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Water and sodium conservation response induced by SGLT2 inhibitor ipragliflozin in Dahl salt-sensitive hypertensive rats

Hypertension Research volume 47, pages 3173–3181 (2024)Cite this article

Abstract

Sodium-glucose cotransporter 2 (SGLT2) inhibitors increase urine volume with glucosuria and natriuresis. We recently reported that osmotic diuresis by the SGLT2 inhibitor ipragliflozin induces fluid homeostatic action via the stimulation of fluid intake and vasopressin-induced water reabsorption in euvolemic rats. However, the effects of SGLT2 inhibitors on these parameters in hypervolemic animals remain unclear. In this study, Dahl salt-sensitive hypertensive rats, a hypervolemic rat model, were fed a low-salt (0.3%) or high-salt (8%) diet for 14 days, then divided into vehicle or ipragliflozin (0.01%) groups. During 7 days of treatment, the high-salt diet groups significantly increased fluid intake and urine volume. In the ipragliflozin groups, fluid intake and urine volume increased by 63% and 235%, respectively, in rats fed a normal-salt diet and by 46% and 72%, respectively, in rats fed a high-salt diet. Ipragliflozin increased urinary vasopressin by 200% and solute-free water reabsorption by 196% in the normal-salt group but by only 44% and 38%, respectively, in the high-salt group. A high-salt diet significantly increased fluid balance (fluid intake – urine volume) and Na+ balance (Na+ intake – urinary Na+), but ipragliflozin did not change fluid and Na+ balance in normal- or high-salt groups. A high-salt diet significantly increased systolic blood pressure, but ipragliflozin did not significantly change systolic blood pressure in normal- or high-salt groups. In conclusion, SGLT2 inhibitor ipragliflozin did not change fluid and Na+ balance regardless of basal fluid retention, suggesting the potential of SGLT2 inhibitors to maintain body water and Na+.

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Acknowledgements

The authors acknowledge the technical support provided by Mihoko Sejimo, Keiko Fukuda, Minami Watanabe, and Mamiko Watanabe (Division of Nephrology, Department of Internal Medicine, Jichi Medical University). We would like to thank Editage (www.editage.jp) for English language editing. This study was supported in part by the Manpei Suzuki Diabetes Foundation No. 32436025 (to T.M.), the Jichi Medical University Young Investigator Award (to T. M.), Salt Science Research Foundation No. 2232 (to T. M.), and a Grant-in-Aid for Young Scientists No. 15K21321 (to T. M.).

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Authors and Affiliations

  1. Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan

    Takahiro Masuda & Daisuke Nagata

  2. Division of Brain and Neurophysiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan

    Masahide Yoshida & Tatsushi Onaka

Authors
  1. Takahiro Masuda
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  2. Masahide Yoshida
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  4. Daisuke Nagata
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Contributions

T.M. conceived and designed the research, performed the experiments, analyzed the data, prepared the figures, and drafted the manuscript. M.Y. performed the experiments, analyzed the data, and drafted the manuscript. T.M., M.Y., and T.O. interpreted the results of the experiments; T.M., M.Y., T.O, and D.N. edited and revised the manuscript; T.M., M.Y., T.O., and D.N. approved the final version of the manuscript.

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Correspondence to Takahiro Masuda.

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Astellas Pharma (Tokyo, Japan) provided SGLT2 inhibitor ipragliflozin for this study.

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Masuda, T., Yoshida, M., Onaka, T. et al. Water and sodium conservation response induced by SGLT2 inhibitor ipragliflozin in Dahl salt-sensitive hypertensive rats. Hypertens Res 47, 3173–3181 (2024). https://doi.org/10.1038/s41440-024-01893-3

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