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EXPERIMENTAL STUDY

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

^a Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
^b Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
^c Cardiovascular Research Center of the Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

Manuscript received January 13, 2000; revised manuscript received February 20, 2001, accepted February 26, 2001.

Reprint requests and correspondence: Dr. Marc J. Semigran, Bigelow 626, Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02114
semigran.marc{at}mgh.harvard.edu

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.

Abbreviations and Acronyms   ANOVA = analysis of variance   cAMP = adenosine 3':5'-cyclic phosphate   CAPR = coronary artery patency ratio   CFR = cyclic flow reduction   cGMP = cyclic guanosine monophosphate   GP = glycoprotein   LAD = left anterior descending coronary artery   MI = myocardial infarction   NO = nitric oxide   PDE5 = type 5 phosphodiesterase   SNP = sodium nitroprusside   t-PA = tissue plasminogen activator

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