Sildenafil improves skeletal muscle oxygenation during exercise in men with

24 Endothelial dysfunction caused by defective NO-signaling plays a pivotal role in the 25 pathogenesis of intermittent claudication (IC). In the present study, we evaluated the 26 acute effects of sildenafil, a phosphodiesterase type 5 inhibitor that acts by prolonging 27 NO-mediated cGMP signaling in vascular smooth muscle, on blood pressure (BP), 28 skeletal muscle oxygenation and walking tolerance in patients with IC. A randomized, 29 double-blind, crossover study was conducted in which 12 men with stable IC received 2 30 consecutive doses of 50 mg of sildenafil or matching placebo and underwent a symptom31 limited exercise test on the treadmill. Changes in gastrocnemius deoxy-hemoglobin by 32 near-infrared spectroscopy estimated peripheral muscle O2 delivery-to-utilization 33 matching. Systolic BP was significantly lower during the sildenafil trial relative to 34 placebo during supine rest (~15 mmHg), submaximal exercise (~14 mmHg) and 35 throughout recovery (~18 mmHg) (p<0.05). Diastolic BP was also lower after sildenafil 36 during upright rest (~6 mmHg) and during recovery from exercise (~7 mmHg) (p<0.05). 37 Gastrocnemius deoxygenation was consistently reduced during submaximal exercise 38 (~41%) and at peak exercise (~34%) following sildenafil compared to placebo (p<0.05). 39 However, pain-free (placebo: 335±42s vs. sildenafil: 294±35s) and maximal walking 40 times (placebo: 701±58s vs. sildenafil: 716±62s) did not differ between trials. Acute 41 administration of sildenafil lowers BP and improves skeletal muscle oxygenation during 42 exercise but does not enhance walking tolerance in patients with IC. Whether the 43 beneficial effects of sildenafil on muscle oxygenation can be sustained over time and 44 translated into positive clinical outcomes deserve further consideration in this patient 45 population.