1-3-dihydroxy-4-4-5-5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole and Thrombosis

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.. 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.. 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.

Topics: Adenosine Diphosphate; Amino Acids; Animals; Aspirin; Benzoates; Blood Pressure; Clopidogrel; Collagen; Cyclooxygenase Inhibitors; Drug Evaluation; Drug Therapy, Combination; Fibrinolytic Agents; Free Radical Scavengers; Guanylate Cyclase; Heart Rate; Hemorheology; Imidazoles; Membrane Proteins; Nitric Oxide; Nitric Oxide Donors; Nitroso Compounds; Oxadiazoles; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Quinoxalines; Random Allocation; Receptors, Purinergic P2Y12; rhoA GTP-Binding Protein; Sus scrofa; Thrombosis; Ticlopidine