Document Detail

Phosphodiesterase-5 inhibitor, tadalafil, protects against myocardial ischemia/reperfusion through protein-kinase g-dependent generation of hydrogen sulfide.
MedLine Citation:
PMID:  19752383     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Tadalafil is a novel long-acting inhibitor of phosphodiesterase-5. Because cGMP-dependent protein kinase (PKG) signaling plays a key role in cardioprotection, we hypothesized that PKG activation with tadalafil would limit myocardial ischemia/reperfusion (I/R) injury and dysfunction. Additionally, we contemplated that cardioprotection with tadalafil is mediated by hydrogen sulfide (H(2)S) signaling in a PKG-dependent fashion. METHODS AND RESULTS: After baseline transthoracic echocardiography (TTE), adult ICR mice were injected i.p. with vehicle (10% DMSO) or tadalafil (1 mg/kg) with or without KT5823 (KT, PKG blocker, 1 mg/kg) or dl-propargylglycine (PAG, Cystathionine-gamma-lyase [CSE, H(2)S-producing enzyme] blocker; 50 mg/kg) 1 hour before coronary artery ligation for 30 minutes and reperfusion for 24 hours, whereas C57BL wild-type and CSE-knockout mice were treated with either vehicle or tadalafil. After reperfusion, TTE was performed and hearts were collected for infarct size (IS) measurement using TTC staining. Survival was increased with tadalafil (95%) compared with control (65%, P<0.05). Infarct size was reduced with tadalafil (13.2+/-1.7%) compared to vehicle (40.6+/-2.5%; P<0.05). KT and PAG abolished tadalafil-induced protection (IS: 39.2+/-1% and 51.2+/-2.4%, respectively) similar to genetic deletion of CSE (47.2+/-5.1%). Moreover, tadalafil preserved fractional shortening (FS: 31+/-1.5%) compared to control (FS: 22+/-4.8%, P<0.05). Baseline FS was 44+/-1.7%. KT and PAG abrogated the preservation of LV function with tadalafil by decline in FS to 17+/-1% and 23+/-3%, respectively. Compared to vehicle, myocardial H(2)S production was significantly increased with tadalafil and was abolished with KT. CONCLUSIONS: PKG activation with tadalafil limits myocardial infarction and preserves LV function through H(2)S signaling.
Fadi N Salloum; Vinh Q Chau; Nicholas N Hoke; Antonio Abbate; Amit Varma; Ramzi A Ockaili; Stefano Toldo; Rakesh C Kukreja
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Circulation     Volume:  120     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-09-15     Completed Date:  2009-10-06     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  S31-6     Citation Subset:  AIM; IM    
Department of Internal Medicine, Virginia Commonwealth University, Richmond, 23298, USA.
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MeSH Terms
Carbolines / pharmacology*
Cyclic GMP-Dependent Protein Kinases / physiology*
Cyclic Nucleotide Phosphodiesterases, Type 5 / antagonists & inhibitors*
Cystathionine beta-Synthase / physiology
Hydrogen Sulfide / metabolism*
Mice, Inbred C57BL
Mice, Inbred ICR
Myocardial Infarction / drug therapy,  pathology
Myocardial Reperfusion Injury / mortality,  prevention & control*
Phosphodiesterase Inhibitors / pharmacology*
Ventricular Remodeling
Grant Support
Reg. No./Substance:
0/Carbolines; 0/Phosphodiesterase Inhibitors; 0/tadalafil; 7783-06-4/Hydrogen Sulfide; EC GMP-Dependent Protein Kinases; EC Nucleotide Phosphodiesterases, Type 5; EC beta-Synthase

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