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

Abstract

Background Tadalafil is a novel long acting inhibitor of phosphodiesterase-5. Since 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-γ-lyase (CSE, H2S-producing enzyme) blocker; 50 mg/kg] 1 h prior to coronary artery ligation for 30 min and reperfusion for 24 h, 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 a 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.

Tadalafil Integrates Nitric Oxide-Hydrogen Sulfide Signaling to Inhibit High Glucose-induced Matrix Protein Synthesis in Podocytes

“…Additionally, H 2 S is not beneficial in all models of renal injury as its effect can vary with the context (70). Whereas H 2 S ameliorates renin-induced hypertension (71), ischemia-reperfusion injury in the kidney and heart (17,20), obstructive kidney injury (72), preeclampsia (73), and hyperhomocysteinemia-induced chronic kidney disease (74) and protects endothelium against high glucose (75), it assumes a pathologic role as a mediator in cisplatinum-induced kidney cell injury (76), streptozotocin-induced pancreatic ␤ cell injury (77), and colon carcinoma (78). These considerations suggest that a critical evaluation of PDE5 inhibitors and H 2 S donors should be done in long term models of kidney injury in diabetes.…”

Concomitant Phosphodiesterase 5 Inhibition Enhances Myocardial Protection by Inhaled Nitric Oxide in Ischemia-Reperfusion Injury

“…Dose and timing of NO inhalation was selected on the basis of previously reported results (Hataishi et al, 2006). Tadalafil (Kemprotec Ltd., Cumbria, UK) dissolved in 30% solution of 2-hydroxypropyl-b-cyclodextrin (SigmaAldrich, St. Louis, MO) was administered via gastric gavage (4 mg/kg) 1 hour prior to I/R, which was determined on the basis of previously reported interspecies dose extrapolations (Ahmad et al, 2009;Salloum et al, 2009;Koka et al, 2010). To determine acute cardiac cGMP responses to myocardial ischemia during different treatment regimens, an additional subset of animals (n 5 6-8 per treatment arm) was euthanized 20 minutes after reperfusion (Fig.…”

Gas Mediators in the Nervous System: Nitric Oxide, Hydrogen Sulfide and Carbon Monoxide

“…110,116 Spontan hipertansif sıçanlarda kan basıncını dü-şürdüğü ve "remodelling"i azalttığı ortaya konmuştur. 117 Ayrıca, antiaterosklerotik etkisi bulunmaktadır.…”