Sodium Glucose Cotransporter-2 Inhibition Attenuates the Exaggerated Blood Pressure Response to Exercise in Simulated Peripheral Artery Disease

Sodium glucose cotransporter-2 inhibitors (SGLT2is) are commonly used in the management of type 2 diabetes and recently were found to offer cardiovascular benefits mediated by broad spectrum antioxidant and anti-inflammatory properties. Peripheral artery disease (PAD) is a highly prevalent atherosclerotic vascular disease associated with an exaggerated blood pressure (BP) response to exercise that is mediated, at least in part, by oxidative stress and inflammation. Investigation of therapies that attenuate the exaggerated BP response to exercise in PAD is important given the link between exercise BP and an increased risk of stroke, fibrillation, and other vascular injuries. Thus, we hypothesized that, in male and female rats with simulated PAD, acute administration of the SGLT2i empagliflozin (empa) would reduce the blood pressure response to submaximal treadmill exercise. Methods: Sprague-Dawley rats (n=16, 5M/11F) had their femoral arteries surgically ligated ~72 hours prior to experimental protocols. A sham surgical procedure was performed in a separate group of rats (n=9, 5M/4F). These groups are referred to as “ligated” and “sham”, respectively. On the day of the experiments, the right carotid artery and jugular vein were cannulated (PE-50) for blood pressure measurement and empa (or vehicle) administration, respectively. After recovery (~2 hrs), rats completed a 4 min treadmill exercise bout (15 m/min, 1° incline). Following a 10-minute recovery from exercise, empa (n=10F, 75 ug; n=10M,100 ug) dissolved in a 0.2 mL saline/2% DMSO solution was infused into the jugular vein over 5 min. 30 minutes following empa infusion, a second treadmill exercise bout was performed as described for the control condition. Vehicle control experiments were performed in ligated female rats (n=5). The peak increase in mean arterial blood pressure (peak ΔMAP) in response to exercise was compared before and after empa/vehicle with paired Student’s t-tests. Data are expressed as mean±SEM. Statistical significance was defined as P≤0.05. Results: In ligated rats, empa significantly reduced the peak ΔMAP response to exercise in females (n=6, control: 23±2; empa: 17±3 mmHg; P=0.034) but not males (n=5, control 25±3; empa: 27±3 mmHg; P=0.312). In vehicle control experiments in ligated female rats, 0.2 ml of 2% DMSO/saline had no effect on the peak ΔMAP response to exercise (n=5, control: 23±4; DMSO/saline: 22±4 mmHg; P=0.589) In sham rats, empa had no effect on the peak ΔMAP response to exercise in either females (n=4, 15±2; empa: 15±8 mmHg; P=0.954) or males (n=5, control 14±3; empa: 21±4 mmHg; P=0.176). Conclusion: Empa attenuated the exaggerated blood pressure response to exercise in ligated female rats, but not male rats. These results demonstrate a sex difference in the effect of SGLT2is on the blood pressure response to exercise in a preclinical model of PAD. Thus, the possibility of sex differences should be factored into the evaluation of SGLT2is as a possible treatment for impaired cardiovascular function 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.