THE SCAVENGING OF HYDROXYL RADICAL ((OH)-O-CENTER-DOT) BY A PROSTACYCLIN ANALOG, TAPROSTENE

A possible mechanism by which prostacyclin (PGI(2)) analogues provide beneficial effects including improved survival in shock experimentally induced by endotoxin, polytrauma or hypovolemia was studied. Since se veral studies have implicated oxygen free radical-mediated tissue dama ge, we investigated whether PGI(2)-analogues exert their 'cytoprotecti ve' effects by inhibiting overproduction of oxygen free radicals. For this reason, the efficiency of Taprostene to scavenge hydroxyl radical s(.OH) and to possibly prevent the subsequent formation of reactive ox ygen species was studied. Competition experiments were performed in wh ich the .OH generated by H2O2/Fe2+ abstracted a hydrogen from Taproste ne (CG-4203) ene-6,9-epoxy-11,15-dihydroxy-15-cyclohexyl-16,17, 18,19, 20-pentanor-pros ta-5,13-dienoic acid sodium salt], and the resulting carbon-centered radical was trapped with the spin trap 3,3,5,5-tetrame thyl-1-pyrroline-N-oxide (M(4)PO). This spin trap reacted with .OH to yield an M(4)PO-OH spin adduct observable by Electron Paramagnetic Res onance (EPR) spectroscopy and resulted in the rate constant, k(2) = 1. 5 x 10(10) M(-1)s(-1), for the reaction between . OH and Taprostene. T he results show that Taprostene is an efficient .OH scavenger. In addi tion, reactions of hypochlorous ion ((-)OCL) with hydrogen peroxide (H 2O2) in the presence of Taprostene were monitored using the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) and M(4)PO dissolved in deuter ium oxide.