NDT Advance Access originally published online on May 15, 2006
Nephrology Dialysis Transplantation 2007 22(1):68-76; doi:10.1093/ndt/gfl110
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Lithium effectively complements vasopressin V2 receptor antagonist in the treatment of hyponatraemia of SIADH rats
1Division of Molecular Medicine, Center for Translational and Advanced Animal Research, Tohoku University School of Medicine, Sendai, Japan, 2Division of Advanced Surgical Science and Technology and 3Department of Anesthesiology, Tohoku University Hospital, Sendai, Japan and 4Department of Homeostasis Medicine and Nephrology, Tokyo Medical and Dental University, Tokyo, Japan
Correspondence and offprint requests to: Mitsunobu Matsubara, MD, PhD, Division of Molecular Medicine, Center for Translational and Advanced Animal Research, Tohoku University School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan. Email: mmitsu2i{at}mail.tains.tohoku.ac.jp
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Abstract |
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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
*The authors wish it to be known that, in their opinion, the first two authors contributed equally to this work.