[Prevention of cerebral vasospasms after experimental subarachnoid hemorrhage by the endothelin receptor antagonist RO 47-0203].

Endothelins have attracted scientific interest because of their extremely potent and long lasting vasoconstrictive effects, similar to cerebral vasospasm in man. In this study the efficacy of the orally active endothelin-receptor-antagonist RO 47-0203 for prevention and treatment of cerebral vasospasm after experimental subarachnoid hemorrhage (SAH), using the canine two-hemorrhage model, was investigated. In the preventive study 28 beagle dogs were used. Fourteen animals each were assigned to the treatment and to the control group. 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 at day one to 1.19 +/- 0.23 mm at day eight in the treatment group while in the control group the vessel diameter decreased from 1.48 +/- 0.19 mm at day one to 1.02 +/- 0.22 mm at day eight. 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). In the therapeutic study the intraarterial infusion of 15.0 mg/kg RO 47-0203, at day 8 after experimental subarachnoid hemorrhage, caused no significant increase of the vessel diameter after 10 min., 20 min. or 30 min. These results underline the important role of endothelin in the development of cerebral vasospasm, and give for the first time evidence that prevention of cerebral vasospasm can be achieved by the endothelin-receptor-antagonist RO 47-0203.