A sodium-glucose co-transporter 2 inhibitor empagliflozin prevents abnormality of circadian rhythm of blood pressure in salt-treated obese rats

Abstract

Studies were performed to examine the effects of the selective sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin on urinary sodium excretion and circadian blood pressure in salt-treated obese Otsuka Long Evans Tokushima Fatty (OLETF) rats. Fifteen-week-old obese OLETF rats were treated with 1% NaCl (in drinking water), and vehicle (0.5% carboxymethylcellulose, n=10) or empagliflozin (10 mg kg(-1)per day, p.o., n=11) for 5 weeks. Blood pressure was continuously measured by telemetry system. Glucose metabolism and urinary sodium excretion were evaluated by oral glucose tolerance test and high salt challenge test, respectively. Vehicle-treated OLETF rats developed non-dipper type blood pressure elevation with glucose intolerance and insulin resistance. Compared with vehicle-treated animals, empagliflozin-treated OLETF rats showed an approximately 1000-fold increase in urinary glucose excretion and improved glucose metabolism and insulin resistance. Furthermore, empagliflozin prevented the development of blood pressure elevation with normalization of its circadian rhythm to a dipper profile, which was associated with increased urinary sodium excretion. These data suggest that empagliflozin elicits beneficial effects on both glucose homeostasis and hypertension in salt-replete obese states.

Simultaneous GLP-1 receptor activation and angiotensin receptor blockade increase natriuresis independent of altered arterial pressure in obese OLETF rats

“…Although U Na V increased on day 40 in the Combo group, this effect disappeared when U Na V was corrected for dietary Na + intake, suggesting that combination treatment protected against Na + retention, which is supported by a reduction in Na + balance on day 40 in the Combo group compared with that in the OLETF group. This finding is noteworthy, because increased Na + intake without the appropriate increased U Na V can disrupt the normal circadian rhythm of blood pressure [43]. Furthermore, although U aldo V remained low in the Combo group for the duration of the study, cleaved and active γENaC protein expression was not suppressed in the Combo group, suggesting that aldosterone may not regulate activation of γENaC [33].…”

Canagliflozin Prevents Intrarenal Angiotensinogen Augmentation and Mitigates Kidney Injury and Hypertension in Mouse Model of Type 2 Diabetes Mellitus

“…In a small study, patients with T2DM, SGLT2 inhibitors exhibited a decreasing trend, but not significant, in urinary AGT excretion rates [27]. In contrast, the db/db mouse model of T2DM exhibited decreased renal AGT mRNA expression that was enhanced by treatment with an SGLT2 inhibitor [28] and increased urinary AGT levels in response to Empagliflozin treatment of the OLETF DM rat [29] has been reported. Therefore, the effects of SGLT2 inhibition on intrarenal and/or urinary AGT augmentation in T2DM may be dependent on the animal model used.…”

Responses of renal hemodynamics and tubular functions to acute sodium–glucose cotransporter 2 inhibitor administration in non-diabetic anesthetized rats

“…A review article reported that SGLT2 inhibition reduces blood pressure 5 ; however, the mechanism responsible for SGLT2 inhibitor-induced blood pressure reduction is unclear. We have recently reported that reductions in blood pressure using SGLT2 inhibitors are associated with natriuresis in metabolic syndrome 6 , 7 . Similarly, a clinical study reported that treatment with canagliflozin, the SGLT2 inhibitor, significantly increased urinary sodium excretion in patients with type 2 diabetes 8 .…”