A vasopressin receptor antagonist (VRA) is an agent that interferes with action at the
vasopressin receptor
The actions of vasopressin are mediated by stimulation of tissue-specific G protein-coupled receptors (GPCRs) called vasopressin receptors that are classified into the V1 (V1A), V2, and V3 (V1B) receptor subtypes. These three subtypes diffe ...
s. Most commonly VRAs are used in the treatment of
hyponatremia
Hyponatremia or hyponatraemia is a low concentration of sodium in the blood. It is generally defined as a sodium concentration of less than 135 mmol/L (135 mEq/L), with severe hyponatremia being below 120 mEq/L. Symptoms can be abs ...
, especially in patients with
congestive heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
, liver
cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
or
SIADH
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterized by excessive unsuppressible release of antidiuretic hormone (ADH) either from the posterior pituitary gland, or an abnormal non-pituitary source. Unsuppressed ADH ca ...
.
Types
Vaptans
The "vaptan" drugs act by directly blocking the action of vasopressin at its
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
s (
V1A,
V1B and
V2). These receptors have a variety of functions, with the V
1A and V
2 receptors are expressed peripherally and involved in the modulation of blood pressure and kidney function respectively, while the V
1A and V
1B receptors are expressed in the central nervous system. V
1A is expressed in many regions of the brain, and has been linked to a variety of social behaviors in humans and animals.
The vaptan class of drugs contains a number of compounds with varying selectivity, several of which are either already in clinical use or in clinical trials as of 2009.
;Unselective (mixed V
1A/V
2)
*
Conivaptan
Conivaptan, sold under the brand name Vaprisol, is a non-peptide inhibitor of the receptor for anti-diuretic hormone, also called vasopressin. It was approved in 2004 for hyponatremia (low blood sodium levels). The compound was discovered by As ...
;V
1A selective (V
1RA)
*
Relcovaptan
;V
1B selective (V
3RA)
*
Nelivaptan
Nelivaptan (INN) (developmental codename SSR-149,415) is a selective, orally active, non-peptide vasopressin receptor antagonist selective for the V1B subtype. The drug had entered clinical trials for treatment of anxiety and depression. In J ...
;V
2 selective (V
2RA)
*
Lixivaptan
Lixivaptan (VPA-985) is an orally-active, non-peptide, selective vasopressin 2 receptor antagonist being developed as an investigational drug by Palladio Biosciences, Inc. (Palladio), a subsidiary of Centessa Pharmaceuticals plc. , lixivaptan is i ...
*
Mozavaptan
Mozavaptan (INN) is a vasopressin receptor antagonist marketed by Otsuka. In Japan, it was approved in October 2006 for hyponatremia (low blood sodium
Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomi ...
*
Satavaptan
Satavaptan ( INN; developmental code name SR121463, former tentative brand name Aquilda) is a vasopressin-2 receptor antagonist which was investigation by Sanofi-Aventis and was under development for the treatment of hyponatremia. It was also be ...
*
Tolvaptan
Tolvaptan, sold under the brand name Samsca among others, is an aquaretic drug that functions as a selective, competitive vasopressin receptor 2 (V2) antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive hea ...
Somatostatin
Somatostatin is a competitive inhibitor.
[Inhibition by somatostatin of the vasopressin-stimulated adenylate cyclase in a kidney-derived line of cells grown in defined medium. FEBS Letters. https://doi.org/10.1016/0014-5793(84)80304-X]
Demeclocycline and lithium
Demeclocycline, a tetracycline antibiotic, is sometimes used to block the action of vasopressin in the kidney in hyponatremia due to inappropriately high secretion of vasopressin (
SIADH
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterized by excessive unsuppressible release of antidiuretic hormone (ADH) either from the posterior pituitary gland, or an abnormal non-pituitary source. Unsuppressed ADH ca ...
), when fluid restriction has failed.
Demeclocycline is not a direct antagonist of the vasopressin receptors however, but rather inhibits activation of the
intracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
second messenger cascade
Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form or cell signaling, encompassing both first me ...
of this receptor in the kidney by an unknown mechanism.
Lithium
Lithium (from el, λίθος, lithos, lit=stone) is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard conditions, it is the least dense metal and the least dense solid el ...
, as
lithium carbonate
Lithium carbonate is an inorganic compound, the lithium salt (chemistry), salt of carbonate with the chemical formula, formula . This white Salt (chemistry), salt is widely used in the processing of metal oxides. It is listed on the World Health O ...
, possesses similar properties to those of demeclocycline on the action of vasopressin in the kidney, and was used clinically before demeclocycline, which largely superseded it for this indication.
Medical use
Hyponatremia
V
2R antagonists have become a mainstay of treatment for
euvolemic (i.e.,
SIADH
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterized by excessive unsuppressible release of antidiuretic hormone (ADH) either from the posterior pituitary gland, or an abnormal non-pituitary source. Unsuppressed ADH ca ...
, postoperative
hyponatremia
Hyponatremia or hyponatraemia is a low concentration of sodium in the blood. It is generally defined as a sodium concentration of less than 135 mmol/L (135 mEq/L), with severe hyponatremia being below 120 mEq/L. Symptoms can be abs ...
