S-51-3: EMPAGLIFLOZIN AMELIORATES CARDIAC HYPERTROPHY AND RENAL INJURY WITH SYMPATHOINHIBITION IN A RAT MODEL OF HYPERTENSIVE HEART FAILURE

Abstract

Objective: SGLT2 inhibitors have been reported to have cardio- and reno-protective effects; however, its mechanisms are not fully understood. Sympathetic activation is critically involved in cardiac and renal damage during the development of hypertensive heart failure. In this study, we examined whether empagliflozin inhibits cardiac and renal damage with sympathoinhibition in the phase of cardiac hypertrophy using a rat model of hypertensive heart failure. Design and method: Male Dahl salt-sensitive rats were fed 0.3% low-salt (LS, n = 6) or 8% high-salt diet from 6 weeks of age and the high-salt-fed rats were assigned to the vehicle (HS-VEH, n = 6) or empagliflozin (HS-EMPA, n = 6) treatment groups at 8 weeks. Systolic blood pressure was measured by tail-cuff method at 6, 8, and 12 weeks. At 12 weeks, organ weight, plasma creatinine, and plasma norepinephrine were measured. Renal fibrosis was evaluated by Sirius red staining. The expression of c-Fos, a marker of neuronal activity, in the hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM), in which the presympathetic neurons are located, was evaluated by immunostaining. Results: Systolic blood pressure was elevated in HS-VEH and HS-EMPA compared to LS, whereas there was no significant difference between HS-VEH and HS-EMPA (at 12 weeks, LS 127.1 ± 5.3 mmHg, HS-VEH 224.5 ± 20.1 mmHg, HS-EMPA 223.8 ± 24.4 mmHg; p < 0.05 vs LS). Left ventricular weight was increased in HS-VEH compared to LS (1.13 ± 0.02 vs 0.90 ± 0.02 g, p < 0.05), and the increase was attenuated in HS-EMPA (1.06 ± 0.04 g, p < 0.05 vs HS-VEH). Kidney weight was similarly increased both in HS-VEH and HS-EMPA compared to LS; however, empagliflozin significantly attenuated the high salt-induced increases in renal fibrosis and plasma creatinine (LS 0.20 ± 0.02 mg/dL, HS-VEH 0.34 ± 0.06 mg/dL, HS-EMPA 0.20 ± 0.04 mg/dL; p < 0.05 for HS-VEH vs LS and HS-EMPA vs HS-VEH). Plasma norepinephrine was increased in HS-VEH compared to LS (1304 ± 627 vs 268 ± 54.5 pg/mL, p < 0.05) and was suppressed in HS-EMPA (648 ± 419 pg/mL, p = 0.05 vs VEH), which was consistent with the finding that the increase in c-Fos positive neurons within the PVN and RVLM in HS-VEH was significantly attenuated in HS-EMPA. Conclusions: In Dahl salt-sensitive hypertensive heart failure model, empagliflozin inhibits sympathetic activation and ameliorates cardiac hypertrophy and renal injury without lowering blood pressure in the pre-heart failure phase.