BSC1 inhibition complements effects of vasopressin V2 receptor antagonist on hyponatremia in SIADH rats.
BACKGROUND
Severe hyponatremia is most frequently caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Although the expressional alteration of the kidney-specific apical water channel, aquaporin 2 (AQP2), in the collecting duct has been demonstrated to be involved in the development of hyponatremia and the subsequent physiologic reaction that is resistant to arginine vasopressin (AVP; vasopressin escape) in SIADH, the complete pathogenesis of and the appropriate medical treatment for hyponatremia have yet to be elucidated.


METHODS
Hyponatremia was induced in male Sprague-Dawley rats by water loading and subcutaneous infusion of 1-deamino-8-D-arginine vasopressin (dDAVP). For the treatment, a selective AVP V(2) receptor antagonist (OPC-31260) and/or a loop diuretic (furosemide) were administered orally. Protein expression of AQP2 and rat bumetanide-sensitive cotransporter (rBSC1) was examined by Western blotting during the hyponatremia and the subsequent treatment.


RESULTS
We noted a markedly high expression of rBSC1 during the development of hyponatremia, and a relatively low expression during vasopressin escape. OPC-31260 administration elevated serum sodium level in a dose-dependent manner. The therapeutic effect, however, declined with increasing number of treatment days, and doses higher than 15 mg/kg/day induced severe toxicity. The physiologic parameters and the alterations of AQP2 and rBSC1 expression during the treatment demonstrated reactions that were completely opposite to those of vasopressin escape. Combination of a furosemide (100 mg/kg/day) and a low dose of OPC-31260 (5 mg/kg/day) additively elevated serum sodium level and sustained the elevated serum sodium level by significantly reducing sodium accumulation in the renal medulla.


CONCLUSIONS
AVP-induced alterations of rBSC1 expression, as well as those of AQP2, are involved in the pathogenesis of SIADH. The pharmacologic blockade of AVP stimulus in SIADH limits its therapeutic efficacy by discontinuing the vasopressin escape, and the selective inhibition of rBSC1 complements this limitation.
Kazama
Itsuro
I
Division of Molecular Medicine, Center for Translational and Advanced Animal Research, Tohoku University School of Medicine, Sendai, Japan.
Hatano
Ryo
R
Michimata
Mari
M
Suzuki
Katsuya
K
Arata
Tomohiro
T
Suzuki
Michiko
M
Miyama
Noriyuki
N
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; D020346:Aquaporins / Q000378:metabolism; D001552:Benzazepines / Q000008:administration & dosage; D003894:Deamino Arginine Vasopressin / Q000008:administration & dosage; D004232:Diuretics / Q000008:administration & dosage; D005665:Furosemide / Q000008:administration & dosage; D007010:Hyponatremia / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism; D007177:Inappropriate ADH Syndrome / Q000150:complications* / Q000378:metabolism; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000378:metabolism; D012964:Sodium / Q000097:blood / Q000378:metabolism; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1; D014508:Urea / Q000378:metabolism; D014867:Water / Q000008:administration & dosage
D065092:Antidiuretic Hormone Receptor Antagonists; C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D020346:Aquaporins; D001552:Benzazepines; D004232:Diuretics; D017483:Receptors, Vasopressin; C578716:Slc12a1 protein, rat; D049994:Sodium Potassium Chloride Symporter Inhibitors; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D014867:Water; C076251:mozavaptan; D005665:Furosemide; D014508:Urea; D012964:Sodium; D003894:Deamino Arginine Vasopressin; D011188:Potassium