) and
hypervolemic
Hypervolemia, also known as fluid overload, is the medical condition where there is too much fluid in the blood. The opposite condition is hypovolemia, which is too little fluid volume in the blood. Fluid volume excess in the intravascular compa ...
hyponatremia (i.e.,
CHF and
cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
).
V
2RAs predictably cause
aquaresis leading to increased
+">a+in majority of patients with hyponatremia due to SIADH, CHF, and cirrhosis. The optimum use of VRAs has not yet been determined, but some predictions can be made with reasonable certainty. For hyponatremia in hospitalized patients, who are unable to take medication orally or for those in whom a more rapid correction of hyponatremia is desired,
conivaptan
Conivaptan, sold under the brand name Vaprisol, is a non-peptide inhibitor of the receptor for anti-diuretic hormone, also called vasopressin. It was approved in 2004 for hyponatremia (low blood sodium levels). The compound was discovered by As ...
(V
1/V
2R antagonist) will likely be the preferred agent. Selective V
2R antagonists such as
tolvaptan
Tolvaptan, sold under the brand name Samsca among others, is an aquaretic drug that functions as a selective, competitive vasopressin receptor 2 (V2) antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive hea ...
,
lixivaptan
Lixivaptan (VPA-985) is an orally-active, non-peptide, selective vasopressin 2 receptor antagonist being developed as an investigational drug by Palladio Biosciences, Inc. (Palladio), a subsidiary of Centessa Pharmaceuticals plc. , lixivaptan is i ...
etc. will likely be useful in patients for whom oral therapy is suitable and for more chronic forms of hyponatremia.
Congestive heart failure
Neurohormonal activation characteristic of
CHF, including increased renin, angiotensin, aldosterone, and catecholamines, contributes to progression of CHF. It has been suggested that cardiovascular mortality may be reduced by selective V
2RA such as
tolvaptan
Tolvaptan, sold under the brand name Samsca among others, is an aquaretic drug that functions as a selective, competitive vasopressin receptor 2 (V2) antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive hea ...
in the higher risk group with kidney function impairment or severe congestive findings.
But until FDA indication is granted for use in CHF with or without accompanying hyponatremia, VRAs are not recommended in patients with CHF.
Cirrhosis
V
2RA may be particularly beneficial in the treatment of patients with advanced liver
cirrhosis
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
and
ascites
Ascites is the abnormal build-up of fluid in the abdomen. Technically, it is more than 25 ml of fluid in the peritoneal cavity, although volumes greater than one liter may occur. Symptoms may include increased abdominal size, increased weight, ab ...
.
Blockade of V
2R will induce an effective
aquaresis and inhibition of V
2-mediated vasodilation. This aquaresis, in combination with a
diuresis
Diuresis () is increased urination (polyuria) or, in the related word senses more often intended, the physiological process that produces such an increase or the administration of medications to encourage that process. It involves extra urine pr ...
, may provide a potential therapy for patients with resistant ascites. V
2 receptor antagonism increases plasma vasopressin concentration, which may cause unopposed hyperstimulation of the vasoconstrictor V
1 receptor. Given the potential hyperstimulation of V
1R, V
2RA may have additional secondary preventative benefits in patients with cirrhosis through a reduction in portal pressure and a decreased risk of variceal bleeding.
Polycystic kidney disease
Polycystin defects increase intracellular
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
, secondary messenger for vasopressin acting at V
2R, leading to cyst development.
cAMP-dependent genes promote fluid secretion into developing renal cysts and increase cell proliferation. Studies in several animal models of polycystic kidney disease have shown a reduction in kidney size and cyst volume after treatment with specific V
2 receptor antagonist.
Full scale therapeutic trials of V
2RAs in patients with autosomal dominant polycystic kidney disease are currently ongoing.
Nephrogenic diabetes insipidus
Congenital
nephrogenic diabetes insipidus
Nephrogenic diabetes insipidus, also known as renal diabetes insipidus, is a form of diabetes insipidus primarily due to pathology of the kidney. This is in contrast to central or neurogenic diabetes insipidus, which is caused by insufficient le ...
(NDI) may result from V
2R or
aquaporin-2
Aquaporin-2 (AQP-2) is found in the apical cell membranes of the kidney's collecting duct principal cells and in intracellular vesicles located throughout the cell. It is encoded by the gene.
Regulation
It is the only aquaporin regulated by ...
(AQP2) mutations. Exogenously administered V
2R antagonists can bind to misfolded intracellular V
2R, and improve transport of V
2R to the cell membrane.
Clinical studies in patients with X-linked
NDI showed that the selective V
1R antagonist
relcovaptan (SR49059, Sanofi-Aventis) significantly increased urine osmolality and decreased 24-hour urine flow.
Thus V
1R and/or V
2R antagonists may serve as molecular chaperones to mitigate misfolding defects in selected patients with type 2 NDI.
References
{{Oxytocin and vasopressin receptor modulators
World Anti-Doping Agency prohibited substances