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

OBJECTIVES We sought to evaluate the ability of type 5 phosphodiesterase (P DE5) inhibitors to augment the antithrombotic effects of inhaled nitric oxi de (NO) in a canine model of platelet-mediated coronary thrombosis after th rombolysis. BACKGROUND Type 5 phosphodiesterase inhibitors potentiate the ability of NO to inhibit platelet aggregation in vitro by preventing platelet cyclic gua nosine monophosphate catabolism. We previously reported that breathing low concentrations of NO gas attenuated, but did not prevent, cyclic flow reduc tions (CFRs) in a canine model of coronary thrombosis after thrombolysis. METHODS Cyclic flow reductions were induced after creation of a left anteri or descending coronary artery stenosis, endothelial injury, thrombus format ion 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 ac hieved 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 frequ ency of CFRs was unaffected by NO, dipyridamole or zaprinast alone. Systemi c arterial blood pressure and bleeding time were unchanged with any treatme nt. Ex vivo thrombin-induced platelet aggregation in dogs breathing NO and receiving dipyidamole was reduced by 75 +/- 7% (p < 0.05). CONCLUSIONS The PDE5 inhibitors potentiated the antithrombotic properties o f inhaled NO in a canine model of platelet-mediated coronary artery thrombo sis after thrombolysis, without prolonging the bleeding time or causing sys temic hypotension. (J Am Coll Cardiol 2001;37:1981-8) (C) 2001 by the Ameri can College of Cardiology.