Pharmacological preconditioning with sildenafil: Basic mechanisms and clinical implications.
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.
Kukreja
Rakesh C
RC
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
Salloum
Fadi
F
Das
Anindita
A
Ockaili
Ramzi
R
Yin
Chang
C
Bremer
Yvonne A
YA
Fisher
Patrick W
PW
Wittkamp
Michael
M
Hawkins
John
J
Chou
Eric
E
Kukreja
Amit K
AK
Wang
Xiaoyin
X
Marwaha
Vijay R
VR
Xi
Lei
L
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
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