Dapagliflozin Attenuates Sympathetic and Pressor Responses to Stress in Young Prehypertensive Spontaneously Hypertensive Rats

Abstract

Background: SGLT2i (sodium-glucose cotransporter 2 inhibitor), a class of anti-diabetic medications, is shown to reduce blood pressure (BP) in hypertensive patients with type 2 diabetes. Mechanisms underlying this action are unknown but SGLT2i-induced sympathoinhibition is thought to play a role. Whether SGLT2i reduces BP and sympathetic nerve activity (SNA) in a nondiabetic prehypertension model is unknown. Methods: Accordingly, we assessed changes in conscious BP using radiotelemetry and alterations in mean arterial pressure and renal SNA during simulated exercise in nondiabetic spontaneously hypertensive rats during chronic administration of a diet containing dapagliflozin (0.5 mg/kg per day) versus a control diet. Results: We found that dapagliflozin had no effect on fasting blood glucose, insulin, or hemoglobin A 1C levels. However, dapagliflozin reduced BP in young (8-week old) spontaneously hypertensive rats as well as attenuated the age-related rise in BP in adult spontaneously hypertensive rat up to 17-weeks of age. The rises in mean arterial pressure and renal SNA during simulated exercise (exercise pressor reflex activation by hindlimb muscle contraction) were significantly reduced after 4 weeks of dapagliflozin (Δmean arterial pressure: 10±7 versus 25±14 mm Hg, Δrenal SNA: 31±17% versus 68±39%, P <0.05). Similarly, rises in mean arterial pressure and renal SNA during mechanoreflex stimulation by passive hindlimb stretching were also attenuated by dapagliflozin. Heart weight was significantly decreased in dapagliflozin compared with the control group. Conclusions: These data demonstrate a novel role for SGLT2i in reducing resting BP as well as the activity of skeletal muscle reflexes, independent of glycemic control. Our study may have important clinical implications for preventing hypertension and hypertensive heart disease in young prehypertensive individuals.

Narrative review investigating the nephroprotective mechanisms of sodium glucose cotransporter type 2 inhibitors in diabetic and nondiabetic patients with chronic kidney disease

“…That may be due to lower adipose tissue insulin resistance ( 17 ). Furthermore, SGLT2i, dapagliflozin, may directly attenuate the sympathetic response ( 94 ).…”

The relationship between SGLT2 and systemic blood pressure regulation

“…An investigation from Kim et al reveals that SGLT2i has a role in non-diabetic models. The findings from this study showed that in prehypertensive rats, ongoing administration of SGLT2i reduces heart rate and resting blood pressure while attenuating the progression of hypertension [54]. Kim et al divided young spontaneously hypertensive rats (SHRs) into two groups, one as the control group and one that would be administered the SGLT2i dapagliflozin.…”

The effect of SGLT2i on in-hospital acute heart failure risk in acute myocardial infarction patients—a retrospective study

“…SGLT2i may not directly inhibit coronary thrombosis, but instead may inhibit neurohumoral activation ( 13 ), myocardial cell necrosis ( 14 ), and reperfusion injury ( 15 ). It may also enhance endothelial cell function and vasodilation ( 16 ), promote myocardial energy metabolism, maintain myocardial contractility ( 17 ), inhibit oxidative stress ( 18 ), improve coronary blood flow, and reduce ventricular load ( 19 ). These mechanisms of action may further prevent myocardial hypertrophy, myocardial fibrosis, and heart failure ( 20 ).…”