Abstract Body: Background:
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for metabolic disease, but their effects on hypertension remain incompletely understood. This study tested the hypothesis that semaglutide, a long-acting GLP-1RA, attenuates blood pressure elevation and cardiometabolic abnormalities in a preclinical model of diet-induced hypertension.

Methods:
Male Dahl Salt-Sensitive rats (n=17) were fed a control diet (CD; 10% kcal from fat) or a high-fat diet (HFD; 60% kcal from fat) beginning at 4 weeks of age. After 21 weeks, rats received daily subcutaneous semaglutide (0.1 mg/kg) or vehicle for 28 days. Radiotelemetry enabled continuous monitoring of mean arterial pressure (MAP), heart rate, activity, and core temperature. Metabolic endpoints included body weight, food intake, fasting glucose, blood chemistry (renal, hepatic, lipid panels), and micro-CT imaging of adiposity.

Results:
HFD-fed rats exhibited significantly higher body weight (CD: 446.0 ± 4.7 g vs. HFD: 466 ± 3.2 g; p<0.05) and MAP (CD: 131.4 ± 0.7 mmHg vs. HFD: 142.5 ± 2.3 mmHg; p<0.05) than CD-fed controls. Semaglutide significantly reduced body weight in HFD rats (-11.2 ± 5.2 g from baseline; p<0.05) and decreased MAP in both CD and HFD groups (-8.4 ± 1.1 mmHg and -8.4 ± 0.9 mmHg, respectively; p<0.05). Treatment elicited a sustained heart rate increase (peak: +97.4 BPM in CD; +87.8 BPM in HFD; p<0.05), along with transient reductions in food/fluid intake and core body temperature. Locomotor activity declined temporarily, consistent with treatment-related malaise. Micro-CT imaging revealed substantial reductions in both visceral and subcutaneous fat depots with semaglutide. Markers of renal and hepatic function remained within normal ranges, though changes in biliary markers warrant further study. Correlation analysis linked reductions in adiposity and body weight to the antihypertensive effect of semaglutide.

Conclusions:
Semaglutide reduces blood pressure and body weight in a model of diet-induced hypertension. These findings support a role for GLP-1RAs in mitigating obesity-related hypertension via mechanisms beyond glucose lowering.

Grant Support: NHLBI P01HL152951.