmolality or hypo-osmolality.

### Vasopressin

The control of plasma osmolality and intravascular volume involves a complex integration of endocrine, neural, and paracrine pathways. Plasma osmolality is regulated principally via vasopressin release from the posterior pituitary, or neurohypophysis, while volume homeostasis is determined largely through the action of the renin-angiotensin-aldosterone system, with contributions from both vasopressin and the natriuretic peptide family. The nine amino acid vasopressin consists of a six amino acid disulfide ring plus a three amino acid tail, with amidation of the carboxy-terminus (Figure 3-1). Vasopressin has both antidiuretic and pressor activities, actions caused by the hormone binding to different receptors, as discussed subsequently. A synthetic analog of vasopressin, dDAVP (desamino-D-arginine vasopressin, desmopressin) with twice the antidiuretic potency and 100 times the duration of action of vasopressin, and no pressor activity, is routinely used to treat vasopressin-deficient patients (Figure 3-1).3

###### Figure 3-1

Molecular structure of vasopressin and desmopressin. Substitution of the 8th amino acid L-Arginine of the nonapeptide vasopressin with D-Arginine confers selective agonist activity on the V2 receptors. Removal of the amino group from the 1st amino acid cysteine prolongs the half-life significantly since vasopressinase attacks vasopressin from this end of the molecule.

#### Synthesis and Secretion

Vasopressin is synthesized in hypothalamic paraventricular and supraoptic magnocellular neurons, whose axons transport the hormone to the posterior pituitary, its primary site of storage and release into the systemic circulation (Figure 3-2). The bilaterally paired hypothalamic paraventricular and supraoptic nuclei are separated from one another by relatively large distances (approximately 1 cm). Their axons course caudally and converge at the infundibulum, before terminating at different levels within the pituitary stalk and posterior pituitary gland.4 This anatomy has important clinical implications, as will be discussed. Vasopressin is also synthesized in the parvocellular neurons of the paraventricular nucleus, where it may have a role in regulating the hypothalamic-pituitary-adrenal axis, and in the hypothalamic suprachiasmatic nucleus, where it may participate in the generation of circadian rhythms.

###### Figure 3-2

Steps in the synthesis and release of vasopressin. 1. Nucleus: Transcription of the vasopressin ...

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