Neurological impact of vasopressin dysregulation and hyponatremia

Abstract

Hyponatremia is frequently associated with neurological disease, neurosurgical procedures, and use of psychoactive drugs. Arginine vasopressin (AVP), or antidiuretic hormone, is the principal physiological regulator of water and electrolyte balance, and disruption of the normal AVP response to osmotic stimuli is a common cause of dilutional hyponatremia in neurological disorders. The hyponatremia-induced shift in water from the extracellular to the intracellular compartment can lead to cerebral edema and serious neurological complications, especially if the decrease in serum sodium concentration ([Na+]) is large or rapid. Overly rapid correction of the serum [Na+] may lead to osmotic demyelination and irreversible brain injury. Fluid restriction is considered first-line treatment and pharmacological agents currently used in the treatment of hyponatremia are limited by inconsistent response and adverse side effects. AVP receptor antagonists represent a new approach to the treatment of hyponatremia by blocking tubular reabsorption of water by binding to V2 receptors in the renal collecting ducts, resulting in aquaresis. Initial clinical experience with AVP receptor antagonists for hyponatremia has shown that these agents augment free water clearance, decrease urine osmolality, and correct serum [Na+] and serum osmolality. Controlled clinical trials now underway will help elucidate the role of AVP receptor antagonism in the treatment of hyponatremia.

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

“…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).…”

“…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].…”

“…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].…”

“…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].…”

“…Developed in the 1990s, the nonpeptide AVP antagonists-also referred to as the vaptans-overcame these limitations [3]. This class of drugs now includes those that selectively antagonize the V1a receptor (reclovaptan, OPC-21268, SR-49059), the V1b receptor (SSR-149415), the V2 receptor (lixivaptan, satavaptan, and tolvaptan), and both the V1a/V2 receptor (conivaptan, mozavaptan) [3,6,8]. Thus far, only conivaptan has been approved for clinical use in the United States.…”