Sildenafil improves coronary artery patency in a canine model of platelet-mediated cyclic coronary occlusion after thrombolysis.
OBJECTIVE
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 microg/kg bolus followed by 4 microg/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 > or =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.
Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Gregory D
GD
Lewis
Christian
C
Witzke
Pedro
P
Colon-Hernandez
J Luis
JL
Guerrero
Kenneth D
KD
Bloch
Marc J
MJ
Semigran
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000097:blood / Q000503:physiopathology*; D003331:Coronary Vessels / Q000187:drug effects*; D004285:Dogs; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology; D010507:Periodicity; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D014654:Vascular Patency / Q000187:drug effects*
D005343:Fibrinolytic Agents; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D006493:Heparin; D000068677:Sildenafil Citrate; D010959:Tissue Plasminogen Activator; D001241:Aspirin