Background and Purpose:The rat is now extensively used for studies on focal cerebral ischemia, and several novel pharmacological principles have been worked out in rat models of middle cerebral artery occlusion. The objective of the present study was to assess how ischemic tissue can be salvaged by reperfusion in a model of transient focal ischemia that gives infarction of both the caudoputamen and the neocortex.Methods: The middle cerebral artery of anesthetized rats was occluded for 15, 30, 60, 90, 120, or 180 minutes by an intraluminal filament, and recirculation was instituted for 7 days to allow assessment of the density and localization of ischemic brain damage using histopathologic techniques. Local cerebral blood flow was measured in separate animals to verify that removal of the filament was followed by adequate recirculation.Results: Following 15 minutes of middle cerebral artery occlusion seven of eight rats showed selective neuronal necrosis in the caudoputamen, while the neocortex was normal. After 30 minutes of occlusion, seven of eight animals had infarcts localized to the lateral caudoputamen, and four of eight had selective neuronal necrosis in the neocortex. Prolongation of the ischemia to 60 minutes induced cortical infarction in all eight rats. The infarct size increased progressively with increasing occlusion time, up to 120-180 minutes, when the infarcts were as extensive as those observed following 24 hours of permanent middle cerebral artery occlusion.Conclusions: The results demonstrate a time window for salvage of penumbral tissues by reperfusion that is shorter than that suggested on the basis of previous data in other species. The results probably reflect a lower collateral blood flow in the rat than in other species. This should be taken into account when the effect of pharmacological agents is studied in rats. (Stroke 1992;23:552-559)

Summary: Although preis chemic hyperglycemia is known to aggravate damage due to transient ischemia, it is a matter of controversy whether or not this is a result of the exaggerated acidosis. It has recently been reported that although tissue acidosis of a comparable severity could be induced in normoglycemic dogs by an excessive rise in arterial CO2 tension, short-term functional recov ery was improved, rather than compromised. In the present experiments we induced excessive hypercapnia (P ac02, -300 mm Hg) in normoglycemic rats before in ducing forebrain ischemia of lO-min duration. This re duced the brain extracellular pH to values normally en countered in hyperglycemic rats subjected to ischemia.As discussed in recent review articles, preisch emic hyperglycemia invariably aggravates brain damage due to severe transient ischemia (Siesj6, 1988; Siesj6 et aI., 1993). The aggravation is ob served whether the ischemia is complete or near complete, and whether it is of the global or the fore brain type; in fact, hyperglycemia also aggravates damage due to focal ischemia, if the latter is tran sient and of a brief duration (Nedergaard, 1987). In most published reports, the hyperglycemia has been marked to excessive; however, even very moderate hyperglycemia aggravates damage (Pulsinelli et aI., 1982). Hyperglycemia affects ischemic brain dam age in four principal ways: It accelerates the evolu tion of the damage, it disrupts the blood-brain bar- Abbreviations used: NMDA, N-methyl-D-aspartate; NMR, nuclear magnetic resonance; pHe' extracellular pH; pHi' intra cellular pH; SNPR, substantia nigra, pars reticulata. 243The events induced by hypercapnia clearly enhanced ischemic brain damage, as assessed histologically after 7 days of recovery. We hypothesize that the decisive event was an exaggerated decrease in extra-and intracellular pH and that the results thus demonstrate an adverse ef fect of acidosis. However, since postischemic seizures did not occur in the hypercapnic ischemic rats, the results also demonstrate that changes in intra-extracellular pH and bicarbonate concentrations modulated ischemic dam age in an unexpected way.