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(Circulation. 2009;120:S31-S36.)
© 2009 American Heart Association, Inc.

Myocardial Protection, Perioperative Management, and Vascular Biology

Phosphodiesterase-5 Inhibitor, Tadalafil, Protects Against Myocardial Ischemia/Reperfusion Through Protein-Kinase G–Dependent Generation of Hydrogen Sulfide

Fadi N. Salloum, PhD; Vinh Q. Chau, BS; Nicholas N. Hoke, BS; Antonio Abbate, MD; Amit Varma, MD; Ramzi A. Ockaili, PhD; Stefano Toldo, MS; Rakesh C. Kukreja, PhD

From the Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond.

Correspondence to Rakesh C. Kukreja, PhD, Professor of Medicine, Physiology, Biochemistry, and Emergency Medicine, Box 980204, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-046, Richmond, VA 23298. E-mail rakesh{at}vcu.edu; or Fadi N. Salloum, PhD, Assistant Professor of Medicine and Physiology & Biophysics, Box 980204, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-020A, Richmond, VA 23298. E-mail fnsalloum@vcu.edu

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 (H₂S) 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--lyase [CSE, H₂S-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 H₂S production was significantly increased with tadalafil and was abolished with KT.

Conclusion— PKG activation with tadalafil limits myocardial infarction and preserves LV function through H₂S signaling.

Key Words: phosphodiesterase inhibitors • ischemia-reperfusion injury • PKG • CSE • H₂S