title: Sildenafil improves skeletal muscle oxygenation during exercise in men with intermittent claudication.
abstract: 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.
authors.affiliation: Pulmonary Function and Clinical Exercise Physiology Unit, Department of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil;
authors.forename: Bruno T
authors.initials: BT
authors.lastname: Roseguini
authors.affiliation: Pulmonary Function and Clinical Exercise Physiology Unit, Department of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil;
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Hirai
authors.affiliation: Pulmonary Function and Clinical Exercise Physiology Unit, Department of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil;
authors.forename: Maria C
authors.initials: MC
authors.lastname: Alencar
authors.affiliation: Pulmonary Function and Clinical Exercise Physiology Unit, Department of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil;
authors.forename: Roberta P
authors.initials: RP
authors.lastname: Ramos
authors.affiliation: Department of Physiology, Federal University of Sao Paulo, Sao Paulo, Brazil;
authors.forename: Bruno M
authors.initials: BM
authors.lastname: Silva
authors.affiliation: Department of Surgery, Division of Vascular Surgery, University of Sao Paulo, Sao Paulo, Brazil; and.
authors.forename: Nelson
authors.initials: N
authors.lastname: Wolosker
authors.affiliation: Pulmonary Function and Clinical Exercise Physiology Unit, Department of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil; Queen's University and Kingston General Hospital, Laboratory of Clinical Exercise Physiology, Department of Medicine, Kingston, Ontario, Canada alberto.neder@queensu.ca.
authors.forename: J Alberto
authors.initials: JA
authors.lastname: Neder
authors.affiliation: Pulmonary Function and Clinical Exercise Physiology Unit, Department of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil;
authors.forename: Luiz E
authors.initials: LE
authors.lastname: Nery
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D001938:Brazil; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005080:Exercise Test; D017079:Exercise Tolerance / Q000187:drug effects; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007383:Intermittent Claudication / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D035002:Lower Extremity; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D010100:Oxygen / Q000097:blood; D010101:Oxygen Consumption / Q000187:drug effects*; D058986:Phosphodiesterase 5 Inhibitors / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use; D020127:Recovery of Function; D000068677:Sildenafil Citrate; D019265:Spectroscopy, Near-Infrared; D013450:Sulfones / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000627:therapeutic use*; D016138:Walking
chemical_list: D015415:Biomarkers; D006454:Hemoglobins; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; C100003:deoxyhemoglobin; D000068677:Sildenafil Citrate; D010100:Oxygen
keywords: blood flow; exercise; intermittent claudication; sildenafil