In vivo diuretic effect of a new non-peptide arginine vasopressin antagonist, OPC-31260, in conscious rats

Tsuboi, Yasushi; Ishikawa, San‐e; Fujisawa, Genro; Okada, Keiko; Saito, Toshikazu

doi:10.1677/joe.0.1430227

Cited by 17 publications

(5 citation statements)

References 9 publications

(11 reference statements)

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“…Second, an increase in endogenous AVP level has been well documented in response to the rise in plasma osmolality induced by the water loss after administration of aquaretics. 33,34 Thus, the increased natriuresis could also be due to enhanced V1aR effects because these effects are natriuretic, as shown in this study; however this does not seem to be the case because the co-injection of 10 mg/kg V1a antagonist with 10 mg/kg V2 antagonist resulted in changes in V, osmolality, and sodium excretion very similar to those observed with the V2 antagonist alone (data not shown).…”

Section: V2r Effectssupporting

confidence: 57%

Sodium Excretion in Response to Vasopressin and Selective Vasopressin Receptor Antagonists

Perucca

Bichet²,

Bardoux

et al. 2008

Journal of the American Society of Nephrology

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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 g/kg but increased it at doses Ͼ5 g/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. 19: 172119: -173119: , 200819: . doi: 10.1681 The mechanisms by which arginine vasopressin (AVP) exerts its antidiuretic and its pressor effects are relatively well understood. On the one hand, AVP improves water conservation by increasing the permeability to water of the renal collecting duct (CD), an effect mediated by the V2 receptors (V2R) and permitted by the insertion in the luminal membrane of principal cells of preformed aquaporin 2 (AQP2) molecules. This allows more water to be reabsorbed when these ducts traverse the hyperosmotic medulla. On the other hand, AVP increases blood pressure (BP) by inducing a vasoconstriction through its binding to V1a receptors (V1aR) expressed in vascular smooth muscle cells. For these two different effects, in vivo studies are in good agreement with the expectations based on results obtained in vitro. J Am Soc NephrolIn contrast, the experiments intended to study the effects of AVP on sodium handling in vitro or in vivo provide results that are difficult to reconcile. In the isolated microperfused CD, V2R activation increases sodium transport, 1 an effect that should reduce sodium excretion in vivo; however, in a number of studies, AVP infusion in animals and humans

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Section: V2r Effectssupporting

confidence: 57%

Sodium Excretion in Response to Vasopressin and Selective Vasopressin Receptor Antagonists

Perucca

Bichet²,

Bardoux

et al. 2008

Journal of the American Society of Nephrology

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“…The question arises as to whether the relative increase in AQP2 expression back to control levels may reflect an increase in circulating vasopressin to levels where it can overcome the competitive block caused by OPC-31260. However, the dose of OPC-31260 used in this study (40 mg • kg Ϫ1 • day Ϫ1 in divided doses) is greater than that shown to be effective in opposing the antidiuresis induced by continuous infusion of DDAVP in rats at rates up to 5 ng/h (8,9,24) and induced in humans by thirsting for 14 h (23). Tsuboi et al (24) showed that OPC-31260 could induce a profound diuresis even in rats thirsted for 24 h when given orally at a similar dose (100 mg/kg).…”

Section: Table 1 Effect Of Oral Opc-31260 In Rats Thirsted For 24 H P...mentioning

confidence: 96%

“…However, the dose of OPC-31260 used in this study (40 mg • kg Ϫ1 • day Ϫ1 in divided doses) is greater than that shown to be effective in opposing the antidiuresis induced by continuous infusion of DDAVP in rats at rates up to 5 ng/h (8,9,24) and induced in humans by thirsting for 14 h (23). Tsuboi et al (24) showed that OPC-31260 could induce a profound diuresis even in rats thirsted for 24 h when given orally at a similar dose (100 mg/kg). Moreover, when Brattleboro rats, with subcutaneous infusion of 1 ng/h DDAVP (which markedly decreased urine output to 12.6 from 148.7 ml/day), were treated with OPC-31260 (30 mg/ kg), this resulted in a promptly increased urine volume to levels similar to those before the administration of DDAVP (24).…”

Section: Table 1 Effect Of Oral Opc-31260 In Rats Thirsted For 24 H P...mentioning

confidence: 96%

“…Tsuboi et al (24) showed that OPC-31260 could induce a profound diuresis even in rats thirsted for 24 h when given orally at a similar dose (100 mg/kg). Moreover, when Brattleboro rats, with subcutaneous infusion of 1 ng/h DDAVP (which markedly decreased urine output to 12.6 from 148.7 ml/day), were treated with OPC-31260 (30 mg/ kg), this resulted in a promptly increased urine volume to levels similar to those before the administration of DDAVP (24). This strongly supports the view that OPC-31260 at the same doses as in the present study effectively can block V 2 effects even with vasopressin or DDAVP at high supraphysiological doses in rats.…”

Section: Table 1 Effect Of Oral Opc-31260 In Rats Thirsted For 24 H P...mentioning

confidence: 99%

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Dehydration reverses vasopressin antagonist-induced diuresis and aquaporin-2 downregulation in rats

