The scavenging of hydroxyl radical(.OH) by a prostacyclin analogue, taprostene.

ABSTRACT

A possible mechanism by which prostacyclin (PGI2) analogues provide beneficial effects including improved survival in shock experimentally induced by endotoxin, polytrauma or hypovolemia was studied. Since several studies have implicated oxygen free radical-mediated tissue damage, we investigated whether PGI2-analogues exert their 'cytoprotective' effects by inhibiting overproduction of oxygen free radicals. For this reason, the efficiency of Taprostene to scavenge hydroxyl radicals (.OH) and to possibly prevent the subsequent formation of reactive oxygen species was studied. Competition experiments were performed in which the .OH generated by H2O2/Fe2+ abstracted a hydrogen from Taprostene (CG-4203) [5Z,13E, 9,11,15S)-2,3,4-trinor-1,5-inter-m-phenylene-6,9-epoxy-11,15-di hyd roxy-15-cyclohexyl-16,17,18,19,20-pentanor-prosta-5,13-dieno ic acid sodium salt], and the resulting carbon-centered radical was trapped with the spin trap 3,3,5,5-tetramethyl-1-pyrroline-N-oxide (M4PO). This spin trap reacted with .OH to yield an M4PO-OH spin adduct observable by Electron Paramagnetic Resonance (EPR) spectroscopy and resulted in the rate constant, k2 = 1.5 x 10(10) M-1s-1, for the reaction between .OH and Taprostene. The results show that Taprostene is an efficient .OH scavenger. In addition, reactions of hypochlorous ion (-OCL) with hydrogen peroxide (H2O2) in the presence of Taprostene were monitored using the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) and M4PO dissolved in deuterium oxide.