| 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 |
Abstract/OtherAbstract:
|
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. |
| | |
Authors:
|
Fadi N Salloum; Vinh Q Chau; Nicholas N Hoke; Antonio Abbate; Amit Varma; Ramzi A Ockaili; Stefano Toldo; Rakesh C Kukreja |
Related Documents
:
|
3569543 - Consequences of activation and adenosine-mediated inhibition of granulocytes during myo... 19279053 - Sivelestat reduces myocardial ischemia and reperfusion injury in rat hearts even when a... 22515643 - Optimal fluid control can normalize cardiovascular risk markers and limit left ventricu... |
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 |
Affiliation:
|
Department of Internal Medicine, Virginia Commonwealth University, Richmond, 23298, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Carbolines / pharmacology* Cyclic GMP-Dependent Protein Kinases / physiology* Cyclic Nucleotide Phosphodiesterases, Type 5 / antagonists & inhibitors* Cystathionine beta-Synthase / physiology Female Hemodynamics Hydrogen Sulfide / metabolism* Male Mice Mice, Inbred C57BL Mice, Inbred ICR Myocardial Infarction / drug therapy, pathology Myocardial Reperfusion Injury / mortality, prevention & control* Phosphodiesterase Inhibitors / pharmacology* Ventricular Remodeling |
| Grant Support | |
ID/Acronym/Agency:
|
HL51045/HL/NHLBI NIH HHS; HL59469/HL/NHLBI NIH HHS; HL79424/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Carbolines; 0/Phosphodiesterase Inhibitors; 0/tadalafil; 7783-06-4/Hydrogen Sulfide; EC 2.7.1.37/Cyclic GMP-Dependent Protein Kinases; EC 3.1.4.35/Cyclic Nucleotide Phosphodiesterases, Type 5; EC 4.2.1.22/Cystathionine beta-Synthase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Clinical outcomes of medical therapy and timely operation in initially diagnosed type a aortic intra...
Next Document: Paclitaxel-eluting biodegradable synthetic vascular prostheses: a step towards reduction of neointim...