Systemic administration of the endothelin-A receptor antagonist TBC 11251 attenuates cerebral vasospasm after experimental subarachnoid hemorrhage: dose study and review of endothelin-based therapies in the literature on cerebral vasospasm.
OBJECTIVE
Increasing evidence implicates endothelin (ET)-1 in the pathophysiological development of cerebral vasospasm. This study examined the ability of TBC 11251 (TBC), a new ETA receptor antagonist, to prevent vasospasm in a rabbit model of subarachnoid hemorrhage (SAH).


METHODS
Eighty-five New Zealand White rabbits were assigned to 1 of 10 groups. SAH was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: 1) control (no SAH), 2) SAH alone, 3) SAH plus vehicle every 12 hours (BID), 4) SAH plus 5 mg/kg TBC BID, 5) SAH plus 10 mg/kg TBC BID, 6) SAH plus 20 mg/kg TBC BID, 7) SAH plus vehicle at 24 and 36 hours after SAH (24/36), 8) SAH plus 5 mg/kg TBC 24/36, 9) SAH plus 10 mg/kg TBC 24/36, and 10) SAH plus 20 mg/kg TBC 24/36. Animals were killed 48 hours after SAH, by perfusion-fixation, and then basilar arteries were histologically prepared and their cross-sectional areas were measured.


RESULTS
The mean basilar artery cross-sectional area was constricted from 0.332 mm2 in the control group to 0.131 mm2 in the SAH alone group, 0.132 in the vehicle 24/36 group, and 0.125 in the vehicle BID group. All groups treated with TBC showed an increase in cross-sectional luminal basilar artery area, relative to the vehicle-treated groups. The 5 mg/kg TBC BID group exhibited a mean basilar artery area of 0.217 mm2, and the 10 mg/kg TBC BID group showed a mean basilar artery area of 0.240 mm2; both groups were statistically improved, compared with the vehicle-treated groups (P < 0.05). No side effects were seen, and there were no differences in the mean arterial pressures between drug- and vehicle-treated groups.


CONCLUSIONS
These findings demonstrate that systemic administration of the ETA receptor antagonist TBC significantly attenuates cerebral vasospasm after SAH, thus providing additional support for the role of ET-1 in vasospasm.
Wanebo
J E
JE
Department of Neurosurgery, National Naval Medical Center, Bethesda, Maryland, USA.
Arthur
A S
AS
Louis
H G
HG
West
K
K
Kassell
N F
NF
Lee
K S
KS
Helm
G A
GA
D000818:Animals; D001488:Basilar Artery / Q000473:pathology; D020013:Calcium Signaling / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D007262:Infusions, Intravenous; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D007555:Isoxazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D011817:Rabbits; D044022:Receptor, Endothelin A; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D013876:Thiophenes / Q000008:administration & dosage / Q000627:therapeutic use*
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007555:Isoxazoles; D044022:Receptor, Endothelin A; D013876:Thiophenes; C106276:sitaxsentan