Lithium effectively complements vasopressin V2 receptor antagonist in the treatment of hyponatraemia of SIADH rats.
BACKGROUND
Although, pharmacological intervention with a selective arginine vasopressin (AVP) V(2) 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 V(2) receptor antagonist for SIADH by reducing AQP2 expression.
Kazama
Itsuro
I
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.
Arata
Tomohiro
T
Michimata
Mari
M
Hatano
Ryo
R
Suzuki
Michiko
M
Miyama
Noriyuki
N
Sanada
Satoru
S
Sato
Akira
A
Satomi
Susumu
S
Ejima
Yutaka
Y
Sasaki
Sei
S
Matsubara
Mitsunobu
M
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D051399:Aquaporin 2 / Q000378:metabolism; D001552:Benzazepines / Q000008:administration & dosage*; D018500:Diabetes Insipidus, Nephrogenic / Q000188:drug therapy; D004195:Disease Models, Animal; D004357:Drug Synergism; D005665:Furosemide / Q000494:pharmacology; D007010:Hyponatremia / Q000628:therapy*; D007177:Inappropriate ADH Syndrome / Q000188:drug therapy; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000737:chemistry*
D065092:Antidiuretic Hormone Receptor Antagonists; D051399:Aquaporin 2; D001552:Benzazepines; D017483:Receptors, Vasopressin; C076251:mozavaptan; D005665:Furosemide; D018021:Lithium Chloride