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

Abstract

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.

A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors

“…These data illustrate that sympathoinhibition is a possible mediator of the kidney, and possibly cardiovascular, protective effects of SGLT2 inhibitors. 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). These reductions were also observed with another proximal diuretic, namely acetazolamide, but not with insulin or perindopril.…”

“…The diuretic effects of SGLT2 inhibitors are the most likely mechanism for their blood pressure-lowering effects. 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). The relation between increased SNS activity and increased blood pressure and impaired glycemic control has been well described (Schlaich et al, 2015).…”

“…These reductions were also observed with another proximal diuretic, namely acetazolamide, but not with insulin or perindopril. 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). Further clinical research is needed to confirm these findings and to investigate whether blunting of SNS activity is causal to kidney benefits seen with SGLT2 inhibitors.…”

Lowering of blood pressure and pulse rate by switching from DPP-4 inhibitor to luseogliflozin in patients with type 2 diabetes complicated with hypertension: A multicenter, prospective, randomized, open-label, parallel-group comparison trial (LUNA study)

“…Suppression of sympathetic nerve activ- ity is a well-known hypothesis for the effect of SGLT2i on PR modulation. Addition of empagliflozin for 1 week affected renal sympathetic nerve activity and baroreflexes in diabetic rabbits [40], while ketone bodies suppressed sympathetic activity through binding to free fatty acid receptors [41]. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) increased nighttime PR by affecting the sympathovagal balance or stimulating sino-atrial node myocytes [42,43].…”

“Greedy Organs Hypothesis” for sugar and salt in the pathophysiology of non-communicable diseases in relation to sodium-glucose co-transporters in the intestines and the kidney

“…Conversely, SGLT2 activity may modulate SNA. Alloxan-induced diabetic rabbit showed increased blood glucose, elevated BP, and exaggerated renal sympathetic nerve (RSN) response to lowering BP, although heart rate and RSN activity itself were not changed [ 54 ]. Empagliflozin reduced this exaggerated RSN response to the level in non-diabetic rabbits, effectively normalizing the baroreflex.…”