SYSTEMIC ADMINISTRATION OF THE ENDOTHELIN-A RECEPTOR ANTAGONIST TBC-11251 ATTENUATES CEREBRAL VASOSPASM AFTER EXPERIMENTAL SUBARACHNOID HEMORRHAGE - DOSE STUDY AND REVIEW OF ENDOTHELIN-BASED THERAPIES IN THE LITERATURE ON CEREBRAL VASOSPASM

OBJECTIVE: Increasing evidence implicates endothelin (ET)-1 in the pat hophysiological development of cerebral vasospasm. This study examined the ability of TBC 11251 (TBC), a new ETA receptor antagonist, to pre vent vasospasm in a rabbit model of subarachnoid hemorrhage (SAH). MET HODS: Eighty-five New Zealand White rabbits were assigned to 1 of 10 g roups. SAH was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: 1) control (no SAH), 2) SAH alone, 3) SAH plus vehicle every 12 hours (BID), 4) SAH plus 5 mg/ kg TBC BID, 5) SAH plus 10 mg/kg TBC BID, 6) SAH plus 20 mg/kg TBC BID , 7) SAH plus vehicle at 24 and 36 hours after SAH (24/36), 8) SAH plu s 5 mg/kg TBC 24/36, 9) SAH plus 10 mg/kg TBC 24/36, and 10) SAH plus 20 mg/kg TBC 24/36. Animals were killed 48 hours after SAH, by perfusi on-fixation, and then basilar arteries were histologically prepared an d their cross-sectional areas were measured. RESULTS: The mean basilar artery cross-sectional area was constricted from 0.332 mm(2) in the c ontrol group to 0.131 mm2 in the SAH alone group, 0.132 in the vehicle 24/36 group, and 0.125 in the vehicle BID group. All groups treated w ith TBC showed an increase in cross-sectional luminal basilar artery a rea, relative to the vehicle-treated groups. The 5 mg/kg TBC BID group exhibited a mean basilar artery area of 0.217 mm(2), and the 10 mg/kg TBC BID group showed a mean basilar artery area of 0.240 mm(2); both groups were statistically improved, compared with the vehicle-treated groups (P < 0.05). No side effects were seen, and there were no differ ences in the mean arterial pressures between drug- and vehicle-treated groups. CONCLUSION: These findings demonstrate that systemic administ ration of the ETA receptor antagonist TBC significantly attenuates cer ebral vasospasm after SAH, thus providing additional support for the r ole of ET-1 in vasospasm.