title: Repeated daily dosing with sildenafil provides sustained protection from endothelial dysfunction caused by ischemia and reperfusion: a human in vivo study.
abstract: Sildenafil and nitroglycerin (GTN) are effective pharmacological preconditioning agents, protecting from the adverse effects of ischemia and reperfusion (I/R). The objective of the present study was to determine whether repeated, daily administration of sildenafil or GTN provides sustained preconditioning from I/R in the human forearm vasculature. Thirty-six healthy volunteers participated in this investigator-blind, randomized, placebo-controlled trial. Subjects received transdermal GTN (0.6 mg/h, 2 h/day), sildenafil (50 mg once daily), or placebo. Twenty-four hours after the first dose of medication, subjects underwent an assessment of flow-mediated dilation (FMD) before and after I/R (15 min of upper arm ischemia followed by 15 min of reperfusion). Subjects continued their study medication for 7 days, at which point FMD measurements were repeated before and after I/R. Venous blood samples were obtained for the determination of myeloperoxidase, P-selectin, and myoglobin before and after each I/R episode. Twenty-four hours after the first dose, both sildenafil and GTN (but not placebo) provided protection from the adverse effects of I/R. After 7 days of repeated daily doses and 24 h after the last dose, FMD was significantly blunted after I/R in placebo- and GTN-treated groups. In contrast, repeated daily administration of sildenafil provided continued protection from the adverse effects of I/R on endothelial function. There was no significant change in plasma levels of myeloperoxidase, P-selectin, or myoglobin at any time point. In conclusion, the present study establishes, for the first time in humans, that sildenafil, but not GTN, provides sustained pharmacological preconditioning of the endothelium and protection from adverse I/R effects on vascular function.
authors: Division of Cardiology, Mount Sinai and University Health Network Hospitals, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; and.
authors: Kelsey
authors: K
authors: McLaughlin
authors: Division of Cardiology, Mount Sinai and University Health Network Hospitals, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; and.
authors: Yuliya
authors: Y
authors: Lytvyn
authors: Division of Cardiology, Mount Sinai and University Health Network Hospitals, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; and.
authors: Mary Clare
authors: MC
authors: Luca
authors: Division of Cardiology, Mount Sinai and University Health Network Hospitals, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; and.
authors: Andrew
authors: A
authors: Liuni
authors: Department of Medicine, University Hospital of Mainz, Mainz, Germany.
authors: Tommaso
authors: T
authors: Gori
authors: Division of Cardiology, Mount Sinai and University Health Network Hospitals, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; and john.parker@uhn.ca.
authors: John D
authors: JD
authors: Parker
mesh_terms: D000279:Administration, Cutaneous; D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005542:Forearm / Q000098:blood supply*; D064368:Healthy Volunteers; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D009211:Myoglobin / Q000097:blood; D005996:Nitroglycerin / Q000008:administration & dosage; D019007:P-Selectin / Q000097:blood; D009195:Peroxidase / Q000097:blood; D010879:Piperazines / Q000008:administration & dosage*; D011687:Purines / Q000008:administration & dosage; D017534:Radial Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D015427:Reperfusion Injury / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage*; D013997:Time Factors; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D009211:Myoglobin; D019007:P-Selectin; D010879:Piperazines; D011687:Purines; C546937:SELP protein, human; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D009195:Peroxidase; D005996:Nitroglycerin
keywords: endothelium; ischemia; pharmacological preconditioning; reperfusion; sildenafil