Journal Article

Lithium effectively complements vasopressin V<sub>2</sub> receptor antagonist in the treatment of hyponatraemia of SIADH rats

Itsuro Kazama, Tomohiro Arata, Mari Michimata, Ryo Hatano, Michiko Suzuki, Noriyuki Miyama, Satoru Sanada, Akira Sato, Susumu Satomi, Yutaka Ejima, Sei Sasaki and Mitsunobu Matsubara

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 22, issue 1, pages 68-76
Published in print January 2007 | ISSN: 0931-0509
Published online May 2006 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfl110
Lithium effectively complements vasopressin V2 receptor antagonist in the treatment of hyponatraemia of SIADH rats

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Background. Although, pharmacological intervention with a selective arginine vasopressin (AVP) V2 receptor antagonist has been demonstrated to be effective for syndrome of inappropriate secretion of antidiuretic hormone (SIADH), its long-term administration has some therapeutic limitations. Lithium, a drug for bipolar disorders, has been known to cause nephrogenic diabetes insipidus by reducing kidney-specific apical water channel, aquaporin 2 (AQP2) expression in the collecting ducts. However, its pharmacological efficacy for SIADH still remains to be elucidated.

Methods. Hyponatraemia was induced in male Sprague–Dawley rats by water loading and subcutaneous infusion of 1-deamino-8-d-arginine vasopressin. For the treatment, lithium chloride (LiCl) was administered singly or in combination with OPC-31260 and/or furosemide for 7 days. Protein expression of AQP2 was examined by western blotting at the end of the observation period.

Results. The LiCl administration elevated serum sodium levels in a dose-dependent manner. The therapeutic effect started 3 days after the initial administration and gradually increased. Western blot analysis at the end of the treatment demonstrated dose-dependent reduction of AQP2 protein expression. Additional administration of LiCl (100 mg/kg/day, the dose demonstrated to maintain serum lithium concentration within therapeutic range) to low dose OPC-31260 maintained well the initial elevation of serum sodium level during the treatment. Western blot analysis after combination therapy demonstrated the absence of re-increase in AQP2 expression noted at the end of OPC-31260 treatment. However, further additive effect could not be obtained even when both LiCl and furosemide were added together to low dose OPC-31260.

Conclusions. Although the single effect of therapeutic dose of lithium was weak, it effectively and safely compensated for the therapeutic limitations of a low dose of AVP V2 receptor antagonist for SIADH by reducing AQP2 expression.

Keywords: adenylate cyclase; aquaporin 2; combination therapy; lithium chloride; nephrogenic diabetes insipidus; OPC-31260

Journal Article.  5223 words.  Illustrated.

Subjects: Nephrology

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