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  • Unmasking a sustained negative effect of SGLT2 inhibition on body fluid volume in the rat.

Unmasking a sustained negative effect of SGLT2 inhibition on body fluid volume in the rat.

American journal of physiology. Renal physiology (2018-05-24)
Takahiro Masuda, Yuko Watanabe, Keiko Fukuda, Minami Watanabe, Akira Onishi, Ken Ohara, Toshimi Imai, Hermann Koepsell, Shigeaki Muto, Volker Vallon, Daisuke Nagata
ABSTRACT

The chronic intrinsic diuretic and natriuretic tone of sodium-glucose cotransporter 2 (SGLT2) inhibitors is incompletely understood because their effect on body fluid volume (BFV) has not been fully evaluated and because they often increase food and fluid intake at the same time. Here we first compared the effect of the SGLT2 inhibitor ipragliflozin (Ipra, 0.01% in diet for 8 wk) and vehicle (Veh) in Spontaneously Diabetic Torii rat, a nonobese type 2 diabetic model, and nondiabetic Sprague-Dawley rats. In nondiabetic rats, Ipra increased urinary excretion of Na+ (UNaV) and fluid (UV) associated with increased food and fluid intake. Diabetes increased these four parameters, but Ipra had no further effect, probably because of its antihyperglycemic effect, such that glucosuria and, as a consequence, food and fluid intake were unchanged. Fluid balance and BFV, determined by bioimpedance spectroscopy, were similar among the four groups. To study the impact of food and fluid intake, nondiabetic rats were treated for 7 days with Veh, Ipra, or Ipra+pair feeding+pair drinking (Pair-Ipra). Pair-Ipra maintained a small increase in UV and UNaV versus Veh despite similar food and fluid intake. Pair-Ipra induced a negative fluid balance and decreased BFV, whereas Ipra or Veh had no significant effect compared with basal values. In conclusion, SGLT2 inhibition induces a sustained diuretic and natriuretic tone. Homeostatic mechanisms are activated to stabilize BFV, including compensatory increases in fluid and food intake.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Na+/H+ Exchanger-3 Antibody, Chemicon®, from rabbit
Sigma-Aldrich
Anti-Aquaporin 1 Antibody, 1.0 mg/mL, Chemicon®
Sigma-Aldrich
Anti-Epithelial Sodium Channel-β Antibody, Chemicon®, from rabbit
Sigma-Aldrich
Anti-Epithelial Sodium Channel-γ Antibody, Chemicon®, from rabbit
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Anti-Thiazide-Sensitive NaCl Cotransporter Antibody, Chemicon®, from rabbit
Sigma-Aldrich
Anti-Epithelial Sodium Channel-α Antibody, Chemicon®, from rabbit