INTRODUCTION

Vasopressin receptor antagonists are molecules designed for their inhibiting effects on the receptors for the signaling hormone vasopressin (also known as ADH). The different receptor sub-groups have different location, structure and mechanism, which can be selectively inhibited to produce or suppress a certain physiological and/or psychological effects.

LECTURE-SPECIFIC INFORMATION

In this section we have collected some information from physiology lectures relevant to this topic.

Vasopressin, also known as antidiuretic hormone (ADH), plays the primary role in regulating the plasma osmolality. The hormone is secreted from the neurohypophysis and its secretion is primarily triggered by hyperosmosis of the plasma sensed by osmoreceptors in the hypothalamus. Stress- and pain-reactions also stimulate the secretion of ADH. Baroreceptors in the heart detecting increased blood pressure, stress and volume receptors in the left atrium and the lungs and central and atrial ANP production all have negative effects on the ADH secretion. (Kidney powerpoint)

Vasopressin stimulates the water reabsorption in the distal tubules and collecting ducts of the kidneys. It also increases the blood pressure through V1 receptors and IP3 (leading to vasoconstriction). (Endocrinology powerpoint).

Dehydration of the body leads to a decrease in blood volume. There can be different reasons to dehydration, e.g. decreased fluid intake or injury. The concentration of salts in the blood increases, which leads to a rise in osmotic pressure. The osmoreceptors in the hypothalamus respond to the change in osmotic pressure and mediate the release of ADH from the pituitary. At the same time, the sensation of thirst is triggered by the thirst center in the hypothalamus also. The result of increased ADH secretion is increased reabsorption of H2O in the kidney, which will raise the blood volume and thereby normalizing the salt concentration (and osmotic pressure).

By using an experimentally perfused kidney (heart-lung preparation) hypoosmotic urine is produced because of the lack of endocrine mechanisms. ADH will quickly readjust isosmosis. Also damage to the hypothalamic ADH secreting locus results in hyposmotic urine (e.g. diabetes insipidus) and if there is an increased diuresis due to excessive water intake, this can be promptly blocked by ADH. Hydropenia results in immediate blood-ADH increase. (Kidney powerpoint) VASOPRESSIN RECEPTORS

The vasopressin receptors are classified into three different subgroups which all belong to the G-protein coupled receptor family. The subgroups (V1a, V1b and V2) have different function, location and transduction mechanism. The V1a and V2b receptors are primarily related with the increase of intracellular calcium concentration, which in turn leads to vasoconstriction, while the V2 receptor is mainly associated with the antidiuretic function of vasopressin in the kidney.

V1a receptors are located in vascular smooth muscle cells, hepatocytes, platelets and cardiomyocytes. When the vasopressin is bound to the receptor, it activates phospholipases which in turn promotes hydrolysis of phosphatidylinositol biphosphate. The cascading effect causes a calcium outflow from the endoplasmatic reticulum. Emptying of calcium supplies triggers calcium influx via divalent cationic channels (Lemmens-Gruber and Kamyar 2006). Increased intracellular calcium concentration initiates calcium facilitated effects such as vasoconstriction.