NONPEPTIDE ENDOTHELIN ANTAGONIST - CEREBROVASCULAR CHARACTERIZATION AND EFFECTS ON DELAYED CEREBRAL VASOSPASM

Background and Purpose (+/-)-SB 209670, a potent nonpeptide endothelin (ET) receptor antagonist, was used to investigate the potential role of ET in cerebral vasospasm associated with subarachnoid hemorrhage. M ethods The effects of (+/-)-SB 209670 were evaluated in isolated segme nts of canine posterior cerebral arteries in vitro, vascular smooth mu scle cells in culture, and in the canine two-hemorrhage model of delay ed cerebral vasospasm in vivo. Results In the canine basilar and anter ior spinal arteries, (+/-)-SB 209670 caused a dose-related inhibition of contractile responses mediated by ET (K-B = 4.6 nmol/L and apparent K-B = 2.7 nmol/L, respectively). The effects of (+/-)-SB 209670 were mediated by inhibition of ETA receptors since the ETB selective agonis t sarafotoxin 6c did not contract these posterior cerebral vessels. (/-)-SB 209670 also produced a concentration-dependent inhibition (IC50 = 1 nmol/L) of the mitogenic response induced by ET-1 in vascular smo oth muscle cell culture. In the canine model of delayed cerebral vasos pasm, animals received intracisternal vehicle (saline) or (+/-)-SB 209 670 (360+/-10 mu g/d) via osmotic minipump for 7 days. On day 7, the c ross-sectional areas in the (+/-)-SB 209670 group were significantly g reater than those in the vehicle group in both the basilar artery (68% versus 27%) and anterior spinal artery (78% versus 38%). No differenc es in blood pressure or heart rate were noted in the two groups, and t he vasospasm in the vehicle group did not differ from that of historic controls in this model. Conclusions The results suggest that ET plays a significant role in the development of delayed cerebral vasospasm v ia an interaction with ETA receptors. Furthermore, ETA receptor antago nists may represent a novel therapeutic approach to the treatment of s ubarachnoid hemorrhage.