Phosphodiesterase-5 inhibitor, tadalafil, protects against myocardial ischemia/reperfusion through protein-kinase g-dependent generation of hydrogen sulfide.

Full Abstract

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.

Author information

Author/s: Salloum, Fadi N (FN); Chau, Vinh Q (VQ); Hoke, Nicholas N (NN); Abbate, Antonio (A); Varma, Amit (A); Ockaili, Ramzi A (RA); Toldo, Stefano (S); Kukreja, Rakesh C (RC);

Affiliation: Department of Internal Medicine, Virginia Commonwealth University, Richmond, 23298, USA. fnsalloum(-atsign-)vcu.edu

Grants: HL51045 (Agency:NHLBI NIH HHS) ; HL59469 (Agency:NHLBI NIH HHS) ; HL79424 (Agency:NHLBI NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: Circulation (Circulation), published in United States. (Language: eng)

Reference: 2009-Sep; vol 120 (issue 11 Suppl) : pp S31-6

Dates: Created 2009/09/15; Completed 2009/10/06; Revised 2009/10/13;

PMID: 19752383, status: MEDLINE (last retrieval date: 10/13/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

Comments and Corrections

ErratumIn: Circulation. 2009 Oct 13;120(15):e139.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

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

Associated Chemicals: Carbolines (0) ; Phosphodiesterase Inhibitors (0) ; tadalafil (0) ; Hydrogen Sulfide (7783-06-4) ; Cyclic GMP-Dependent Protein Kinases (EC 2.7.1.37) ; Cyclic Nucleotide Phosphodiesterases, Type 5 (EC 3.1.4.35) ; Cystathionine beta-Synthase (EC 4.2.1.22)

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