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Temporary occlusion of an intracranial artery is frequently necessary in the surgical management of intracranial aneurysms, arteriovenous malformations, and tumors. While the risks of vessel damage associated with clip application have been lessened by improved design, the threat of ischemic damage remains. It is unclear whether multiple, brief periods of clip application are more or less safe than a single period of occlusion, and whether the underlying cerebrovascular status influences the outcome from either method. The effect of each of these paradigms (single: 1-hour occlusion; multiple: three 20-minute episodes separated by 10 minutes of reperfusion) on histopathological outcome was assessed in a middle cerebral artery (MCA) occlusion model using both normotensive and spontaneously hypertensive rats. The mean volume of infarction (+/- standard error of the mean) was not different between the single-ischemic (49.4 +/- 17.3 cu mm) and the multiple-ischemic (42.9 +/- 12.9 cu mm) episode groups of normotensive rats, whereas in the spontaneously hypertensive rats a significant difference existed between the volume of infarction for the single-occlusion group (126.7 +/- 18.7 cu mm) and the multiple-occlusion group (162.4 +/- 15.5 cu mm) (p < 0.05). The metabolic data obtained from spontaneously hypertensive animals did not provide an explanation for the larger infarction in that there were no significant differences between the single- and multiple-occlusion groups with respect to tissue glucose, adenosine triphosphate, or lactate levels. The results suggest that intermittent reperfusion may have different effects depending not only on the degree and duration of ischemia and reperfusion, but also on the underlying cerebrovascular status.