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

Abstract

Sodium‐glucose cotransporter 2 inhibitor (SGLT2i) is a class of anti‐diabetic medications approved for lowering blood glucose in type 2 diabetes mellitus (T2DM) and reducing cardiovascular risks in heart failure patients with or without T2DM. SGLT2i is also known to reduce blood pressure (BP) in hypertensive patients with T2DM. Mechanisms underlying these benefits of SGLT2i are unclear, but sympathetic overactivation is known to play a major role in the pathogenesis and progression of hypertension and heart failure. Whether SGLT2i reduces sympathetic nerve activity (SNA) and BP in a non‐diabetic prehypertension model is undetermined. Therefore, we conducted studies to determine effects of a SGLT2i, dapagliflozin (DAPA), on conscious BP as well as SNA in prehypertensive spontaneously hypertensive rats (SHRs) during physical stress. Accordingly, we randomly assigned 4‐week‐old non‐diabetic SHRs to either a normal powdered food treated (control) group or a normal powdered food containing DAPA treated (0.5mg/kg/day) group. After 4 weeks on the diet, we measured conscious BP in both groups of rats using radiotelemetry. We also assessed changes in mean arterial pressure (MAP) and renal SNA (RSNA) in response to hindlimb muscle contraction (ie, activation of the exercise pressor reflex, EPR), passive muscle stretch (ie, activation of the mechanically sensitive component of the EPR, known as the mechanoreflex), and intra‐arterial capsaicin injection (ie, activation of the metabolically sensitive component of the EPR, known as the metaboreflex) in a separate group of decerebrate control and DAPA SHRs. We found that fasting blood glucose levels were not significantly different between DAPA and control groups (65±27 vs. 78±20 mg/dL). Heart weight and heart weight‐to‐tibial length was significantly (all P<0.01) decreased by 19% and 16%, respectively in DAPA rats compared to control rats. We also found that daytime/nighttime MAP were markedly lower in DAPA SHRs than control SHRs (daytime: 120±5 vs. 130±6 mmHg, nighttime: 123±6 vs. 132±6 mmHg, P<0.05). A significant reduction in HR in DAPA rats was also observed compared to control rats (daytime: 299±15 vs. 337±20 bpm, nighttime: 320±12 vs. 357±12 bpm, P<0.01). Similarly, the rises in MAP and RSNA during EPR activation were significantly attenuated in DAPA SHRs compared to control SHRs (ΔMAP: 10±5 vs. 29±15 mmHg, ΔRSNA: 43±17 vs. 96±48 %, P<0.05). The pressor and sympathetic responses to mechanoreflex stimulation were also markedly lower in DAPA than control (ΔMAP: 10±7 vs. 25±14 mmHg, ΔRSNA: 31±17 vs. 68±39 %, P<0.05). There was a tendency for MAP and RSNA responses to metaboreflex activation to be lower in the DAPA group, but the difference did not reach statistical significance (ΔMAP: 38±18 vs. 58±24 mmHg, P=0.07, ΔRSNA: 58±29 vs. 95±45 %, P=0.08). In conclusion, our data demonstrate a novel role for SGLT2i in reducing resting BP as well as the activity of skeletal muscle reflexes, independent of blood glucose. Our study may have important clinical implications for preventing hypertension and related cardiovascular damage in young prehypertensive individuals.