Pharmacological characterization of the human vasopressin receptor subtypes stably expressed in Chinese hamster ovary cells

Tahara, Atsuo; Saito, Masayuki; Sugimoto, Toru; Tomura, Yuichi; Wada, Koh-ichi; Kusayama, Toshiyuki; Tsukada, Junko; Ishii, Noe; Yatsu, Takeyuki; Uchida, Wataru; Tanaka, Akihiro

doi:10.1038/sj.bjp.0702220

Cited by 60 publications

(40 citation statements)

References 35 publications

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“…AVP stimulation of WT-V 2 R expressing cells promoted cAMP production with an EC 50 of 1.54 ± 0.16 n M , in accordance with a previous report [15]. In cells expressing V88M-V 2 R, the dose-dependent AVP-stimulated cAMP production was found to be right-shifted by more than 100-fold compared to WT-receptor expressing cells with an EC 50 of 248 ± 45 n M (fig.…”

Section: Resultssupporting

confidence: 78%

Vasopressin Type 2 Receptor V88M Mutation: Molecular Basis of Partial and Complete Nephrogenic Diabetes Insipidus

et al. 2009

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Background/Aims: Mutations in the type 2 vasopressin receptor gene (AVPR2) underlie X-linked recessive nephrogenic diabetes insipidus (NDI). Here, we report on a family with a mutation in AVPR2, c.262G>A (p.V88M). This recurrently identified mutation was previously shown to abolish AVPR2 function, yet in some affected members, urine osmolalities of up to 570 mosm/kg were observed. We detail the variable clinical phenotype and investigate its molecular basis. Methods: Retrospective analysis of clinical data and in vitro assessment of wild-type and V88M-mutant receptors. Results: Clinical data were available on 6 patients. Four of these demonstrated a substantial increase in urinary concentration after 1-desamino[8-D-arginine] vasopressin, consistent with partial NDI, while 2 did not respond. In vitro analysis revealed a reduced cell surface expression and decreased binding affinity for arginine-vasopressin of the mutant receptor, leading to blunted signaling activity. Treatment with the pharmacological chaperone SR121463 enhanced cell surface expression. Conclusion: The V88M mutation is associated with phenotypical diversity, which may be explained by the fact that both the expression level and the hormone-binding affinity are affected by the mutation. Our results provide a rational basis for treatment trials with vasopressin analogues in combination with pharmacologic chaperones in patients with this recurrently identified mutation.

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Section: Resultssupporting

confidence: 78%

Vasopressin Type 2 Receptor V88M Mutation: Molecular Basis of Partial and Complete Nephrogenic Diabetes Insipidus

et al. 2009

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“…It mediates vasoconstriction, vascular smooth muscle cell proliferation [8], glycogen metabolism, platelet aggregation, positive inotropy, hypertension and coronary vasospasm. Furthermore, the V1a-receptor promotes hypertrophic growth of myocardial cells [9][10]. Antagonism of V1a-receptors may result in increased cardiac output, reduced total peripheral resistance, reduced mean arterial blood pressure and inhibition of vasopressin-induced protein synthesis of cardiomyocytes.…”

Section: Introductionmentioning

confidence: 98%

Vasopressin antagonists

Lemmens‐Gruber

Kamyar

2006

Cell. Mol. Life Sci.

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Effects of vasopressin via V1a- and V2-receptors are closely implicated in a variety of water-retaining diseases and cardiovascular diseases, including heart failure, hyponatraemia, hypertension, renal diseases, syndrome of inappropriate antidiuretic hormone secretion, cirrhosis and ocular hypertension. As vasopressin receptors are found in many different tissues, vasopressin antagonists may benefit the treatment of disorders such as cerebral ischaemia and stroke, Raynaud's disease, dysmenorrhoea and tocolytic treatment. V1b selective vasopressin antagonists are discussed in terms of their usefulness in the treatment of emotional and psychiatric disorders. The vaptans are vasopressin receptor antagonists with V1a (relcovaptan) or V2 (tolvaptan, lixivaptan) selectivity or non-selective activity (conivaptan) which may be advantageous in some disorders. The V1a/V2 non-selective vasopressin antagonist conivaptan is the first vaptan which is approved by the FDA for the treatment of euvolaemic hyponatraemia.

