The role of endothelin in experimental cerebral vasospasm.
Endothelin (ET) may play a role in vasospasm after subarachnoid hemorrhage (SAH). The aim of our study was to test whether the systemic administration of bosentan, a nonpeptidic ET(A) and ETB receptor antagonist, could reverse vasospasm without inducing hypotension. In rabbits (single-hemorrhage model) and in dogs (double-hemorrhage model), SAH was induced; after vasospasm was established, the animals received intravenously either saline or a 30 mg/kg bolus of bosentan. The cross-sectional area of the basilar artery was analyzed by quantitative angiography. In rabbits (n = 13), bosentan reversed basilar vasospasm to the same extent as did an intravertebral injection of sodium nitroprusside. In dogs (n = 10), bosentan reversed only 52 +/- 10% of the vasospasm reversible by papaverine. Bosentan did not alter the heart rate or the arterial blood pressure in either the rabbits or the dogs. In the cerebrospinal fluid, SAH increased endothelin-1 (ET1) and big ET1 by 6 and 3.8 times, respectively; in the basilar artery, SAH increased ET1 concentration, big ET1 concentration, and ET-converting enzyme activity by 1.3, 2, and 2.7 times, respectively. In addition, a local involvement of ET was also suggested by the relaxing effect of bosentan on basilar artery rings from rabbits with SAH and not from control rabbits. Receptor binding studies performed on dog basilar arteries revealed a shift in the phenotype expression of ET receptors from the A to the B type after SAH. We conclude that ET plays a major role in SAH and that systemic ET blockade might selectively dilate spastic arteries.
Roux
S
S
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Löffler
B M
BM
Gray
G A
GA
Sprecher
U
U
Clozel
M
M
Clozel
J P
JP
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D000077300:Bosentan; D002533:Cerebral Angiography; D004195:Disease Models, Animal; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000097:blood*; D066298:In Vitro Techniques; D002546:Ischemic Attack, Transient / Q000000981:diagnostic imaging / Q000503:physiopathology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D011817:Rabbits; D017466:Receptors, Endothelin / Q000187:drug effects / Q000378:metabolism; D013345:Subarachnoid Hemorrhage / Q000000981:diagnostic imaging / Q000503:physiopathology*; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D017466:Receptors, Endothelin; D013449:Sulfonamides; D000077300:Bosentan