title: Sildenafil (Viagra) attenuates ischemic cardiomyopathy and improves left ventricular function in mice.
abstract: We tested the hypothesis that chronic treatment with sildenafil attenuates myocardial infarction (MI)-induced heart failure. Sildenafil has potent protective effects against necrosis and apoptosis following ischemia-reperfusion in the intact heart and cardiomyocytes. ICR mice underwent MI by left anterior descending coronary artery ligation and were treated with sildenafil (0.71 mg/kg bid) or saline for 4 wk. Infarct size (IS) was measured 24 h postinfarction, and apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Left ventricular end-diastolic diameter (LVEDD) and fractional shortening (FS) were measured by echocardiography. Sildenafil reduced IS (40.0 +/- 4.6%) compared with that in saline (69.6 +/- 4.1%, P < 0.05). NG-nitro-l-arginine methyl ester, a nitric oxide synthase (NOS) inhibitor (15 mg/kg bid), blocked the protective effect of sildenafil (IS, 60.2 +/- 1.6%, P < 0.05 vs. sildenafil). Western blot analysis revealed a significant increase in endothelial NOS/inducible NOS proteins 24 h post-MI after treatment with sildenafil versus saline. Apoptosis decreased from 2.4 +/- 0.3% with saline to 1.2 +/- 0.1% with sildenafil (P < 0.05) on day 7 and from 2.0 +/- 0.2% with saline to 1.2 +/- 0.1% with sildenafil on day 28 (P < 0.05), which was associated with an early increase in the Bcl-2-to-Bax ratio. LVEDD increased from baseline value of 3.6 +/- 0.1 to 5.2 +/- 0.2 and to 5.5 +/- 0.1 mm on days 7 and 28, respectively, with saline (P < 0.05) but was attenuated to 4.4 +/- 0.2 and 4.4 +/- 0.1 mm following sildenafil treatment on days 7 and 28, respectively (P > 0.05 vs. baseline). FS significantly improved post-MI with sildenafil. A marked decline in cardiac hypertrophy was observed with sildenafil, which paralleled a reduction in pulmonary edema. Survival rate was lower with saline (36%) compared with sildenafil (93%, P < 0.05). Sildenafil attenuates ischemic cardiomyopathy in mice by limiting necrosis and apoptosis and by preserving left ventricular function possibly through a nitric oxide-dependent pathway.
authors.affiliation: Division of Cardiology, Department of Internal, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Fadi N
authors.initials: FN
authors.lastname: Salloum
authors.forename: Antonio
authors.initials: A
authors.lastname: Abbate
authors.forename: Anindita
authors.initials: A
authors.lastname: Das
authors.forename: Jon-Erik
authors.initials: JE
authors.lastname: Houser
authors.forename: Colin A
authors.initials: CA
authors.lastname: Mudrick
authors.forename: Ian Z
authors.initials: IZ
authors.lastname: Qureshi
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Hoke
authors.forename: Sion K
authors.initials: SK
authors.lastname: Roy
authors.forename: William R
authors.initials: WR
authors.lastname: Brown
authors.forename: Shashi
authors.initials: S
authors.lastname: Prabhakar
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Kukreja
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006332:Cardiomegaly / Q000209:etiology / Q000517:prevention & control; D002313:Cardiomyopathy, Restrictive / Q000188:drug therapy* / Q000503:physiopathology*; D003331:Coronary Vessels / Q000502:physiology; D015150:Echocardiography, Doppler; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D008026:Ligation; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009203:Myocardial Infarction / Q000188:drug therapy / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009336:Necrosis / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D010879:Piperazines / Q000627:therapeutic use*; D011654:Pulmonary Edema / Q000209:etiology / Q000517:prevention & control; D011687:Purines / Q000627:therapeutic use; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000627:therapeutic use*; D016019:Survival Analysis; D014665:Vasodilator Agents / Q000627:therapeutic use*; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019331:NG-Nitroarginine Methyl Ester