Chapter 8 - The Posterior Pituitary

Abstract

Disorders of water balance are a common feature of clinical practice. An understanding of the physiology and pathophysiology of vasopressin, perception of thirst, vasopressin receptors, and aquaporin water channels is key to the diagnosis and management of these disorders. Mammals are osmoregulators: they have evolved mechanisms that maintain extracellular fluid osmolality near a stable value, and osmoregulatory neurons express a truncated delta-N variant of the Transient Receptor Potential Vanilloid (TRPV1) channel involved in hypertonicity and thermic perception, while systemic hypotonicity might be perceived by TRPV4 channels. Mutations in the vasopressin gene arginine vasopressin (AVP) are responsible for familial neurohypophyseal diabetes insipidus, a conformational disease, where misfolded fibrillar aggregates within the endoplasmic reticulum cause magnocellular toxicity and death. The antidiuretic action of vasopressin is explained by the interaction of vasopressin with a renal G (guanine nucleotide-binding)-protein-coupled V2 receptor coupled to adenylate cyclase. The activation of V2 receptors on principal cells of renal collecting tubules promotes the cyclic adenosine monophosphate-mediated incorporation of water channels in the luminal membrane of these cells. Hereditary nephrogenic diabetes insipidus (NDI) is secondary to mutations in the gene coding for the vasopressin V2 receptor (AVPR2, X-linked NDI) or to mutations in the gene coding for the aquaporin-2 water channel (AQP2, autosomal dominant or recessive NDI). Some rare gain-of-function mutations of the vasopressin V2 receptor are responsible for the nephrogenic syndrome of inappropriate antidiuresis. Nonpeptide vasopressin V2 receptor antagonists are aquaretic compounds useful for the treatment of hyponatremic patients.