Non-Peptide Arginine-Vasopressin Antagonists (Vaptans) for the Treatment of Hyponatremia in Neurocritical Care: A New Alternative?

The nonapeptide hormone arginine-vasopressin (AVP), also known as antidiuretic hormone (ADH), is the primary regulator of body water content and plasma osmolality. It is synthesized within two hypothalamic nuclei (supraoptic and paraventricular) and stored in the neurohypophysis. Small (parvocellular) vasopressin-containing neurons in the anterior hypothalamus give rise to a complex fiber system that extends throughout the brain. Utilizing immunohistochemical and audioradiographic techniques, extra-hypophyseal vasopressinergic pathways in the brain have been demonstrated that may allow for independent release of central as well as systemic AVP. It has been postulated that these pathways influence water regulation and water permeability in nonneuronal brain cells (glia) [1, 2]. Effects of AVP are mediated through three receptor subtypes, each of which belongs to the rhodopsin-like classA G-protein-coupled receptor family [3]. The V1a receptors are primarily located within the vascular smooth muscle and their stimulation results in vasoconstriction. They are also expressed within the brain where they may play an important role in brain water homeostasis and the evolution of brain edema [4], as well as in the myocardium, platelets, hepatocytes, superior cervical ganglion, the uterus, and cells of the adrenal glands [3, 5]. The V1b (formerly designated V3) receptors are found within the anterior pituitary, adrenal medulla, brain, and pancreas and are implicated in the neurohumoral regulation of centrally and peripherally mediated stress response [3, 5]. V2 receptors are expressed predominantly in basolateral membrane of the renal collecting tubule and to a lesser degree within type 2 pneumocytes and the vascular endothelium [3, 5]. AVP regulates water homeostasis through its interaction with the V2 receptors in the renal collecting tubule [3, 5, 6]. Binding of AVP to the V2 receptor activates adenylate cyclase, increasing intracellular concentration of cyclic adenosine monophosphate (cAMP), leading to stimulation of protein kinase A (PKA). PKA increases water resorption by both immediate and delayed mechanisms, namely: (1) phosphorylation of the aquaporin-2 (AQP 2) channel by PKA results in immediate translocation of AQP 2 to the cell membrane and (2) downstream effects resulting in increased expression of AQP-2 within hours [6]. The release of AVP from the neurohypophysis is exquisitely sensitive to plasma osmolality. AVP is secreted at low levels until plasma osmolality reaches approximately 280 mOsm/kg. Above this threshold, the secretion of AVP increases approximately linearly to a maximum output at a serum osmolality of about 295 mOsm/kg, resulting in maximum antidiuresis (urine osmolality > 800 mOsm/kg) [6]. In addition to plasma osmolality, AVP may be released as a normal physiologic response to decreased blood pressure or effective circulating volume (>10% from baseline), nausea, pain, stress, hypoxia, fear, and anxiety [6, 7]. Finally, inappropriate release of AVP may occur in association with a variety of neoplasms and drugs, as well as with diseases affecting the central nervous system, peripheral nervous system, or lungs [7]. J. D. Fields A. Bhardwaj Neurosciences Critical Care Program, Department of Neurology, Oregon Health & Science University, Portland, OR, USA