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PRECLINICAL STUDIES

Sildenafil Improves Coronary Artery Patency in a Canine Model of Platelet-Mediated Cyclic Coronary Occlusion After Thrombolysis

Gregory D. Lewis, MD^_*, Christian Witzke, MD^_*, Pedro Colon-Hernandez, MD^_*, J. Luis Guerrero^_*, Kenneth D. Bloch, MD^_*, and Marc J. Semigran, MD^_*,_*

^_* Cardiology Division
Cardiovascular Research Center of the Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

Manuscript received July 6, 2005; revised manuscript received November 3, 2005, accepted November 21, 2005.

^_* Reprint requests and correspondence: Dr. Marc J. Semigran, Cardiology Division, Bigelow 800, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114 (Email: msemigran{at}partners.org).

OBJECTIVES: We sought to assess the effect of sildenafil, a highly-specific type 5 phosphodiesterase (PDE5) inhibitor, on platelet-mediated cyclic coronary flow reductions occurring in a canine model of coronary thrombosis despite aspirin therapy.

BACKGROUND: The PDE5 inhibitors augment the antithrombotic effects of nitric oxide in vitro and in vivo, but it has been proposed that the PDE5 inhibitor sildenafil is prothrombotic.

METHODS: Cyclic coronary flow reductions were induced in the left anterior descending coronary artery by creation of a stenosis, endothelial injury, and thrombus formation followed by treatment with aspirin, heparin, and tissue plasminogen activator. After an initial observation period, dogs were treated with or without sildenafil (100 µg/kg bolus followed by 4 µg/kg/min infusion).

RESULTS: Cyclic coronary flow reductions ceased in five of six animals 18 ± 5 min after initiation of sildenafil but continued in all six control animals. The portion of the observation period during which the coronary artery was patent increased from 52 ± 9% to 83 ± 5% after sildenafil administration (p = 0.008) but did not differ between the first and second observation periods in untreated dogs (49 ± 11% vs. 44 ± 11%, respectively). Among animals with plasma-free sildenafil levels 20 nmol/l, cyclic coronary flow reductions were 73 ± 12% less frequent and the time to cessation of cycling 72 ± 14% shorter than in animals with levels <20 nmol/l (p < 0.05 for both). Sildenafil transiently decreased blood pressure 7 ± 1% but did not change heart rate. Sildenafil treatment reduced ex vivo thrombin-induced platelet aggregation by 39 ± 3% (p < 0.005).

CONCLUSIONS: Sildenafil improves coronary patency in a canine model of platelet-mediated coronary artery thrombosis, likely via inhibition of platelet aggregation.

Abbreviations and Acronyms   ACS = acute coronary syndromes   CAPR = coronary artery patency ratio   CFR = cyclic coronary flow reductions   cGMP = cyclic guanosine monophosphate   GP = glycoprotein   LAD = left anterior descending coronary artery   MAP = mean systemic arterial blood pressure   NO = nitric oxide   PDE5 = type 5 phosphodiesterase

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