EFFECT OF TS-011, AN INHIBITOR OF THE SYNTHESIS OF 20-HETE, ON CEREBRAL BLOOD FLOW AFTER SUBARACHNOID HEMORRHAGE (SAH) IN RATS

This study examined the effects of TS-011 on the metabolism of arachidonic acid and the regional cerebral blood flow (rCBF) in rats. TS-011 selectively inhibited the formation of 20-hydroxy-eicosatetraenoic acid (20-HETE) in rat and human renal microsomes. The IC50 values averaged 9.2 nM, and 8.4 nM, respectively and it had no effect on the synthesis of epoxyeicosatrienoic acids. TS-011 also inhibited the formation of 20-HETE by human recombinant CYP4F2, CYP4F3A, CYP4F3B and CYP4A11 enzymes with IC50 values of 30.4, 42.6, 43.0 and 188 nM, respectively. In control rats, iCBF measured with laser-Doppler flowmetry fell by 30 % 10 mm. after induction of SAH by injecting of 0.3 ml of arterial blood into the cistema magna, and it remained at this level for 2 hr. Treatment with TS-011 (0.1 mg/kg) reduced the acute fall in rCBF after SAH by 40% and ICBF fully recovered to control within 2hr. These results indicate that TS-011 is a potent and selective inhibitor of the synthesis of 20-NETE and it reverses the acute fall in cerebral blood flow after SAH in rats.