The present study assessed the impact of time (6 h) on cerebral blood flow (CBF) during isoflurane anesthesia with and without vasopressor administration. All animals were prepared for measurement of CBF by the radiolabeled microsphere method under 1.4% end-tidal (1.0 MAC) isoflurane anesthesia. Surgery required 45 min and was followed by a 15 min stabilization period. In group 1 (n = 6), isoflurane 1.4% was administered for 6 h. CBF after 1 h of isoflurane was 92 ± 9 ml/min/100 g (mean ± SEM) and declined to 61 ± 5 ml/min/100 g at 2 h and further declined to 37 ± 5 ml/min/100 g at 6 hr. In group 2 (n = 6), isoflurane 1.4% was administered during the first hour. Thereafter, isoflurane 1.4% was continued, angiotensin II (0.3 μg/kg/min) was administered intravenously, and blood was withdrawn to maintain CPP constant for an additional 5 h, with hourly CBF determination. In this group, control CBF was 95 ± 16 ml/min/100 g and flow was maintained at the control level through 4 h and then declined to 50 ± 5 ml/min/100 g at 5 and 6 h. In group 3 (n = 6), 1.4% isoflurane was administered and phenylephrine (2.0 μg/kg/min) infusion was combined with hemorrhage to maintain control CPP in an identical sequence to group 2. In group 3, control CBF was 88 ± 14 ml/min/100 g. As in group 1, CBF decreased significantly at 2 h (p < 0.05) to 68 ± 13 ml/min/100 g and further declined to 49 ± 7 ml/min/100 g at 6 h. In all three groups, CMRO2 remained at control levels and there were no changes in arterial carbon dioxide or CPP for the duration of the study. These data demonstrate that the hyperemia caused by isoflurane resolves over time during stable 1 MAC isoflurane anesthesia. The unanticipated interaction of angiotensin II and isoflurane producing a sustained cerebral hyperemia suggests that previous studies that used angiotensin II to support MABP during isoflurane may have reported the effects of angiotensin II in addition to or rather than the effects of isoflurane.