Identification of a nitric oxide-dependent hypotensive effect of anticoagulation factor II from the venom of Agkistrodon acutus

Anticoagulation factor II (ACF II) isolated from the venom of Agkistrodon acutus is a member of the coagulation factor IX/coagulation factor X-binding protein (IX/X-bp) family. ACF II forms a 1:1 complex with activated coagulation factor X in a Ca2+-dependent fashion and thereby blocks the amplification of the coagulation cascade. In the present study, we have investigated the effect of ACF II on the mean arterial blood pressure (MABP) and heart rate (HR) in anaesthetized rats. The results indicate that ACF II induces a dose-dependent response in rats with a short fast drop of MABP followed by an increase and then a longer lasting slight decrease in MABP, but does not obviously affect HR. ACF II-induced hypotension is significantly blocked by the nitric oxide (NO) synthase inhibitor N-omega-l-arginine methyl ester (l-NAME). ACF II produces a concentration-dependent relaxation of rat aortic rings with functional-endothelium. The ACF II-induced vasodilatation is completely inhibited by removal of endothelium and significantly inhibited by pretreatment with l-NAME. These observations demonstrate that ACF II induces hypotension through an endothelium-dependent vasodilation, which is strongly mediated by the release of NO from endothelium. ACF II exhibits high anticoagulation activity in vivo based on activated partial thromboplastin time assay. Therefore, ACF II is so far identified as the first unique bifunctional protein in the IX/X-bp family that has both anticoagulant and hypotensive effects on the blood of rats through different pathways.

Anticoagulation factor II (ACF II) not only binds with FXa to prolong the clotting time, but also induces hypotension in rats through an endothelium-dependent vasodilation.Figure optionsDownload as PowerPoint slide