1,3-Butanediol Administration Recapitulates the Anti-Hypertensive Effect of Dapagliflozin in Spontaneously Hypertensive R ats

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) is a glucose lowering drug that has been shown to reduce blood pressure (BP) in hypertensive patients with type 2 diabetes mellitus. A recent study from our group demonstrated a novel action of dapagliflozin (DAPA), a selective SGLT2i, in preventing the development of hypertension and attenuating the rise in BP during physical stress (e.g., muscle contraction) in young prehypertensive spontaneously hypertensive rats (SHRs), independent of glycemic control. The mechanisms underlying these benefits of SGLT2i are not completely understood, but ketones such as 3-bhydroxybutyrate (3-OHB) may play a role as SGLT2i therapy increases circulating 3-OHB levels by shifting energy metabolism towards fat utilization. Moreover, 3-OHB administration has been shown to exert an anti-hypertensive effect in the Dahl rat model of salt-induced hypertension. Therefore, the purpose of this pilot study was to test if chronic administration of 1,3-butanediol (BD), a precursor of endogenous ketone bodies, to young SHRs elicits a similar effect on BP as chronic DAPA administration. We hypothesized that the BP response to BD in SHRs at rest and in response to muscle contraction would be similarly attenuated to the levels observed in DAPA-treated SHRs. Conscious telemetry BP was measured in 3 groups of young SHRs; 1) control chow with normal tap water (control), 2) DAPA chow (0.5 mg/kg per day) with normal water, 3) normal chow with BD (20% v/v in drinking water) beginning at 12-weeks of age and followed prospectively for a total of 5 weeks. Subsequently, in decerebrate animals, changes in mean arterial pressure (MAP) during hindlimb muscle contraction were assessed. Compared to control diet-treated SHRs, chronic BD administration significantly elevated levels of fasting blood 3-OHB similar to levels observed in DAPA-treated SHRs (1.96±0.59 vs. 3.10±0.65* vs. 2.79±0.75* mmol/L, post hoc : * P <0.01 vs. control). At baseline (week 0), daytime/nighttime MAP was similar between the groups. Following 5 weeks of the diet, daytime/nighttime MAP was markedly attenuated in the BD and DAPA groups compared with the control group (daytime: 143±10* vs. 143±5* vs. 161±17 mmHg, nighttime: 147*±14 vs. 144±5* vs. 165±19 mmHg, post hoc : * P <0.05 vs. control). The rise in MAP during muscle contraction was not reduced by BD treatment to the same extent as it was after DAPA treatment (ΔMAP: 36±6 vs. 34±24 vs. 24±9 mmHg, control vs. BD vs. DAPA, respectively). In conclusion, our data show a BP-lowering effect of BD administration that achieves similar levels of 3-OHB as SGLT2i treatment in a rat model of human essential hypertension. However, BD failed to reproduce the effects of SGLT2i in attenuating the pressor response to muscle contraction in SHRs. Further studies are needed to clarify mechanisms underlying the divergent effects of BD vs. SGLT2i on the exercise pressor response. the Norman & Audrey Kaplan Chair in Hypertension to W.V. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.