Antithrombotic effect of beta,beta'-monochloromethylene diadenosine 5',5"'-P1,P4-tetraphosphate

Abstract

The feasibility of using beta,beta'-monochloromethylene diadenosine 5',5"'-P1,P4-tetraphosphate (AppCHCl-ppA) as an antithrombotic agent was studied in a rabbit intracarotid cannula thrombosis model previously shown to be sensitive to antiplatelet agents. This analogue, having a P-C-P bridge in place of a P-O-P internucleoside linkage, has been found resistant to phosphodiesterase activity. Rabbits were infused with the dinucleotide at a dose of 50 mg per kg over a 2-hr period, at a controlled rate by pump. A 1-cm length of polyethylene cannula (1 mm i.d.) was tied into the carotid artery. Animals were stable under general anesthesia during the entire period of the experiment. In the control group, 16 of 20 animals formed clots, an incidence of 80%, whereas in the test animals, 6 of the 20 formed clots (30% incidence, P < 0.05). After preincubation of whole blood with 50 microM AppCHClppA at 37 degrees C for up to 3 hr, a consistent suppression of ADP-induced platelet aggregation was observed. The present study suggests that AppCHClppA may be useful as an antithrombotic agent in certain clinical situations, such as hemodialysis, arteriovenous shunts, and introduction of artificial heart valves. It may also possibly prevent extension of recent clots. The toxicity and metabolism of AppCHClppA have, however, yet to be explored.