Abstract: FR-PO554
Additive Diuretic Action of SGLT2 Inhibitor and Loop Diuretic Combination Avoids Body Fluid Loss by Promoting Vasopressin-Independent Compensatory Fluid Intake
Session Information
- Fluid, Electrolyte, and Acid-Base Disorders: Basic
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Fluid, Electrolytes, and Acid-Base Disorders
- 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic
Authors
- Masuda, Takahiro, Jichi Medical University, Shimotsuke, Tochigi, Japan
- Yoshida, Masahide, Jichi Medical University, Shimotsuke, Tochigi, Japan
- Onaka, Tatsushi, Jichi Medical University, Shimotsuke, Tochigi, Japan
- Vallon, Volker, University of California San Diego, La Jolla, California, United States
- Nagata, Daisuke, Jichi Medical University, Shimotsuke, Tochigi, Japan
Background
We have shown that SGLT2 inhibitors maintain euvolemic fluid status by stimulating antidiuretic hormone (vasopressin: AVP) secretion and fluid intake in response to diuresis, whereas loop diuretics reduce AVP secretion and cause net body fluid loss (Physiol Rep 2020, AJP Renal 2022). In addition, we recently reported that the combination of SGLT2 inhibitor and loop diuretic maintains body fluid balance in chronic kidney disease patients (Front Med 2023), but the mechanism remains unclear.
Methods
Non-diabetic Sprague-Dawley rats were divided into 4 groups: 1) Vehicle (Veh), 2) SGLT2 inhibitor ipragliflozin 5 mg/kg (Ipra), 3) loop diuretic furosemide 50 mg/kg (Furo), and 4) ipragliflozin and furosemide combination (Ipra+Furo) with free access to fluid and normal rodent chow. Drugs were suspended in 0.5% methylcellulose and given by gavage, and rats were kept in metabolic cages for 2 days. * p<0.05 vs. Veh; # vs. Ipra; + vs. Furo.
Results
Urine volume on day 2 increased equally in Ipra and Furo and was highest in Ipra+Furo (Veh 8±9, Ipra 120±21*, Furo 102±26*, Ipra+Furo 287±112* %). The change in fluid intake was highest in Ipra+Furo, with a smaller increase in Furo (-4±5, 21±5, 11±8, 50±6+ %). 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 elevated by Ipra but decreased by Furo and Ipra+Furo combination vs. Ipra. The changes in fluid balance (fluid intake-urine volume) (1±8, -8±5, -32±9*, 6±6+ %) and plasma volume calculated by the Strauss formula (16±6, 18±4, -8±4#, 14±5+ %) were negative in Furo but positive in Ipra+Furo. The changes in serum Na+ (-1.3±0.5, 0.1±0.5, -1.1±0.5, -2.0±0.7# %) and Cl- (0.8±0.7, 1.5±0.6, -3.3±1.2*#, -3.1±0.9*# %) concentrations were significantly lower in Ipra+Furo vs. Ipra. Serum osmolality was similar among the 4 groups.
Conclusion
Combination of SGLT2 inhibitor and loop diuretic avoided body fluid loss by promoting compensatory fluid intake despite suppressed AVP tone and absence of serum Na+ and osmolality increase. These results may indicate a novel non-osmoregulatory thirst mechanism induced by the combination of SGLT2 inhibitors and loop diuretics.
Funding
- Private Foundation Support