title: Cessation of platelet-mediated cyclic canine coronary occlusion after thrombolysis by combining nitric oxide inhalation with phosphodiesterase-5 inhibition.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Anesthesia and Critical Care, Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
authors.forename: U
authors.initials: U
authors.lastname: Schmidt
authors.forename: R O
authors.initials: RO
authors.lastname: Han
authors.forename: T G
authors.initials: TG
authors.lastname: DiSalvo
authors.forename: J L
authors.initials: JL
authors.lastname: Guerrero
authors.forename: H K
authors.initials: HK
authors.lastname: Gold
authors.forename: W M
authors.initials: WM
authors.lastname: Zapol
authors.forename: K D
authors.initials: KD
authors.lastname: Bloch
authors.forename: M J
authors.initials: MJ
authors.lastname: Semigran
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001792:Blood Platelets; D003328:Coronary Thrombosis / Q000188:drug therapy*; D004176:Dipyridamole / Q000627:therapeutic use*; D004285:Dogs; D004359:Drug Therapy, Combination; D009569:Nitric Oxide / Q000008:administration & dosage*; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D011688:Purinones / Q000627:therapeutic use*; D015912:Thrombolytic Therapy
chemical_list: D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D009569:Nitric Oxide; D004176:Dipyridamole; C011145:zaprinast