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“…Moreover, the IC 50 value in a cell culture assay is higher for conivaptan (44) than for NOX-F37 (14.3 nM vs. 6.1 nM), which is further strengthened by the fact that the IC 50 of NOX-F37 was determined in an Ϸ4-fold less-sensitive cell assay (EC 50 Ϸ 5 nM) compared with conivaptan (EC 50 Ϸ 1.3 nM; ref. 37). It can be concluded that NOX-F37 might block AVP-induced V 1a receptor activation very efficiently and could reduce AVP-mediated remodeling in the heart of CHF patients accordingly.…”

Section: Discussionmentioning

confidence: 99%

“…Most advanced are tolvaptan, described as a specific V 2 receptor antagonist, and conivaptan, a dual V 1a and V 2 receptor antagonist. Both antagonists are benzazepine derivatives that show inhibition constants to the human V 2 and V 1a receptors of 0.4 and 12.3 nM for tolvaptan and 1.1 and 6.3 nM for conivaptan, respectively (36,37). In vivo efficacy was demonstrated for both antagonists in preclinical and clinical studies (7,(38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

An l -RNA-based aquaretic agent that inhibits vasopressin in vivo

Purschke

Eulberg

Buchner

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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A class of diuretic͞aquaretic agents based on mirror-image oligonucleotides (so-called Spiegelmers) has been identified. These molecules directly bind and inhibit the neuropeptide vasopressin (AVP). AVP is the major regulatory component of body fluid homeostasis mediated through binding to the renal V2 receptor. Elevated plasma levels of AVP are implicated in several pathological conditions, mainly cardiovascular diseases. In congestive heart failure, AVP is part of a neuroendocrine imbalance that is responsible for progressive worsening of the disease. Employing in vitro selection techniques, RNA aptamers that bind to the unnatural D-configuration of AVP were isolated. The best aptamer displayed an affinity to D-AVP of Ϸ560 pM at 37°C. The corresponding Spiegelmer, a 38-mer mirror-image oligonucleotide (L-RNA) termed NOX-F37, inhibits vasopressin-dependent activation of V1a as well as V2 receptors with IC50 values of 6.1 nM and 1 nM, respectively. NOX-F37 administered to healthy rats effectively neutralized AVP and increased diuresis dose-dependently for 24 h. The mode of action was strictly aquaretic, i.e., the increase in urine volume was not accompanied by an increase in electrolytes. These results clearly prove the in vivo efficacy of NOX-F37 and points out its potential as a drug in the treatment of diseases that are associated with body fluid overload.aptamer ͉ congestive heart failure ͉ diureses ͉ water homeostasis ͉ Spiegelmer T he cyclic nonapeptide vasopressin (AVP) is a neurohormone that is synthesized in the hypothalamus and stored in the hypophysis from where it is released into the circulation (1). AVP is also known as antidiuretic hormone because its main peripheral function is the maintenance of volume and osmolality of body fluids by regulating the free water reabsorption in the kidneys. Under physiological concentrations, AVP acts vasoconstrictive. AVP's actions are mediated through specific G proteincoupled receptors (2). The V 2 receptor, mainly expressed on cells of the basolateral membrane of the collecting duct in the kidneys, mediates the antidiuretic effect via enhanced cAMP levels (3). As a result, aquaporin channels are inserted into the cytoplasma membranes, and the transcription of aquaporin mRNA is induced. The V 1a receptor, mainly expressed on vascular smooth muscle cells and on cells of the myocardium, exerts vasoconstrictive effects through the second messengers inositoltrisphosphate and diacylglycerol. Subsequently, intracellular Ca 2ϩ is mobilized from the endoplasmic reticulum, and Ca 2ϩ channels as well as Na ϩ ͞H ϩ exchangers are activated (4). In addition to vasoactive effects, binding of AVP to the V 1a receptor also stimulates cell growth and proliferation in vascular smooth muscle cells through activation of the mitogen-activated protein kinase pathway (5).AVP release into the circulation is tightly regulated by osmoreceptors in the hypothalamus and baroreceptors in the heart and large arteries. Whereas osmoreceptors respond to small changes (1%) in osmolality, barorec...

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Pharmacological characterization of the human vasopressin receptor subtypes stably expressed in Chinese hamster ovary cells

Cited by 60 publications

References 35 publications

Vasopressin Type 2 Receptor V88M Mutation: Molecular Basis of Partial and Complete Nephrogenic Diabetes Insipidus

Vasopressin Type 2 Receptor V88M Mutation: Molecular Basis of Partial and Complete Nephrogenic Diabetes Insipidus

Vasopressin antagonists

An l -RNA-based aquaretic agent that inhibits vasopressin in vivo

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