Rabbit Models

The first use of rabbits for the study of vasospasm was reported in 1969 (59). In this report, an occipital burr hole was placed and, under fluoroscopic guidance, a catheter was directed into the subarachnoid space close to the orbit and inserted into the right carotid artery. The goal of the study was to analyze the electrocardiographic changes that occur after SAH; vasospasm was not evaluated.

In the most common rabbit model used today, the atlanto-occipital membrane is surgically exposed, cerebrospinal fluid (CSF) is withdrawn, and 1.25 ml/kg of autologous arterial blood are injected into the surgically exposed cisterna magna, followed by placement of the animal head-down at 30° for 30 min to confine the blood to the intracranial cisterns (Fig. 2) (28,60). With this technique, peak vasospasm occurs 72 hr after SAH, and a 40% to 45% reduction in the diameter of the basilar artery is observed. A variation of this technique, using percutaneous injection of 1 ml/kg into the cisterna magna, produces similar results. A high correlation between angiographic and morphometric vasospasm has been observed in this model (61).

Advantages of this model include evaluation of an intracranial vessel, extensive histo-pathologic characterization, well-defined time course, and lower cost. Disadvantages include absence of reduction of CBF after single hemorrhage. Proponents of this model have used a double hemorrhage to induce more severe vasospasm (62,63). The need for double injection, however, has been questioned, because vasospasm is not significantly greater when compared to the single-injection technique (64).

Figure 2 Rabbit model of subarachnoid hemorrhage (SAH). (A) An artist's illustration of the surgical technique for induction of SAH in the rabbit. (B) Photograph of a macroscopic specimen showing a blood clot around the basilar artery of a rabbit after induction of SAH. (C) Microphotograph of a cross-section of the basilar artery of rabbit after SAH. Source: From Ref. 31.

Figure 2 Rabbit model of subarachnoid hemorrhage (SAH). (A) An artist's illustration of the surgical technique for induction of SAH in the rabbit. (B) Photograph of a macroscopic specimen showing a blood clot around the basilar artery of a rabbit after induction of SAH. (C) Microphotograph of a cross-section of the basilar artery of rabbit after SAH. Source: From Ref. 31.

Numerous therapeutic agents have been tested, and those shown to prevent vasospasm include endothelin antagonists (65-67), calcium-channel blockers (68-70), nonsteroidal anti-inflammatory drugs (NSAIDs) (71), monoclonal antibodies against CD11/CD18 (72) and intercellular adhesion molecule 1 (ICAM-1) (73), and NO donors (31). Reversal of established vasospasm in this model has been achieved by intracardiac infusion of papaverine, sodium nitroprusside, and adenosine (74 ), by local delivery of diethyl-triamine nitric oxide (DETA-NO) (75 ), and by various other means.

To induce ischemia after posthemorrhagic vasospasm in rabbits, bilateral common carotid artery (CCA) ligations were performed 2 weeks prior to a double-injection SAH. This maneuver caused cerebral infarction in only 15% of animals (76). Other, less common techniques include transorbital blood injection into the chiasmatic cistern, rupture of the MCA (puncture via cra-niotomy), mechanical compression, puncture of the MCA and the superior sagittal sinus, blood injection into the interpeduncular cistern, and transclival puncture of the basilar artery.

An extracranial model using the CCA has also been reported in rabbits (77). In this model, the CCA is encased in polyvinyl chloride cuffs and autologous blood is injected. Vasospasm develops 24 to 48 hr after hemorrhage and persists for approximately 6 days. This model has been used to show eicosanoid production after SAH and induction of vasospasm with the injection of human blood. Therapeutic approaches tested in this model include prophylactic laser treatment and transluminal angioplasty.

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