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