Enhancement by defibrotide of prostanoid neosynthesis from arachidonic acid: an adenosine receptor-mediated effect?

The antithrombotic and anti-ischemic drug defibrotide is known to enhance PGI2 and prostaglandin E2 release and to interact competitively and agonistically with adenosine A1 and A2 receptors. To elucidate a possible molecular mechanism of action of this drug, we measured prostanoid neosynthesis from exogenous AA in isolated, intraluminally perfused RbA (5 to 10 preparations/group). Defibrotide (30 micrograms/ml) almost doubled the conversion rate of AA (15 micrograms) into PGI2-la (quantitated by a bioassay system): 56.8 +/- 5.3 versus 32.9 +/- 7.8 ng, compared with controls. The adenosine receptor antagonist 8-PT, at concentrations of 0.625, 1, and 1.6 micrograms/ml, dose-dependently and up to 100% inhibited the effect of defibrotide; however, a higher concentration of this latter (100 micrograms/ml) shifted to the right the 8-PT inhibition curve. A second AA bolus given into RbA caused homologous desensitization: 43 and 62% reduction of AA conversion after two versus one bolus was observed in controls receiving 15 and 30 micrograms AA. This phenomenon was inhibited by 30 micrograms/ml defibrotide (32% reduction only at two boluses, instead of 62% displayed by comparable controls), but this effect was abolished by 1.6 micrograms/ml 8-PT; once again, 100 micrograms/ml defibrotide overcame the antagonism by 8-PT. We conclude that defibrotide enhances prostanoid neosynthesis from AA and reduces homologous desensitization of the cyclooxygenase pathway through a mechanism possibly linked to stimulation of adenosine receptors.