Rat 2Vessel Occlusion

Another widely used approach to an effective global ischemia model in rats combines carotid artery occlusion with systemic hypotension (81,82). An early study that used this method produced what remains one of the more comprehensive histopathologic assessments of ischemic brain injury in the rat (7). The method can be applied in any strain, but most investigators have used Wistar or Sprague-Dawley rats. The main advantage of this approach over the 4-VO model is the relatively straightforward surgery required for carotid artery occlusion and release. However, as originally described, additional procedures are necessary to insert cannulae into the jugular vein and tail artery for blood withdrawal and blood pressure monitoring, respectively, and animals are routinely heparinized, paralyzed, and ventilated. Temperature control of the withdrawn blood is essential to avoid incidental cooling upon reinfusion.

It is relatively easy to achieve reproducible insult severity across rat strains using the 2-VO approach, as the depth of ischemia is dependent on successful blood pressure reduction rather than surgical attenuation of collateral perfusion. Effective ischemia in some animals may require more severe hypotension than initially reported, with 30 mmHg identified as optimal in 2 independent evaluations (83,84). Increasing the halothane level has been suggested by several investigators as an alternative to hypovolemic hypotension (85-87), although this clearly also impacts metabolic rate (88-90). Another noninvasive approach to blood pressure reduction has been proposed, in which external suction is applied to pool blood in the lower body (91), which also avoids the need for heparin administration.

The comparatively robust pathology initially reported after brief insults in the 2-VO model (7) was subsequently attributed to aggressive head warming in the earlier experiments (92) and has been a consistent finding under such conditions (23). However, repeated rectal temperature measurements in this model also demonstrated a prolonged hyperthermia during 1 to 3 days of reperfusion, followed by a gradual recovery of the diurnal temperature rhythm (93). Although delayed, this phenomenon is much more persistent than the response noted in the gerbil and appears to be of pathophysiologic significance. Pharmacologic intervention to blunt the delayed temperature increase was required to maintain long-term protection after an interval of early postischemic hypothermia (93). If this hyperthermic phase should emerge as a general feature of the 2-VO model as applied across laboratories, it must be considered a significant contributor to insult severity and recognized as a potential source of increased sensitivity to interventions that influence temperature regulation.

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