Antithrombotic Properties of a Novel Sydnonimine Derivative

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Abstract
Summary: Platelets are a main target for endogenous and exogenous nitric oxide (NO). The sydnonimine derivative C 89-4095 slowly consumed oxygen in aqueous solution as a measure of oxidative NO release. The antiplatelet properties of the compound were evaluated in vitro and in vivo. In human platelet-rich plasma, C 89-4095 inhibited aggregation induced by various agonists (IC50 of 2 to 7 μM); the effect was abolished by oxyhemoglobin. The concentration-response curve of prostacyclin was shifted to the left by a threshold concentration of C 89-4095. In rats, caval vein thrombosis, induced by insertion of a stainless steel wire coil, was significantly reduced by oral C 89-4095 for at least 4 h. In dogs and pigs, severe stenosis of a coronary artery resulted in cyclical blood flow reductions caused by repeated formation of platelet thrombi. C 89-4095 significantly reduced cyclical flow reductions; oxyhemoglobin abolished this effect. The data indicate that (a) C 89-4095 exerts antithrombotic properties in vivo due to the inhibition of platelet function, (b) these effects are NO-dependent, and (c) NO donors may be of therapeutic value as antithrombotics.

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