Marples

Christensen²,

Frøkiær

et al. 1998

American Journal of Physiology-Renal Physiology

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To examine the involvement of vasopressin and dehydration in the regulation of aquaporin-2 (AQP2) expression in rat kidney, we investigated the effects of treatment for 60 h with the specific V2-receptor antagonist OPC-31260 (OPC), alone and in conjunction with dehydration for the last 12 h. Changes in AQP2 protein and mRNA expression in kidney inner medulla were determined by Western and Northern blotting, and AQP2 distribution was analyzed by immunocytochemistry and immunoelectron microscopy. Treatment with OPC increased urine output fourfold, with a reciprocal decrease in urine osmolality. AQP2 expression decreased to 52 ± 11% of control levels ( n = 12, P < 0.05), and AQP2 was found predominantly in intracellular vesicles in collecting duct principal cells. This is consistent with efficient blockade of the vasopressin-induced AQP2 delivery to the plasma membrane and with the observed increased diuresis. Consistent with this, AQP2 mRNA levels were also reduced in response to prolonged OPC treatment (30 ± 10% of control levels, n = 9). Five days of treatment with furosemide, despite producing even greater polyuria than OPC, was not associated with downregulation of AQP2 levels, demonstrating that AQP2 downregulation is not secondary to increased urine flow rate or loss of medullary hypertonicity. During 12-h thirsting in the continued presence of OPC, urine output dropped dramatically, to levels not significantly different from that seen in (nonthirsted) control animals. In parallel with this, AQP2 levels rose to control levels. Control experiments confirmed continued effective receptor blockade. These results indicate that the V2-receptor antagonist causes a modest decrease in AQP2 expression that is not a consequence of increased urine flow rate or washout of medullary hypertonicity. However, this decrease is much less marked than that seen in some forms of acquired nephrogenic diabetes insipidus. In conjunction with the effects of thirsting, this suggests that modulation of AQP2 expression is mediated partly, but not exclusively, via V2 receptors.

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“…Mice-To further confirm that OREBP and AVP are independent regulators of the water reabsorption mechanism in the kidney, OREBPdn Tg and Ntg mice were treated with OPC-31260, a V2R antagonist (17,18), under water ad libitum and water deprivation conditions. Under the water ad libitum condition in the Ntg mice, OPC-31260 dramatically lowered the urine osmolality as expected, indicating the significance of AVP in regulating water reabsorption (Fig.…”

Section: Effect Of Opc-31260 On Urine Concentrating Mechanism In Tgmentioning

confidence: 99%

Osmotic Response Element-binding Protein (OREBP) Is an Essential Regulator of the Urine Concentrating Mechanism

Lam¹,

Tam

et al. 2004

Journal of Biological Chemistry

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OREBP (osmotic response element-binding protein), also called TonEBP or NFAT5, is thought to induce the expression of genes that increase the accumulation of organic osmolytes to protect cells against a hypertonic environment. To investigate the consequences of lacking OREBP activity, transgenic (Tg) mice that overexpress OREBPdn (dominant negative form of OREBP) specifically in the epithelial cells of the renal collecting tubules were generated. These mice showed impairment in their urine concentrating mechanism, most likely due to reduced expression of the aquaporin AQP2 and the urea transporter UT-A1 and UT-A2 mRNAs. When deprived of water or after the administration of a vasopressin analogue, urine osmolality of the Tg mice was significantly increased but not to the same extent as that of the wild type mice. The expression of AQP2 and UT-A1, but not UT-A2 mRNAs, was increased to the same level as that of the wild type mice in the water deprivation state, indicating that the vasopressin regulatory mechanism was not affected by OREBPdn. These data indicate that in addition to vasopressin, OREBP is another essential regulator of the urine concentrating mechanism. Furthermore, the OREBPdn Tg mice developed progressive hydronephrosis soon after weaning, confirming the osmoprotective function of OREBP implicated by the in vitro experiments.The mammalian kidney plays an important role in maintaining the homeostasis of osmolality and the electrolyte concentrations of the circulating fluid. The osmolality of the kidney inner medulla is highly hypertonic to facilitate the reabsorption of water from the urine. The cells in the collecting tubules guard against hypertonic stress by increasing the synthesis or import of several organic "compatible" osmolytes. These include sorbitol, which is synthesized by the enzyme aldose reductase, and betaine, myo-inositol, and taurine, which are imported by the betaine/␥-aminobutyric acid transporter, the Na ϩ -dependent myo-inositol transporter, and taurine transporter, respectively (1). The transcription of these genes is induced by a hypertonic medium and regulated by a protein called the osmotic response element-binding protein (OREBP) 1 (2) or tonicity element-binding protein (TonEBP) (3). This protein is also called NFAT5 because of its homology to the NFAT family of transcription factors (4).OREBP consists of a nuclear localization signal near the N terminus followed by a DNA binding domain, a dimerization domain, and a transactivation domain at the carboxyl end. Upon stimulation by hypertonicity, it is rapidly translocated into the nucleus and binds to the osmotic response elements (OREs) (5) in the promoter region of the osmoprotective genes (2) to stimulate transcription. OREBP is highly expressed in the inner medulla as well as in the inner stripe of the outer medulla in the rat kidney (6). In response to water loading, OREBP in the initial portion of the inner medullary collecting ducts (IMCDs) is primarily located in the cytoplasm of the epithelial cells. In dehydrated a...

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In vivo diuretic effect of a new non-peptide arginine vasopressin antagonist, OPC-31260, in conscious rats

Cited by 17 publications

References 9 publications

Sodium Excretion in Response to Vasopressin and Selective Vasopressin Receptor Antagonists

Sodium Excretion in Response to Vasopressin and Selective Vasopressin Receptor Antagonists

Dehydration reverses vasopressin antagonist-induced diuresis and aquaporin-2 downregulation in rats

Osmotic Response Element-binding Protein (OREBP) Is an Essential Regulator of the Urine Concentrating Mechanism

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