Defibrotide mediated inhibition of serotonin, endothelin-I, thromboxane, and serum induced contraction of canine femoral and pulmonary arterial rings.

Defibrotide is a polydeoxyribonucleotide derived agent with a weight average of 15 to 18 kDa. By virtue of its chemical nature, this polyelectrolyte agent exerts multiple pharmacologic actions at various plasmatic and cellular sites. In recent studies, this agent has been demonstrated to exhibit cardioprotective and vasomodulatory actions. To test the effect of defibrotide on the vascular smooth muscle contractile responses, its effects were evaluated on contractile response induced by agonists in canine femoral and pulmonary arterial smooth muscle preparation. These arterial preparations were harvested from anesthetized and anticoagulated (Heparinized 3-5 U/ml) dogs. Defibrotide was administered to dogs at 10 mg/kg, i.v. and segments of canine arteries were harvested at 30 minutes after the administration of this agent. The control and defibrotide treated canine arterial ring preparations were tested against serotonin, endothelin-I, serum and control platelet rich plasma(PRP) with arachidonic acid(AA). The contractile response of arterial rings obtained for treated groups were measured using serotonin, endothelin-I, serum and PRP/AA as agonists. The contractile action of serotonin, endothelin-I, serum and PRP/AA were inhibited by pretreatment of the animal with defibrotide. The arterial ring isolated from dogs treated with defibrotide exhibited a weaker contraction. These studies support the hypothesis that defibrotide modulates endothelial function and the response to the contractile actions of various agonists may be related to this effect.