oxadiazoles and Thrombosis

Sphingosine-1-phosphate receptor (S1PR) modulators provide protection in preclinical and clinical studies for ischemic stroke, but the influences of S1PR modulation on microvascular thrombosis remain poorly understood. This study investigates the impact of a selective S1PR1 modulator RP101075 on microvascular circulation in a mouse model of laser-induced thrombosis. The flow velocity of cortical arterioles in mice was measured

Topics: Animals; Cerebrovascular Circulation; Cerebrovascular Disorders; Indans; Male; Mice; Mice, Inbred C57BL; Microcirculation; Oxadiazoles; Sphingosine 1 Phosphate Receptor Modulators; Thrombosis

Amarogentin, an active principle of Gentiana lutea, possess antitumorigenic, antidiabetic, and antioxidative properties. Activation of platelets is associated with intravascular thrombosis and cardiovascular diseases. The present study examined the effects of amarogentin on platelet activation. Amarogentin treatment (15~60  μM) inhibited platelet aggregation induced by collagen, but not thrombin, arachidonic acid, and U46619. Amarogentin inhibited collagen-induced phosphorylation of phospholipase C (PLC) γ2, protein kinase C (PKC), and mitogen-activated protein kinases (MAPKs). It also inhibits in vivo thrombus formation in mice. In addition, neither the guanylate cyclase inhibitor ODQ nor the adenylate cyclase inhibitor SQ22536 affected the amarogentin-mediated inhibition of platelet aggregation, which suggests that amarogentin does not regulate the levels of cyclic AMP and cyclic GMP. In conclusion, amarogentin prevents platelet activation through the inhibition of PLC γ2-PKC cascade and MAPK pathway. Our findings suggest that amarogentin may offer therapeutic potential for preventing or treating thromboembolic disorders.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenine; Adenosine Triphosphate; Animals; Arachidonic Acid; Collagen; Cyclic GMP; Guanylate Cyclase; Humans; Iridoids; MAP Kinase Signaling System; Mice; Oxadiazoles; Phospholipase C gamma; Plant Extracts; Platelet Activation; Protein Kinase C; Quinoxalines; Thrombin; Thromboembolism; 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