GRADED HYPOTENSION AND MCA OCCLUSION DURATION - EFFECT IN TRANSIENT FOCAL ISCHEMIA

The first 2 h of middle cerebral artery occlusion (MCAO) are likely critical in determining the final outcome in ischemic stroke. To study this early postischemic period, male Wistar rats (n = 161) were subjected to right MCAO with closely spaced step variations in both duration of MCAO and blood pressure (BP), using the intraluminal suture technique. Quantitative neuropathology was performed at 25 coronal planes of the brain after 1-week survival. Atrophy was measured as the difference between the two hemispheres and was added to cortical and striatal necrosis to obtain total tissue loss. Damage consistently increased monotonically with increasing duration of occlusion only when infarct size was expressed as percentage of the contralateral hemisphere, but not when expressed as mm(3), because of variable tissue size. The results showed that already at 1 week, the quantity of tissue loss due to resorption and transsynaptic effects approached the quantity of geographically traceable necrosis in cortex and striatum. Minimum brain damage (5%) occurred after 60 min at a BP of 80 mm Hg, with almost no cortical necrosis. Damage was extremely sensitive to hypotension and MCAO duration. At a BP of 40 mm Hg, 60 min of MCAO produced 25% damage, accelerating every 20 min during the 2-h period studied. At BP 80 mm Hg, 120 min of MCAO produced the same damage as only 80 min of MCAO at BP 60 mm Hg. At 60-, 80-, 100-, and 120-min duration of MCAO, infarct size was significantly reduced with increasing BP. Analysis of the independent contribution of BP and MCAO duration revealed that BP played a greater role in determining infarct size than did MCAO duration. Ipsilateral hippocampal damage was seen in CA1 and, in some animals, CA3. Necrotic neurons in hippocampus were found in 21 animals, including four with bilateral hippocampal damage, largely but not exclusively distributed in the hypotensive groups. Contralateral necrotizing damage was seen in cortex and hippocampus as selective neuronal necrosis and as cortical infarction in two animals. Ipsilateral and contralateral hippocampal damage reproduced the pattern of selective vulnerability seen in global ischemia. The histologic penumbra (rim of selective neuronal necrosis surrounding the infarct) increased over time at BP 80 mm Hg but remained constant at a larger, presumably maximal level at BP 40 mm Hg in spite of increasing infarct size. We conclude that the first 2 h after MCAO is a very dynamic period, with increasing infarct size every 20 min, a process extremely sensitive to hypotension during occlusion. Transsynaptic effects can produce necrotizing damage in the hemisphere opposite to the ischemia.