Empagliflozin modulates renal sympathetic and heart rate baroreflexes in a rabbit model of diabetes.

Cindy Gueguen,Nina Eikelis,Kristy L Jackson,Karin A M Jandeleit-Dahm,Mark E Cooper,Benjamin Barzel,Sandra L Burke,Kyungjoon Lim,Geoffrey A Head,Anna M D Watson,Gavin W Lambert,Yusuke Sata,Jay C Jha,Merlin C Thomas

doi:10.1007/s00125-020-05145-0

Abstract

We determined whether empagliflozin altered renal sympathetic nerve activity (RSNA) and baroreflexes in a diabetes model in conscious rabbits. Diabetes was induced by alloxan, and RSNA, mean arterial pressure (MAP) and heart rate were measured before and after 1week of treatment with empagliflozin, insulin, the diuretic acetazolamide or the ACE inhibitor perindopril, or no treatment, in conscious rabbits. 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). 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.

Highlights

Individuals with diabetes have an increased risk of developing cardiovascular disease which increases their morbidity and mortality
We explored the effects of acute and 1 week treatment with sodium–glucose cotransporter 2 (SGLT2) inhibitor empagliflozin on blood biochemical, cardiovascular and renal sympathetic nerve activity (RSNA) baroreflex variables and compared these responses with the effects of insulin, the natriuretic acetazolamide and the ACE inhibitor perindopril
The present study examined the sympathetic nervous system (SNS) effects of acute and 1 week treatment effects of SGLT2 inhibition, in alloxaninduced diabetic rabbits with hyperglycaemia and mild hypertension, compared with non-diabetic controls

Summary

Methods

Experiments were conducted in 48 male New Zealand white rabbits weighing 2.6–3.3 kg. Alloxan [6] (60 mg/kg i.v.; Sigma-Aldrich, Saint-Louis, MO, USA) was injected under brief propofol sedation (6 mg/kg i.v.; Fresofol 1%, Fresenius Kabi, Pymble, NSW, Australia). From day 2, rabbits received long-acting glargine insulin s.c. daily (Lantus, Sanofi, Macquarie Park, NSW, Australia) to maintain their blood glucose in the target range of 15–25 mmol/l [7]. After a mean of 22 days, rabbits were implanted with a renal nerve recording electrode [8]. They were anaesthetised with propofol (10 mg/kg i.v.) and maintained under isoflurane (3% in 1 l/min oxygen; Forthane, AbbVie, Mascot, NSW, Australia). Carprofen (3 mg/kg; Rimadyl, Zoetis, Rhodes, NSW, Australia) was given before (i.v.) and 24 h after surgery (s.c.) for analgesia

Results

Introduction

Study design

Discussion