GLP-1 Receptor Agonism Attenuates the Exaggerated Blood Pressure Response to Exercise in Simulated Peripheral Artery Disease

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), used in the treatment of diabetes and obesity, offer broad antioxidant, anti-inflammatory and cardiovascular benefit. Peripheral artery disease (PAD) is a highly prevalent atherosclerotic vascular disease associated with an exaggerated blood pressure (BP) response to exercise. The exaggerated BP response to exercise is mediated by oxidative stress and inflammation and increases risk of stroke, fibrillation, and other vascular injuries. We hypothesized that in rats with simulated PAD acute GLP-1 RA liraglutide (lira) administration would 1) reduce the pressor response to submaximal treadmill exercise and 2) improve endothelium-dependent vasodilation in isolated gastrocnemius arterioles. Methods: Sprague-Dawley rats (n=24, 12M/12F) had their femoral arteries surgically ligated ~72 hours prior to experiments. For treadmill experiments (n=18), the right carotid artery and jugular vein were cannulated (PE-50) for BP measurement and lira/vehicle administration, respectively. After recovery (~2 hrs), rats completed a 4 min treadmill exercise bout (15 m/min, 1° incline). Lira (n=14, 7M/7F; 5-15μg for F, 8-25mg for M) was then infused (~5min) into the jugular vein followed by a second treadmill exercise bout. Vehicle control (saline) experiments were also performed (n=4, 2M/2F). For vascular function experiments (n=6), the gastrocnemius muscle was dissected, and a first-order gastrocnemius arteriole was isolated, cannulated, and pressurized at 60 cmH 2 O. Following spontaneous tone development, arterioles were exposed to increasing concentrations of ACh (10 -9 to 10 -4 M) at 2 min intervals to assess endothelium-dependent vasodilation before and after treatment with Lira (15 nM) for 20 min. Data are expressed as mean±SE and analyzed with paired Student’s T-tests. Statistical significance was set at P≤0.05. Results: Lira administration significantly reduced the peak mean arterial pressure response (peak ∆MAP) to treadmill exercise (peak ΔMAP control: 20±2, lira: 12±2mmHg; p<0.001). In vehicle control experiments, saline administration had no effect on the blood pressure response to exercise (peak ΔMAP control: 19±2, saline: 20±4mmHg; P=0.839). In isolated microvessel experiments, lira improved endothelium-dependent vasodilation (percent of maximal dilation control: 50±5, lira: 66±6%; p<0.001). Conclusion: Lira attenuated the BP response to exercise and improved vascular function in a rat model of simulated PAD. GLP-1 RAs may be an effective treatment for improving cardiovascular function and reducing cardiovascular risk during exercise in PAD patients. National Institutes of Health R01HL16116 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.