Cessation of platelet-mediated cyclic canine coronary occlusion after thrombolysis by combining nitric oxide inhalation with phosphodiesterase-5 inhibition.

Schmidt U, Han RO, DiSalvo TG, Guerrero JL, Gold HK, Zapol WM, Bloch KD, Semigran MJ
J Am Coll Cardiol. 2001 37 (7): 1981-8

PMID: 11401142 · DOI:10.1016/s0735-1097(01)01270-0

OBJECTIVES - We sought to evaluate the ability of type 5 phosphodiesterase (PDE5) inhibitors to augment the antithrombotic effects of inhaled nitric oxide (NO) in a canine model of platelet-mediated coronary thrombosis after thrombolysis.

BACKGROUND - Type 5 phosphodiesterase inhibitors potentiate the ability of NO to inhibit platelet aggregation in vitro by preventing platelet cyclic guanosine monophosphate catabolism. We previously reported that breathing low concentrations of NO gas attenuated, but did not prevent, cyclic flow reductions (CFRs) in a canine model of coronary thrombosis after thrombolysis.

METHODS - Cyclic flow reductions were induced after creation of a left anterior descending coronary artery stenosis, endothelial injury, thrombus formation and thrombolysis. Dogs were either untreated or treated with inhaled NO (20 ppm by volume), intravenous zaprinast, intravenous dipyridamole or the combination of inhaled NO with either PDE5 inhibitor (n = 4 per group).

RESULTS - Cyclic flow reductions ceased, and complete coronary patency was achieved in all dogs after they breathed NO combined with zaprinast (by 12.0+/-4.7 min [mean +/- SEM]) or dipyridamole (by 9.8+/-4.7 min). The frequency of CFRs was unaffected by NO, dipyridamole or zaprinast alone. Systemic arterial blood pressure and bleeding time were unchanged with any treatment. Ex vivo thrombin-induced platelet aggregation in dogs breathing NO and receiving dipyridamole was reduced by 75+/-7% (p < 0.05).

CONCLUSIONS - The PDE5 inhibitors potentiated the antithrombotic properties of inhaled NO in a canine model of platelet-mediated coronary artery thrombosis after thrombolysis, without prolonging the bleeding time or causing systemic hypotension.

MeSH Terms (11)

Administration, Inhalation Animals Blood Platelets Coronary Thrombosis Dipyridamole Dogs Drug Therapy, Combination Nitric Oxide Phosphodiesterase Inhibitors Purinones Thrombolytic Therapy

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