PREVENTION OF CEREBRAL VASOSPASM AFTER EXPERIMENTAL SUBARACHNOID HEMORRHAGE BY RO-47-0203, A NEWLY DEVELOPED ORALLY-ACTIVE ENDOTHELIN RECEPTOR ANTAGONIST

SINCE THEIR DISCOVERY in 1988, endothelins have attracted scientific i nterest because of their extremely potent and long-lasting vasoconstri ctive effects, similar to cerebral vasospasm in humans. In this study, the efficacy of the orally active endothelin receptor antagonist RO 4 7-0203 for prevention of cerebral vasospasm after experimental subarac hnoid hemorrhage, using the two-hemorrhage dog model, was investigated . Twenty-eight beagle dogs were used in this laboratory experiment. Fo urteen animals each were assigned to the treatment and control groups. In the treatment group, each dog received two single doses of 30 mg/k g RO 47-0203 orally per day. The diameter of the basilar artery decrea sed from 1.36 +/- 0.17 mm on Day 1 to 1.19 +/- 0.23 mm on Day 8 in the treatment group, whereas in the control group, the vessel diameter de creased from 1.48 +/- 0.19 mm on Day 1 to 1.02 +/- 0.22 mm on Day 8. T hese results corresponded to a decrease of vessel diameter of 13.1% +/ - 11.2% in the treatment group and a decrease of vessel diameter of 30 .7% +/- 12.4% in the control group (P < 0.001). Concentrations of endo thelin-l in cerebrospinal fluid significantly increased with time afte r subarachnoid hemorrhage. These results emphasize the important role of endothelin in the development of cerebral vasospasm and present fir st-time evidence that prevention of cerebral vasospasm can be achieved by the endothelin receptor antagonist RO 47-0203.