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Small emboli can enter penetrating arteries and could therefore produce lacunar infarction. The majority of emboli, however, enter circumferential arteries. The larger the emboli, the more likely that they will enter circumferential arteries rather than penetrating arteries.

Endothelium-dependent vasodilation may be impaired during cerebral vasospasm following subarachnoid hemorrhage. Under normal circumstances nitric oxide (NO) released by endothelial cells induces relaxation of smooth muscle by activating the soluble form of guanylate cyclase within muscle cells. In this study the levels of both endothelial NO synthase, the enzyme that produces NO, and soluble guanylate cyclase were determined in canine basilar arteries in a double-hemorrhage model using Western blot immunoassays. Thirty dogs were assigned to three groups: Group D0, control; Group D2, dogs sacrificed 2 days after cisternal injection of blood; and Group D7, dogs given double cisternal injections of blood and sacrificed 7 days after the first injection. Constriction of the basilar artery was confirmed by arterial angiography. Portions of the affected arteries or the corresponding region in control animals were solubilized for sodium dodecylsulfate-polyacrylamide gel electrophoresis and Western blotting. A specific monoclonal antibody against endothelial NO synthase was used. The extract from basilar arteries showed two bands on the blots: 135 kD, characteristic of endothelial NO synthase, and 120 kD, which may be a degradation product of the enzyme. The densitometer values of the bands were presented as percentages of D0 control values. Although the total signal in the D7 group was less than that of the D0 control group (D2, 97% +/- 22%; D7, 78% +/- 40%), it was not statistically significant. The proportion of the 135-kD form decreased between Groups D0 and D7, but the difference was not significant. A single major band corresponding to the alpha-subunit of soluble guanylate cyclase was seen at 70 kD in the basilar artery extracts. The signals of D2 and D7 samples were 69% +/- 40% and 25% +/- 18%, respectively. There was a significant difference between D7 and D0 (p < 0.001). The reduced expression of soluble guanylate cyclase may be related to the impairment of endothelium-dependent vasodilation in vasospasm.

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.

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