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


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.
Salloum
Fadi N
FN
Department of Internal Medicine, Virginia Commonwealth University, Richmond, 23298, USA. fnsalloum@vcu.edu
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
D000818:Animals; D002243:Carbolines / Q000494:pharmacology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology*; D003541:Cystathionine beta-Synthase / Q000502:physiology; D005260:Female; D006439:Hemodynamics; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000401:mortality / Q000517:prevention & control*; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D000068581:Tadalafil; D020257:Ventricular Remodeling
D002243:Carbolines; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D000068581:Tadalafil; D017869:Cyclic GMP-Dependent Protein Kinases; D003541:Cystathionine beta-Synthase; D006862:Hydrogen Sulfide