deamino-arginine-vasopressin and satavaptan

Topics: Antidiuretic Hormone Receptor Antagonists; Benzazepines; Deamino Arginine Vasopressin; Humans; Hyperkalemia; Hypernatremia; Hyponatremia; Inappropriate ADH Syndrome; Membrane Potentials; Morpholines; Osmolar Concentration; Potassium; Randomized Controlled Trials as Topic; Sodium; Spiro Compounds; Survival Rate; Tolvaptan; Water-Electrolyte Imbalance

Involvement of AVP in several pathological states is now established and specific modulation of the different AVP receptor subtypes (V1a, V1b and V2) offers new clinical perspectives for treating major diseases. Recent years have marked a turning point with the design and the use of the first nonpeptide vasopressin receptor antagonists expressing various selectively profile. In that field, we report here the characterization of SR 121463A a highly selective, orally-active antagonist of vasopressin V2 receptors in several models in vitro and in vivo. This compound displayed competitive nanomolar affinity for V2 receptors in various species including man and exhibited a highly selective AVP V2 profile. In vitro, SR 121463A potently antagonized AVP-stimulated adenylyl cyclase activity in human kidney preparations (Ki = 0.26 +/- 0.04 nM) without any intrinsic agonistic effect. In normally-hydrated rats, SR 121463A induced dose-dependent powerful and long-lasting aquaresis after intravenous (0.003 to 0.3 mg/kg) or oral (0.03 to 10 mg/kg) administration. The action of SR 121463A is purely aquaretic with no changes in urine Na+ and K+ excretions unlike that of known diuretic agents such as furosemide or hydrochlorothiazide. In vasopressin-deficient Brattleboro rats, SR 121463A is devoid of any V2 antidiuretic agonist properties. In addition, this compound potently antagonized DDAVP extrarenal V2 effects on hemostasis factor release (FVIII, vW and t-PA) in dogs (ID50 approximately 10 micrograms/kg i.v.). Thus, SR 121463A is the most potent and selective, orally-active V2 antagonist yet described. It is a useful ligand for exploring V2 receptors and the therapeutical usefulness of pure V2 aquaretic agents in several water-retaining diseases and congestive heart failure.

Topics: Adenylyl Cyclases; Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Deamino Arginine Vasopressin; Dogs; Heart Failure; Humans; Kidney; Morpholines; Rats; Rats, Inbred BB; Receptors, Vasopressin; Spiro Compounds; Water-Electrolyte Imbalance

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.. Retrospective analysis of clinical data and in vitro assessment of wild-type and V88M-mutant receptors.. 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.. 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.

Topics: Adolescent; Adult; Amino Acid Substitution; Child; Cyclic AMP; Deamino Arginine Vasopressin; Diabetes Insipidus, Nephrogenic; Female; Gene Expression Regulation; Genetic Diseases, X-Linked; HEK293 Cells; Humans; Infant; Male; Middle Aged; Morpholines; Mutation; Natriuresis; Pedigree; Phenotype; Polyuria; Protein Binding; Receptors, Vasopressin; Recombinant Fusion Proteins; Retrospective Studies; Second Messenger Systems; Spiro Compounds; Transfection; Urine; X Chromosome Inactivation; Young Adult

The mechanisms by which arginine vasopressin (AVP) exerts its antidiuretic and pressor effects, via activation of V2 and V1a receptors, respectively, are relatively well understood, but the possible associated effects on sodium handling are a matter of controversy. In this study, normal conscious Wistar rats were acutely administered various doses of AVP, dDAVP (V2 agonist), furosemide, or the following selective non-peptide receptor antagonists SR121463A (V2 antagonist) or SR49059 (V1a antagonist). Urine flow and sodium excretion rates in the next 6 h were compared with basal values obtained on the previous day, after vehicle treatment, using each rat as its own control. The rate of sodium excretion decreased with V2 agonism and increased with V2 antagonism in a dose-dependent manner. However,for comparable increases in urine flow rate, the V2 antagonist induced a natriuresis 7-fold smaller than did furosemide. Vasopressin reduced sodium excretion at 1 mug/kg but increased it at doses >5 umg/kg,an effect that was abolished by the V1a antagonist. Combined V2 and V1a effects of endogenous vasopressin can be predicted to vary largely according to the respective levels of vasopressin in plasma,renal medulla (acting on interstitial cells), and urine (acting on V1a luminal receptors). In the usual range of regulation, antidiuretic effects of vasopressin may be associated with variable sodium retention. Although V2 antagonists are predominantly aquaretic, their possible effects on sodium excretion should not be neglected. In view of their proposed use in several human disorders, the respective influence of selective (V2) or mixed (V1a/V2) receptor antagonists on sodium handling in humans needs reevaluation.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Deamino Arginine Vasopressin; Diuretics; Dose-Response Relationship, Drug; Furosemide; Male; Morpholines; Rats; Rats, Wistar; Receptors, Vasopressin; Sodium; Spiro Compounds; Urine

Vasopressin V(2) receptors at high-density and V(1B) receptors are candidates for the V(2)-like receptor, which evokes an increase in [Ca(2+)](i) when stimulated by the vasopressin V(2) receptor agonist 1-desamino-8-D-arginine vasopressin (dDAVP) in kidney inner medullary collecting duct. We compared the pharmacological characteristics of vasopressin V(2) and V(1B) receptors in Chinese hamster ovary (CHO) cells to those of vasopressin V(2)-like receptors in rat inner medullary collecting duct cells. The vasopressin V(1B) receptor-selective agonist [deamino-Cys(1), D-3-(Pyridyl)-Ala(2), Arg(8)]vasopressin (D3PVP) did not stimulate the [Ca(2+)](i) increase in high-density vasopressin V(2) receptor-expressing CHO cells, but did in inner medullary collecting duct cells. Moreover, the vasopressin V(1A)/V(2) receptor dual antagonist 4'-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1] benzazepin-6-yl)carbonyl] 2-phenylbenzanilide (YM087), which has no effect on vasopressin V(1B) receptors, did not block the [Ca(2+)](i) increase in inner medullary collecting duct cells when stimulated by dDAVP and D3PVP. On reverse transcription-polymerase chain reaction (RT-PCR) analysis of kidney, vasopressin V(1B) receptor mRNA was detected only in the medulla. We propose that the true nature of the vasopressin V(2)-like receptor in the inner medullary collecting duct is the vasopressin V(1B) receptor, rather than the vasopressin V(2) receptor expressed at high-density.

