title: Pharmacological preconditioning with sildenafil: Basic mechanisms and clinical implications.
abstract: The phosphodiesterase type-5 (PDE5) inhibitor, sildenafil, is the first drug developed for treatment of erectile dysfunction in patients. Experimental data in animals show that sildenafil has a preconditioning-like cardioprotective effect against ischemia/reperfusion injury in the intact heart. Mechanistic studies suggest that sildenafil exerts cardioprotection through NO generated from eNOS/iNOS, activation of protein kinase C/ERK signaling and opening of mitochondrial ATP-sensitive potassium channels. Additional studies show that the drug attenuates cell death resulting from necrosis and apoptosis, and increases the Bcl2/Bax ratio through NO signaling in adult cardiomyocytes. Emerging new data also suggest that sildenafil may be used clinically for treatment of pulmonary arterial hypertension and endothelial dysfunction. Future demonstration of the cardioprotective effect in patients with the relatively safe and effective FDA-approved PDE5 inhibitors such as sildenafil could have an enormous impact on bringing the long-studied phenomenon of ischemic and pharmacologic preconditioning to the clinical forefront.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, P.O. Box 980281, 1101 East Mashall Street, Room 7-046, Richmond, VA 23298-0281, USA. rakesh@hsc.vcu.edu
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Kukreja
authors.forename: Fadi
authors.initials: F
authors.lastname: Salloum
authors.forename: Anindita
authors.initials: A
authors.lastname: Das
authors.forename: Ramzi
authors.initials: R
authors.lastname: Ockaili
authors.forename: Chang
authors.initials: C
authors.lastname: Yin
authors.forename: Yvonne A
authors.initials: YA
authors.lastname: Bremer
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Fisher
authors.forename: Michael
authors.initials: M
authors.lastname: Wittkamp
authors.forename: John
authors.initials: J
authors.lastname: Hawkins
authors.forename: Eric
authors.initials: E
authors.lastname: Chou
authors.forename: Amit K
authors.initials: AK
authors.lastname: Kukreja
authors.forename: Xiaoyin
authors.initials: X
authors.lastname: Wang
authors.forename: Vijay R
authors.initials: VR
authors.lastname: Marwaha
authors.forename: Lei
authors.initials: L
authors.lastname: Xi
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects / Q000494:pharmacology / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones
chemical_list: D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human