Prospective, randomized, double-blind trial of BQ-123 and bosentan for prevention of vasospasm following subarachnoid hemorrhage in monkeys

Abstract

Thirty-one monkeys were randomly divided into three groups to undergo baseline cerebral angiography followed by induction of subarachnoid hemorrhage by placement of autologous blood clot along the right-sided arteries of the anterior circle of Willis (Day 0). The monkeys were then 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 the bosentan was given by twice-daily injections into an Ommaya reservoir in the subcutaneous space with a catheter along the right middle cerebral artery (MCA). Seven days later (Day 7), angiography was repeated and the animals were killed. Comparison of arterial diameters shown on angiograms between Day 0 and Day 7 groups given placebo and bosentan showed significant reductions in the diameters of the right intradural 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 narrowing of the right extradural internal carotid artery (7% +/- 6%) and the basilar artery (11% +/- 3%), but not of the right MCA. Comparison of arterial diameters between groups at Day 7 showed significant variance in the right extradural internal carotid, both intradural internal carotid, right middle cerebral, and left anterior cerebral arteries; the animals injected with BQ-123 developed significantly less arterial narrowing these those receiving bosentan and placebo. Bosentan was not detected 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 hemorrhage in monkeys, that further investigations of ET antagonists are warranted, and that ET may be an important pathophysiological mediator of vasospasm. The lack of efficacy of bosentan may be related to inadequate cerebrospinal fluid levels obtained by administration twice-daily through an Ommaya reservoir.

Hemoglobin Increases Endothelin-1 in Endothelial Cells by Decreasing Nitric Oxide

“…Several studies have found increased ET-1 concentrations in the cerebrospinal fluid of patients with cerebral vasospasm and during vasospasm in animal models of SAH. Numerous animal studies have documented the efficacy of ET receptor antagonists at preventing or alleviating experimental vasospasm (1,(27)(28)(29). Hemoglobin, and possibly ferrous hemoglobin specifically, is a prime candidate for the cause of vasospasm, and our results suggest that the NO scavenging effect may contribute to vasospasm both by removing vasodilating NO and by simultaneously increasing ET-1.…”

Cerebrovascular Inflammation Following Subarachnoid Hemorrhage

“…This discrepancy is all the more difficult to understand since it has been reported that ET antagonists inhibit vasospasm in primates (147,148) as well as in other species. By far the most significant increases of ET concern ET-1, only sporadic amounts of ET-3 being noted in one report (141).…”

An Improved Canine Model of Subarachnoid Hemorrhage Using Intrathecal Indwelling Catheters.

“…Cerebral vasospasm is a major complication of human aneurysmal SAH gravely affecting outcome, but the underlying pathogenetic mechanism has remained unresolved and the treatment remains to be established. To investigate the pathophysiology and therapy of cerebral vasospasm, various animal models such as dogs [9][10][11][12]18], monkeys [1,6,7], rabbits [2,4,15], cats [17], and rats [3,8,16] have been used. While each model has its merits and demerits, by far the most popular model has been the canine SAH model first proposed by Varsos et al [18], designated the "two-hemorrhage" model.…”

“…The placement of an intrathecally indwelling catheter has already been reported in a monkey SAH model [7], where the indwelling catheter was used solely for the purpose of intrathecal drug administration as SAH was induced by the placement of a blood clot around the middle cerebral artery by craniotomy. Since we hypothesized the use of such catheters not only for drug administration but also for the induction of repeated SAH might improve the canine "twohemorrhage" model, we examined the feasibility of this technique in dogs in the present study.…”