Topics: Animals; Benzazepines; Calcium; CHO Cells; Cricetinae; Deamino Arginine Vasopressin; Dose-Response Relationship, Drug; Humans; Indoles; Inositol Phosphates; Kidney Medulla; Morpholines; Pyrrolidines; Rats; Receptors, Vasopressin; Renal Agents; RNA, Messenger; Spiro Compounds; Vasopressins

1. The pharmacological profile of receptors activated by vasopressin (AVP) in freshly dissociated supraoptic magnocellular neurones was investigated using specific V1a- and V2-type AVP receptor agonists and antagonists. 2. In 97 % of AVP-responding neurones (1-3000 nM) V1a or V2 receptor type agonists (F-180 and dDAVP, respectively) elicited dose-dependent [Ca2+]i transients that were suppressed by removal of external Ca2+. 3. The [Ca2+]i response induced by 1 microM F-180 or dDAVP was selectively blocked by 10 nM of V1a and V2 antagonists (SR 49059 and SR 121463A, respectively). The response to V1a agonist was maintained in the presence of the V2 antagonist, and the V2 agonist-induced response persisted in the presence of the V1a antagonist. 4. The [Ca2+]i response induced by 1 microM AVP was partially (61 %) blocked by 10 nM SR 121463A. This blockade was increased by a further 31 % with the addition of 10 nM SR 49059. Similarly, the AVP-induced response was partially (47 %) decreased by SR 49059, and a further inhibition of 33 % was achieved in the presence of SR 121463A. 5. We demonstrate that AVP acts on the magnocellular neurones via two distinct types of AVP receptors that exhibit the pharmacological profiles of V1a and V2 types. However, since V2 receptor mRNA is not expressed in the supraoptic nucleus (SON), and since V1b receptor transcripts are observed in the SON, we propose that the V2 receptor agonist and antagonist act on a 'V2-like' receptor or a new type of AVP receptor that remains to be elucidated. The possibility that V2 ligands act on the V1b receptor cannot be excluded.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Arginine Vasopressin; Calcium; Deamino Arginine Vasopressin; In Vitro Techniques; Indoles; Kinetics; Male; Morpholines; Neurons; Pyrrolidines; Rats; Rats, Wistar; Receptors, Vasopressin; Spiro Compounds; Supraoptic Nucleus; Transcription, Genetic; Vasoconstrictor Agents; Vasopressins

Although [Arg(8)]vasopressin is a potent vasoconstrictor, it possesses vasorelaxant properties manifested either after vasopressin V1 receptor blockade or directly in some vascular beds. The nature of the receptor involved in the vasorelaxant effect of [deamino-Cys(1) D-Arg(8)]vasopressin (desmopressin), a vasopressin V2 receptor agonist, was studied on rat precontracted aortic rings by the use of highly selective new non-peptide vasopressin receptor antagonists. The present study demonstrates for the first time that desmopressin relaxant effect is antagonized by the vasopressin V2 receptor antagonist SR121463A, but also by the vasopressin V1A receptor antagonist SR49059, suggesting that desmopressin-induced relaxation is mediated by a receptor subtype sharing both V1A and V2 pharmacological profiles.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Aorta; Arginine Vasopressin; Deamino Arginine Vasopressin; Endothelium, Vascular; Hemostatics; Hormone Antagonists; Indoles; Male; Morpholines; Pyrrolidines; Rats; Rats, Wistar; Spiro Compounds

In the Brattleboro rat with diabetes insipidus vasopressin V2 receptor mRNA and the mRNA of various adenylyl cyclase (AC) isoforms are moderately reduced compared with those of normal rats. In the present study renal vasopressin V2 receptor mRNA was modestly higher (by 34%), as was expression of AC 5, 6 and 9 mRNAs (up to 22% greater), in BDI rats treated with the vasopressin V2 receptor agonist desamino-[Arg8] vasopressin than in untreated controls. AC 4 mRNA was decreased by 17% following desamino-[Arg8s] vasopressin treatment. While the stimulatory Gsalpha mRNA was little affected by the desamino-[Arg8] vasopressin treatment, two of the inhibitory G proteins were raised (Galphai-2 by 54% and Galphai-3 by 57%). Treatment of Sprague-Dawley rats with a specific vasopressin V2 receptor antagonist (SR 121463A) was not associated with any marked changes in mRNA expression. These results indicate that the vasopressin V2 receptor adenylyl cyclase system mediating the antidiuretic response to vasopressin is relatively stable. The Gi proteins may be involved in the stabilizing mechanism.

Topics: Adenylyl Cyclases; Animals; Antidiuretic Hormone Receptor Antagonists; Blotting, Northern; Deamino Arginine Vasopressin; Down-Regulation; GTP-Binding Proteins; Kidney; Kidney Concentrating Ability; Male; Morpholines; Potassium; Rats; Rats, Brattleboro; Rats, Sprague-Dawley; Receptors, Vasopressin; Renal Agents; RNA, Messenger; Sodium; Spiro Compounds