Empagliflozin modulates renal sympathetic and heart rate baroreflexes in a rabbit model of diabetes
Open accessAbstract
AIMS/HYPOTHESIS: We determined whether empagliflozin altered renal sympathetic nerve activity (RSNA) and baroreflexes in a diabetes model in conscious rabbits. METHODS: Diabetes was induced by alloxan, and RSNA, mean arterial pressure (MAP) and heart rate were measured before and after 1 week of treatment with empagliflozin, insulin, the diuretic acetazolamide or the ACE inhibitor perindopril, or no treatment, in conscious rabbits. RESULTS: Four weeks after alloxan administration, blood glucose was threefold and MAP 9% higher than non-diabetic controls (p < 0.05). One week of treatment with empagliflozin produced a stable fall in blood glucose (-43%) and increased water intake (+49%) but did not change RSNA, MAP or heart rate compared with untreated diabetic rabbits. The maximum RSNA to hypotension was augmented by 75% (p < 0.01) in diabetic rabbits but the heart rate baroreflex was unaltered. Empagliflozin and acetazolamide reduced the augmentation of the RSNA baroreflex (p < 0.05) to be similar to the non-diabetic group. Noradrenaline (norepinephrine) spillover was similar in untreated diabetic and non-diabetic rabbits but twofold greater in empagliflozin- and acetazolamide-treated rabbits (p < 0.05). CONCLUSIONS/INTERPRETATION: As empagliflozin can restore diabetes-induced augmented sympathetic reflexes, this may be beneficial in diabetic patients. A similar action of the diuretic acetazolamide suggests that the mechanism may involve increased sodium and water excretion. Graphical abstract.
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These sympathetic reductions were also seen with acetazolamide but not with insulin or perindopril.
“These reductions were also observed with another proximal diuretic, namely acetazolamide, but not with insulin or perindopril.”
From A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors (2021) · cites this paper as Gueguen et al., 2020
The absence of a compensatory heart rate increase suggests blunting of sympathetic nervous system activity, which may contribute to SGLT2 inhibitor benefits compared with other diuretics.
“The lack of a compensatory increase in heart rate suggests there may be commensurate blunting of sympathetic nervous system (SNS) activity, which may contribute to the salutary effects of SGLT2 inhibitors compared with other diuretics (Gueguen et al., 2020).”
From A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors (2021) · cites this paper as Gueguen et al., 2020
In a diabetes-induced rabbit model, empagliflozin reduced the hyperactive sympathetic response to levels similar to non-diabetic rabbits and suppressed the renal sympathetic baroreflex.
“Another study in a diabetes-induced rabbit model demonstrated that the SGLT2 inhibitor empagliflozin reduced the hyperactive sympathetic response caused by diabetes to similar levels as in non-diabetic rabbits and suppressed the renal sympathetic baroreflex (Gueguen et al., 2020).”
From A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors (2021) · cites this paper as Gueguen et al., 2020
The lack of SNS effect with insulin and perindopril suggests that specific proximal natriuretic effects are involved in blunting SNS activity.
“The lack of effect in SNS activity during treatment with insulin and perindopril suggests that specific proximal natriuretic effects are involved to blunt SNS activity (Gueguen et al., 2020).”
From A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors (2021) · cites this paper as Gueguen et al., 2020
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A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors
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- Authors
- Gueguen, C., Burke, S. L., Barzel, B., Eikelis, N., Watson, A. M. D., Jha, J. C., Jackson, K. L., Sata, Y., Lim, K., Lambert, G. W., Jandeleit-Dahm, K. A. M., Cooper, M. E., Thomas, M. C., & Head, G. A.
- Affiliations
- Baker Heart and Diabetes Institute (AU)
- Swinburne University of Technology (AU)
- Monash University (AU)
- Deutsches Diabetes-Zentrum e.V. (DE)
- Corresponding author
- Head, Geoffrey A.
- ORCID
- Venue
- Diabetologia
- Published
- 2020-05-05
- Volume
- 63
- Issue
- 7
- Pages
- 1424-1434
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W3021373499
- Cited by
- 38
- References
- 29
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 6 · 2023: 8 · 2022: 9 · 2021: 6 · 2020: 1
- FWCI
- 4.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Diabetologia (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Swinburne figshare (Swinburne University of Technology) (submittedVersion)
- Funders
- Swinburne Research
- Boehringer Ingelheim (IIS-02-058)
- National Health and Medical Research Council (GNT1079645)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Keywords
- empagliflozin, renal sympathetic nerve activity, diabetes mellitus, alloxan-induced diabetes, acetazolamide, noradrenaline spillover, mean arterial pressure, water intake, sodium and water excretion, SGLT2 inhibitors, perindopril, insulin
- MeSH terms
- Sodium-Glucose Transporter 2 Inhibitors, Animals, Benzhydryl Compounds, Blood Glucose, Blood Pressure, Body Weight, Glucosides, Heart Rate, Male, Rabbits, Sympathetic Nervous System, Baroreflex, Perindopril
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