228-LB: Chronic Treatment with a Vasodilator Augments the Effectiveness of Endurance Training to Improve Exercise Capacity and Increases Microvascular Blood Flow in Obese Mice

Peripheral vascular disease is a frequent co-morbidity of type-2 diabetes that impairs exercise capacity. We hypothesized that chronic treatment with a vasodilator would increase microvascular flow and exercise capacity. To test this hypothesis, we chronically treated obese mice with the vasodilatory agent Sildenafil during exercise training. Obese mice were fed a high fat diet (HFD) for 6 weeks prior to the study and remained on the diet for its duration. Mice performed an initial treadmill stress test to assess exercise capacity and injected twice daily with either vehicle or Sildenafil. Groups were matched to initial stress test run distance (Sildenafil 379±74 m vs. Vehicle 373±65 m n=17). Mice were exercise trained for 5-weeks with a 5-days per week 1-hour run at 40% of maximal stress test exercise intensity. After the training period, mice were subjected to a second exercise stress test. Sildenafil treated but not vehicle treated HFD-fed mice showed increased exercise capacity based on stress test run distance (Sildenafil 520±130 m vs. Vehicle 402±164 m n=17). Treating obese mice with a single acute dose of Sildenafil did not alter run distance on a treadmill stress test (Sildenafil 406±64 m vs. Vehicle 460±136 m n=8). To determine the effect of chronic Sildenafil treatment on vascular function, we measured blood flow in the microvasculature of the gastrocnemius muscle by intravital microscopy within one week of the final exercise test. Sildenafil treated mice showed increased vascular flow rate (Sildenafil 671±106 microns/s vs. Vehicle 527±198 microns/s, n=10-11) and vessel perfusion (Sildenafil 96±4% vs. Vehicle 92±4%, n=10-11). Overall, these results indicate that chronic treatment with a vasodilatory agent augments the effect of exercise training to improve exercise capacity in the context of obesity and increases blood flow rate and blood vessel perfusion in the microvasculature of skeletal muscle. Disclosure D.A. Cappel: None. D. Wasserman: None. Funding National Institutes of Health (DK059637, DK054902); American Heart Association