Rat Models

Although rats have been used extensively to reproduce vasospasm, a number of issues have limited the applicability of the obtained findings to the human disease, among them the lack of myointimal cells in intracranial vessels that might play a role in the intimal hyperplasia observed after vascular injury (106), high mortality rates, and early resolution of vasospasm.

Intracranial Models

The first intracranial model consisted of transclival exposure of the basilar artery for either puncture with a microelectrode or clot placement, followed by measurements of vessel diameter under direct vision (107). One study used this technique to measure electrolytic changes in the basilar artery and subarachnoid clot and had a mortality of 26%, with peak vasospasm occurring 1 hr after puncture and maximal delayed spasm of 15% at 48 hr (108). Puncture of the basilar artery, however, resulted in variable amounts of SAH, and direct measurement of the basilar artery suffered from significant interobserver variability.

The next model used transorbital blood injections into the chiasmatic cistern (109). A catheter was placed through a frontal burr hole and advanced around the hemisphere to the cistern to inject heparinized blood. This technique was used to test acute electrocardiographic changes, not vasospasm. Injection of heparinized blood could alter the development of vasospasm by preventing adequate clot formation, and the placement of a catheter "blindly" prevented localization of the SAH to one side and prevented the use of the contralateral side for control.

Models of blood injection into the cisterna magna used in other species were adapted for rats, following different methods. The first method described consisted of placing a burr hole in the parietal region and inserting a cannula into the cisterna magna to inject blood and induce vasospasm of the basilar artery. This model was injected with 0.3 ml of either fresh autologous arterial blood or mock CSF, and CBF was determined by tracking labeled microspheres for 1 hr after injection. Rats with experimental SAH showed a 40% decrease in CBF, whereas those that received saline injection showed only a 15% decrease (110). An increase in the volume of blood injected (0.6 ml) resulted in a decrease in CBF 3 hr after SAH that returned to normal values at 1, 2, 3, 7, and 14 days (111). In this model, variability of vasospasm was observed between Wistar and Sprague-Dawley rats. The second method consisted of a double injection, in which the posterior atlanto-occipital membrane was exposed, 0.1 ml of CSF was aspirated, mixed with 0.4 ml of venous blood, and 0.1 ml of the mixture was reinjected (112). In this model, corrosion casts of the cerebral arteries showed vasospasm that was not altered by nimodipine administration.

Endovascular perforation models were developed in rats and have become quite popular. These models are generally referred to as the "Sheffield model" because they were initially described by researchers using Wistar rats in 1995 at the Royal Hallamshire Hospital in Sheffield, UK (113). This technique has also been described in Sprague-Dawley rats (114). The technique consists of inserting a pointed 3-0 monofilament nylon suture into the ICA and advancing it until it perforates the ACA, which results in SAH in 89% of the animals and in intracerebral hemorrhage in the remaining 11%. This model has a reported mortality of approximately 50%, and the severity of vasospasm varies significantly; pharmacologic responses to delayed vasospasm and pathologic changes in the arterial wall do not occur (115). A study comparing injection into the cisterna magna with endovascular rupture through the ICA using a 3-0 or a 4-0 nylon suture showed that the 4-0 suture produced less SAH and resulted in lower peak intracranial pressure when compared to other groups and that CBF reductions were similar in all groups, with the injection group having a faster CBF recovery (116 ).

A more recent study was performed to compare the severity of vasospasm induced by either endovascular puncture with a 3-0 suture through the ICA, single injection of 0.3 ml of blood into the cisterna magna, or double injection of 0.3 ml (48-hr interval between injections) (117) in male Sprague-Dawley rats. Histopathologic examination and morphometric analysis were performed on the basilar artery and PCoA. The study showed that these techniques caused significant vasospasm, with the double-hemorrhage model inducing the most severe vasospasm. Double hemorrhage, however, caused the highest mortality rate (57%) and had significant variability in hemorrhage volumes when compared to the cisternal injection models. Whereas vasospasm after endovascular perforation or single hemorrhage was more pronounced in the PCoA, vasospasm after double hemorrhage was more pronounced in the basilar artery.

Figure 3 Rat femoral artery model of vasospasm. (A) Artist's illustration of the surgical technique for induction of vasospasm in the femoral artery of a rat. (B) Microphotograph of a cross-section of the femoral artery of a rat after peri-adventitial blood deposition. Source: From Ref. 119.

The authors concluded that the double-hemorrhage model was the most suitable alternative for studying mechanistic and therapeutic approaches for vasospasm.

Extracranial Models

Another currently popular model utilizes the rat femoral artery. This model consists of exposing the femoral artery, isolating it in a silicon cuff, and filling the cuff with blood or blood components (Fig. 3) (118). Peak morphometric vasospasm in this model occurs on day 7 and is accompanied by pathologic changes in the arterial wall. The major advantage of this model is the similarity of its course to that of human vasospasm. Other advantages are the availability of a contralateral control vessel and the controlled volume and localization of the hemorrhage. The main disadvantage of this model is the use of a systemic vessel, which excludes CSF clearance, changes in intracranial pressure, and central nervous system-specific inflammatory responses from the experimental variables. Several groups have shown that pharmacologic responses observed in this model correlate with those observed in other species (31,32,71,72,119-121) and that the pathologic changes observed are comparable to those seen after SAH in intracranial models and in humans.

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