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We hypothesize that enhanced activity of capillary Na, K-ATPase promotes Na+ influx into the brain and causes early edema formation in focal cerebral ischemia. The pharmacologic suppression of brain capillary Na, K-ATPase as a means to ameliorate edema formation was examined using the middle cerebral artery occlusion model in 36 cats. With the help of a catheter inserted into the middle cerebral artery, the ischemic brain area was directly perfused with 10−5 M ouabain. Perfusion was maintained as intermittent 15-second pulse injections given every 5 (n = 6) or 2 (w = 6) minutes. By this method, the naturally occurring circulatory conditions during ischemia were not altered. Four hours after ischemia, the cortical specific gravity at each of six locations over the ischemic area was compared with the corresponding ischemic blood flow measured by the H2 clearance technique. The results show that ouabain perfused every 2 minutes significantly ameliorated edema formation compared with six control cats perfused with Krebs-Ringer solution. In a separate series of experiments, the Na+ flux across the blood-brain barrier was studied by injecting 22NaCl together with an intravascular reference (cobalt-57-labeled microspheres 15/μm in diameter) into the ischemic area. The brain uptake index of 22Na was markedly increased in the ischemic cortex of six control cats; ouabain treatment in six cats suppressed the increase of Na+ influx. The results support our hypothesis that brain capillary Na, K-ATPase activity increases during early focal ischemia, leading to enhanced Na+ together with H2O flux across the blood-brain barrier.