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PRECLINICAL STUDY

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, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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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