Effects of a novel platelet nitric oxide donor (LA816), aspirin, clopidogrel, and combined therapy in inhibiting flow- and lesion-dependent thrombosis in the porcine ex vivo model.
BACKGROUND
Acetylsalicylic acid (ASA), or aspirin, plus clopidogrel is becoming the standard antithrombotic treatment in people with coronary disease. Novel approaches such as the use of platelet-selective nitric oxide (NO) donors may provide additional protection against thrombosis. We evaluated the antithrombotic properties of a novel platelet-selective NO donor (LA816) administered alone and in combination with ASA, clopidogrel, or ASA+clopidogrel.


RESULTS
Thrombogenicity was measured in the porcine experimental model and assessed as platelet-thrombus formation in the ex vivo Badimon perfusion chamber. Pigs were randomly divided into 4 groups: (1) placebo control, (2) clopidogrel, (3) ASA, and (4) ASA+clopidogrel (ASA and clopidogrel were given orally, 10 mg x kg(-1) x d(-1) for 3 d). The animals were anesthetized, heparinized, and catheterized, and the Badimon perfusion chamber was placed in an extracorporeal shunt. After baseline perfusions, all animal groups received the intravenous infusion of LA816 for 2 hours. Platelet aggregation, blood pressure, and heart rate also were evaluated during the experiments. LA816, clopidogrel, and ASA+clopidogrel produced a reduction of approximately 45% on thrombus mass versus placebo control perfusions (P<0.05). Combined treatment of oral ASA+clopidogrel and intravenous LA816 produced a significant further reduction of 25% in platelet deposition (70% from placebo controls; P<0.0001). LA816 intravenous treatment did not modify blood pressure or heart rate.


CONCLUSIONS
Acute NO donation with LA816, without modifying hemodynamic parameters, provides the same inhibitory effect as that obtained with chronic treatment with clopidogrel+ASA. Moreover, LA816 provides platelet inhibitory effects in addition to those of the combined blockade of cyclooxygenase and P2y(12) receptor.
Vilahur
Gemma
G
Cardiovascular Research Center, Institut Català de Ciències Cardiovasculars-Consejo Superior de Investigaciones Científicas, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
Segalés
E
E
Salas
E
E
Badimon
L
L
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000596:Amino Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001241:Aspirin / Q000008:administration & dosage / Q000627:therapeutic use*; D001565:Benzoates / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D000077144:Clopidogrel; D003094:Collagen / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D004341:Drug Evaluation; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006339:Heart Rate / Q000187:drug effects; D018056:Hemorheology; D007093:Imidazoles / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000627:therapeutic use*; D009603:Nitroso Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D010069:Oxadiazoles / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D058919:Purinergic P2 Receptor Antagonists; D011810:Quinoxalines / Q000494:pharmacology; D011897:Random Allocation; D058925:Receptors, Purinergic P2Y12; D034421:Sus scrofa; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D020742:rhoA GTP-Binding Protein / Q000097:blood
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000596:Amino Acids; D001565:Benzoates; D016861:Cyclooxygenase Inhibitors; D005343:Fibrinolytic Agents; D016166:Free Radical Scavengers; D007093:Imidazoles; C500603:LA 816; D008565:Membrane Proteins; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D010069:Oxadiazoles; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D011810:Quinoxalines; D058925:Receptors, Purinergic P2Y12; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; D009569:Nitric Oxide; D000244:Adenosine Diphosphate; D003094:Collagen; D000077144:Clopidogrel; D020742:rhoA GTP-Binding Protein; D006162:Guanylate Cyclase; D013988:Ticlopidine; D001241:Aspirin