PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND TRIAL OF BQ-123 AND BOSENTAN FOR PREVENTION OF VASOSPASM FOLLOWING SUBARACHNOID HEMORRHAGE IN MONKEYS

Thirty-one monkeys were randomly divided into three groups to undergo baseline cerebral angiography followed by induction of subarachnoid he morrhage by placement of autologous blood clot along the right-sided a rteries of the anterior circle of Willis (Day 0). The monkeys were the n given drug vehicle or one of two endothelin (ET) antagonists, BQ-123 (6 mg/kg/day) or bosentan (5 mg/kg/day) intracisternally. The BQ-123 was administered by continuous infusion from a subcutaneous pump and t he bosentan was given by twice-daily injections into an Ommaya reservo ir in the subcutaneous space with a catheter along the right middle ce rebral artery (MCA). Seven days later (Day 7), angiography was repeate d and the animals were killed. Comparison of arterial diameters shown on angiograms between Day 0 and Day 7 groups given placebo and bosenta n showed significant reductions in the diameters of the right intradur al internal carotid (28% +/- 6% and 30% +/- 6%, respectively, paired t -test, p < 0.05), anterior cerebral artery (29% +/- 8% and 32%, +/- 6% respectively +/- 6%, respectively) and MCA (34% +/- 6% and 46% +/- 4% , respectively). Animals injected with BQ-123 had significant narrowin g of the right extradural internal carotid artery (7% +/- 6%) and the basilar artery (11% +/- 3%), but not of the right MCA. Comparison of a rterial diameters between groups at Day 7 showed significant variance in the right extradural internal carotid, both intradural internal car otid, right middle cerebral, and left anterior cerebral arteries; the animals injected with BQ-123 developed significantly less arterial nar rowing these those receiving bosentan and placebo. Bosentan was not de tected in the cerebrospinal fluid aspirated from the cisterna magna on Day 7, whereas BQ-123 was detected in two animals. We can infer from these results that BQ-123 prevents vasospasm following subarachnoid he morrhage in monkeys, that further investigations of ET antagonists are warranted, and that ET may be an important pathophysiological mediato r of vasospasm. The lack of efficacy of bosentan may be related to ina dequate cerebrospinal fluid levels obtained by administration twice-da ily through an Ommaya reservoir.