Vasopressin antagonists
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.
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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.
Effects of the V1a receptor are vasoconstriction, myocardial hypertrophy (thickening of the heart muscle), platelet aggregation(can lead to formation of a thrombus), glycogenolysis and uterine contraction. Vasopressin’s positive inotrope effect is caused by the binding to V1a receptors. Both the V1a and the V1b receptors have the same transduction mechanism, which commence with the hydrolysis of phospholipids. However, v1b receptors are located in the central nervous system, in cells in the anterior pituitary gland. This receptor mediates the release of ACTH, prolactin and endorphin. While the other two receptor subgroups are strictly connected to physiological effects, animal experiments links the V1b receptor to a role in emotional and psychological expression (Lemmens-Gruber and Kamyar 2006).
The V2 receptors are localized in the distal tubules and the collection duct of the kidney. The activation of the V2 receptors enables the well-known antidiuretic effect of vasopressin. When vasopressin binds to the V2 receptor, the adenylyl cyclase signaling pathway is stimulated and results in accumulation of cAMP in the cells. The increased intracellular cAMP concentration triggers the function of the aquaporin-2 channels which appear in the luminal side of the apical membrane of cells in the distal tubule and collecting duct in the kidney. The final result of activation of V2 receptors is reabsorption of water through the aquaporin channels.
BACKGROUND
The first descriptions of the action mechanisms in the vasopressors and the antidiuretic activities of the pituitary extracts were at the end of the 19th- and at the beginning of the 20th centuries (Peri 2013). It was first reported that the vasopressin rich posterior pituitary extracts increased the blood pressure, this was in 1895. 18 years later, scientists discovered that the use of these extracts actually inhibited the excretion of urine. Decades later, the osmotic and non-osmotic control systems and their interactions were discovered (Berl 2015). It was not clear that the hormone responsible for vasopressors and antidiuretic effects was the same before after the isolation and synthesis of vasopressin (Peri 2013).
The first studies revealing that the competitive V2 receptor antagonist induced aquaresis in different animals were reported in the early 1980s. However, none of the antagonists identified seemed to be effective clinical antidiuretic antagonists. First at the discovery of the nonpeptide vasopressin type 1 (V1) receptor antagonist in 1991, fully effective vasopressin receptor antagonists were developed. This receptor antagonist counteracted vasopressin-induced vasoconstriction in rats, because the compound selectively and competitively antagonized the binding to the V1 receptor. The nonpeptide vasopressin type 2 (V2) receptor antagonist was discovered one year later, and it led to excretion of solute-free water in rats. The first successful use of a nonpeptide V2 receptor antagonist in humans was reported in 1993 (Peri 2013).
PEPTIDE- AND NON-PEPTIDE ANTAGONISTS (VAPTANS)
Because of the structural and interactional similarity of the three receptors, designing specific non-peptide antagonists has proven a challenge. Although vaptans are a relatively new class of drug, several specific polypeptide antagonists have been created during the last 50 years. Both types of antagonists utilize subtype-specific residues deep within the receptor binding pocket which alters the receptors ability to bind the agonist, vasopressin. In the human V1b receptor for example, four amino acids, located in the membrane helixes, were found responsible for the binding of the antagonist. When taken over longer time periods, the polypeptide antagonists turn agonistic in humans, making the treatment ineffective. Furthermore, the polypeptide antagonists must be administered parenteral. The non-peptide antagonists are cheaper to produce and can be administered orally. Hence the non-peptide variants are currently the preferred variant.
V2 receptor antagnists
These molecules affect the V2 receptors located mainly on the renal collecting ducts. Common for all the vaptans are their mechanism of action, namely competitive antagonism. The competitive effect lowers the activation frequency of the receptor, preventing the synthesis and transport of aquaporin-2. In absence of vasopressin-stimulation, the cells are nearly impermeable to water. Accordingly, an increase in diuresis occurs. In contrast to other diuretics such as thiazide, studies have shown a urine solute (i.e. sodium, potassium) sparing effect in the vaptans. This excretion of free water is called aquaresis. Consequently they are well suited for the treatment of euvolemic or hypervolemic hyponatremia.
Hyponatremia is the most frequent electrolyte disorder, a consequence of excess water relative to total body sodium and increased, normal or reduced plasma osmolality may be related. The most common form of hyponatremia encountered in clinical practice is the hypotonic hyponatremia. As for their diuretic properties, patients with hypovolemic hyponatremia are not suitable patients.
Conivaptan is an effective inhibitor of Cytochrome P450 3A4. This enzyme, found in the liver and intestines, is responsible for the metabolizing of numerous drugs and toxins. This elicits the danger of drug-drug interactions. Conivaptan demonstrates affinity to the V1a receptor as well, but no effect on pulse rate or systolic blood pressure has been attested.
A recent study was performed in Japan examining the early use of Tolvaptan in patients with decompensated heart failure. According to their hypothesis, an early administration of tolvaptan may shorten the rehabilitation time and lead to a shorter hospital stay. 102 patients with decompensated heart failure were divided into two groups; one group was administered tolvaptan within 3 days of admission, the late group later than 3 days. Both groups experienced an increase in urine-volume. The diuretic effect was significantly higher in the early group. An increase of systolic blood pressure was observed, but no notable difference between the two groups was evident. Tolvaptan furthermore produced a significant decrease in heart rate, augmented in the late group. There was no noteworthy change in glomerular filtration rate. The result was accordingly: Average hospital stay in the early group: 20.9 ± 1.3 Average hospital stay in the late group: 35.4 ± 3.7
The physiological changes above may reflect the potential benefits of tolvaptan regarding hospital rehabilitation time. Diuresis is a crucial therapy for congestive symptoms and considering the aquaretic effect of tolvaptan, the complication of hyponatremia is avoided. Regarding the importance of administration timing, it is speculated that the earlier termination in the use of carperitide(Natriuretic diuretic peptide drug commonly used in Japan) may contribute to quicker rehabilitation in the patients (Matsukawa, Kubota et al. 2015).