Nonpeptide endothelin antagonist. Cerebrovascular characterization and effects on delayed cerebral vasospasm.
OBJECTIVE
(+/-)-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.


METHODS
The effects of (+/-)-SB 209670 were evaluated in isolated segments of canine posterior cerebral arteries in vitro, vascular smooth muscle cells in culture, and in the canine two-hemorrhage model of delayed cerebral vasospasm in vivo.


RESULTS
In the canine basilar and anterior spinal arteries, (+/-)-SB 209670 caused a dose-related inhibition of contractile responses mediated by ET (KB = 4.6 nmol/L and apparent KB = 2.7 nmol/L, respectively). The effects of (+/-)-SB 209670 were mediated by inhibition of ETA receptors since the ETB selective agonist 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 smooth muscle cell culture. In the canine model of delayed cerebral vasospasm, animals received intracisternal vehicle (saline) or (+/-)-SB 209670 (360 +/- 10 micrograms/d) via osmotic minipump for 7 days. On day 7, the cross-sectional areas in the (+/-)-SB 209670 group were significantly greater than those in the vehicle group in both the basilar artery (68% versus 27%) and anterior spinal artery (78% versus 38%). No differences in blood pressure or heart rate were noted in the two groups, and the 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 via an interaction with ETA receptors. Furthermore, ETA receptor antagonists may represent a novel therapeutic approach to the treatment of subarachnoid hemorrhage.
SmithKline Beecham Pharmaceuticals, Department of Cardiovascular Pharmacology, King of Prussia, Pa 19406.
R N
RN
Willette
H
H
Zhang
M P
MP
Mitchell
C F
CF
Sauermelch
E H
EH
Ohlstein
A C
AC
Sulpizio
D000818:Animals; D001158:Arteries / Q000187:drug effects; D001488:Basilar Artery / Q000187:drug effects; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D008297:Male; D008934:Mitogens; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D013116:Spinal Cord / Q000098:blood supply; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000503:physiopathology*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007189:Indans; D008934:Mitogens; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-