SGLT2 inhibitor prevents loop diuretic–induced plasma volume loss through a vasopressin-independent thirst-stimulating mechanism

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SGLT2 inhibitor prevents loop diuretic–induced plasma volume loss through a vasopressin-independent thirst-stimulating mechanism

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Co-author 1

Takahiro Masuda takamasu35@gmail.com Jichi Medical University Division of Nephrology, Department of Internal Medicine Shimotsuke Japan *

Co-author 2

Masahide Yoshida y-masa@jichi.ac.jp Jichi Medical University Division of Brain and Neurophysiology, Department of Physiology Shimotsuke Japan -

Co-author 3

Tatsushi Onaka tonaka@jichi.ac.jp Jichi Medical University Division of Brain and Neurophysiology, Department of Physiology Shimotsuke Japan -

Co-author 4

Daisuke Nagata ngtdsktky@gmail.com Jichi Medical University Division of Nephrology, Department of Internal Medicine Shimotsuke Japan -

Co-author 5

Yoshiyuki Morishita ymori@jichi.ac.jp Jichi Medical University Division of Nephrology, Department of Internal Medicine Shimotsuke Japan -

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Introduction

SGLT2 inhibitors promote euvolemic fluid maintenance through activation of vasopressin (AVP) and compensatory water intake during osmotic diuresis, whereas loop diuretics suppress AVP and lead to hypovolemia (Physiol Rep 2020, AJP Renal 2022). We recently reported that SGLT2 inhibitor–loop diuretic combination therapy preserves body fluid balance in chronic kidney disease (Front Med 2023, Diagnostics 2024), but the underlying mechanism remains unclear.

Methods

Non-diabetic male Sprague–Dawley rats were divided into four groups: vehicle (Veh), SGLT2 inhibitor ipragliflozin (Ipra; 5 mg/kg), loop diuretic furosemide (Furo; 50 mg/kg), and combination. Drugs were orally administered once daily for two days. Urine volume, fluid intake, plasma volume (Strauss formula), urinary AVP excretion, solute-free water reabsorption and plasma renin activity and aldosterone were measured in metabolic cages.

Results

Both Ipra and Furo increased urine volume, with the greatest rise in the combination group (Veh 8 ± 9, Ipra 120 ± 21*, Furo 102 ± 26*, Ipra + Furo 287 ± 112*#+ %; *p < 0.05 vs Veh, # p<0.05 vs Ipra, + p<0.05 vs Furo). Fluid intake was markedly enhanced in the combination group (-4±5, 21±5*, 11±8, 50±6*#+ %), while urinary AVP (0.24±0.04, 0.38±0.06, 0.10±0.03#, 0.06±0.01*# ng/day/100g bw) and solute-free water reabsorption (13.3±1.5, 23.5±1.6*, 11.1±1.4#, 16.6±1.2# mL/day/100g bw) were suppressed compared with Ipra alone. Furo alone reduced plasma volume (16±6, 18±4, -8±4#, 14±5+ %) and fluid balance (fluid intake-urine volume) (1±8, -8±5, -32±9*, 6±6+ %), whereas the combination restored them without increases in serum Na⁺, Cl- or osmolality. Plasma renin activity and aldosterone were markedly increased in the combination group.

Conclusion

SGLT2 inhibitor–loop diuretic coadministration prevents diuretic-induced plasma volume contraction by stimulating thirst and fluid intake despite reduced AVP activity. This indicates a novel vasopressin-independent thirst mechanism contributing to maintenance of plasma volume during combined diuretic therapy.

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