MODULATION OF SYMPATHETIC NERVE ACTIVITY BY SGLT2 INHIBITOR EMPAGLIFLOZIN IN DIABETIC RABBITS

Abstract

Objective: Treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin in patients with type-2 diabetes is associated with 38% reduction in cardiovascular mortality. We explored the notion that the mechanisms underlying these benefits may involve an action on the sympathetic nervous system (SNS). Design and method: Diabetes was induced by alloxan in New-Zealand White rabbits. We determined the associated changes in blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) as well as baroreflex responses to changes in BP and norepinephrine spillover in conscious rabbits. The effects of one-week treatment with empagliflozin were compared to those of another blood glucose-lowering treatment insulin, the proximally-acting natriuretic acetazolamide, the ACE inhibitor perindopril, vehicle treatment and to an untreated diabetic group. Results: Diabetic rabbits were treated with daily insulin to maintain a stable elevation in blood glucose over 4 weeks (20.5 ± 0.4 mM vs 6.5 ± 0.4 mM in controls). BP was 9% greater in diabetic than non-diabetic rabbits (P = 0.02) but there were no differences in RSNA or HR. One-week treatment with empagliflozin (without insulin) lowered blood glucose by 43% but there was no difference in BP, HR or RSNA between these animals and untreated diabetic rabbits or those treated with acetazolamide. However, insulin treatment alone lowered blood glucose similarly to empagliflozin (32%) and increased HR (+10%) while perindopril lowered BP (-9%). In diabetic rabbits there was marked augmentation of the maximum RSNA response to baroreceptor unloading compared to non-diabetic (+69%, P < 0.01). Empagliflozin attenuated the baroreflex by 34% and there was a similar reduction after acetazolamide (-29%, both P < 0.05). Empagliflozin also attenuated the HR baroreflex (-8%) but insulin and perindopril had no effect on either baroreflex. Norepinephrine spillover to plasma was similar in diabetic and non-diabetic rabbits but was elevated after both empagliflozin and acetazolamide (+147% and + 134%, P < 0.05). Conclusions: Empagliflozin normalised the maximal RSNA response to lowering BP, which was exaggerated in diabetic rabbits, without altering BP or resting RSNA. A similar action of the natriuretic acetazolamide suggests that the mechanism underlying the cardiovascular benefits of empagliflozin may involve increased sodium and water excretion.