Prevention of Cerebral Vasospasm after Experimental Subarachnoid Hemorrhage by RO 47-0203, a Newly Developed Orally Active Endothelin Receptor Antagonist

Abstract

SINCE THEIR DISCOVERY in 1988, endothelins have attracted scientific interest because of their extremely potent and long-lasting vasoconstrictive effects, similar to cerebral vasospasm in humans. In this study, the efficacy of the orally active endothelin receptor antagonist RO 47-0203 for prevention of cerebral vasospasm after experimental subarachnoid hemorrhage, using the two-hemorrhage dog model, was investigated. Twenty-eight beagle dogs were used in this laboratory experiment. Fourteen animals each were assigned to the treatment and control groups. In the treatment group, each dog received two single doses of 30 mg/kg RO 47-0203 orally per day. The diameter of the basilar artery decreased 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 decreased from 1.48 ± 0.19 mm on Day 1 to 1.02 ± 0.22 mm on Day 8. These 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 endothelin-1 in cerebrospinal fluid significantly increased with time after subarachnoid hemorrhage. These results emph asize the important role of endothelin in the development of cerebral vasospasm and present first-time evidence that prevention of cerebral vasospasm can be achieved by the endothelin receptor antagonist RO 47-0203.