The behavior of the blood-brain barrier (BBB) was studied in cats following release after 1-h middle cerebral artery (MCA) occlusion. The regional cerebral blood flow (rCBF) was determined by hydrogen clearance method in the caudate nucleus and the cerebral cortex. The BBB was assayed with Evans blue (EB) tracer and by immunohistochemical peroxidase-antiperoxidase (PAP) method. Following release of MCA occlusion, there were two openings of the BBB, separated by a refractory period. The first opening, occurred shortly after recirculation; this was associated with rCBF below 15 ml/100 g/min during the ischemic period and a pronounced reactive hyperemia promptly following release of MCA occlusion. A refractory period of the BBB was indicated by the absence of EB leakage in cats injected with the tracer 30 min before killing at 3 h after recirculation, although the rCBF values in these animals were even lower (6 +/- 1 ml/100 g/min) during occlusion, and all of them showed a pronounced hyperemia after recirculation. The occurrence of the previous BBB opening in these animals was confirmed by the PAP staining. The second opening of the BBB was observed at 5 and 72 h after recirculation in cats which were injected with EB 30 min before killing, and which showed rCBF below 15 ml/100 g/min during occlusion, followed by a pronounced reactive hyperemia. No EB extravasations were observed at any time in cats in which the rCBF during occlusion was above 15 ml/100 g/min and which failed to show a marked reactive hyperemia.

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AND IGOR KLATZO. Testing of a hypothesis for osmotic opening of the blood-brain barrier. Am.

The behavior of the BBB in cerebral ischemia was studied in symptom-positive Mongolian gerbils subjected to left common carotid artery occlusion using Evans Blue dye as indicator of BBB injury. The BBB damage was demonstrable grossly by the presence of areas of blue discoloration, and microscopically by the presence of a bright red fluorescent tracer, localized mostly in the neurons. The survey of various groups of animals revealed a direct relationship between the incidence and time of appearance of the BBB lesions and the duration of the ischemic occlusion. This relationship can be interpreted as another example of the previously described "maturation" phenomenon. A relatively late occurrence of the BBB injury in cerebral ischemia, at the time when the affected brain tissue shows severe, edematous histopathologic changes indicates that the brain edema, as the main complication of ischemia, could be regarded as being primarily of the cytotoxic type.

Two mayor types of brain edema, related to two different pathomechanisms, can be recognized: 1) cytotoxic type-where the main feature is the swelling of cellular elements of brain parenchyma and 2) vasogenic type-where an increased vascular permeability leading to accumulation of edema fluid in the extracellular spaces plays the principal role. In this type of edema, there is a close interrelationship between extravasation of serum proteins and retention of water in the brain tissue. In the ischemic brain edema both cytotoxic and vasogenic mechanisms are involved. A biphasic opening of the blood-brain barrier, associated with vasogenic edema, is observed following release of major cerebral artery occlusion. The first opening of the barrier is related to a reactive hyperemia which follows promptly recirculation. The second opening, recognizable after a delay, is associated with a severe ischemic brain tissue injury.

Light microscopic observations were carried out on Mongolian gerbils (Meriones unguiculatus) subjected to a partial cerebral ischemia by occlusion of the left common carotid artery at the neck. About 30% of gerbils developed an ischemic injury in the ipsilateral hemisphere and their brains revealed the following histopathologic features: 1. the changes were related to the intensity (duration) of the ischemic insult and to the time elapsed following release of the occlusion. The ischemic lesions appear to progress after re-establishment of the circulation and this presents one facet of a "maturation" phenomenon which seems to be a general principle applicable to various parameters of ischemic injury. The rate of "maturation" of the lesions is related to the intensity of the ischemic insult, a lesser intensity resulting in longer development of lesions. 2. The changes were either focal or diffuse in character. The former were assumed to be directly related to a vascular involvement; among the latter the topistic distribution of the hippocampal changes suggested a feature of selective vulnerability. 3. An indirect indication of neuronal recovery was surmised from observations on animals sacrificed after different periods following occlusions of the same duration. Also capable of recovery was a "reactive change" observed in the H3 neurons of the hippocampus. This change was characterized by central chromatolysis and resembled the "rimäre Reizung" of Nissl.

The authors present the results of an investigation of the vasogenic type of brain edema using cold injury in cats as a model. Their findings indicate that bulk flow and not diffusion should be considered the main mechanism for the spread of edema through the white matter. This conclusion is based on: 1) comparison of the distances actually traveled by various substances during edema spread with those calculated theoretically for migration of the substances by diffusion; 2) coincidence in the speed of movement by two substances (sucrose and albumin) with widely different diffusion coefficients; 3) measurement of interstitial fluid pressure (IFP) at various distances from the lesion showing the presence of increased IFP in the lesion area and decreasing pressures along the edema pathway toward the normal tissue; and 4) the fact that spreading of edema can be significantly impeded by inducing before the cold lesion an intracellular type of brain edema that reduces the size of the extracellular space (ECS) and increases the resistance to flow of edema fluid. The pressure-volume curve of the brain ECS, as derived from determinations of IFP and tissue water content, indicates that initial steep slope in IFP probably represents the high resistance to fluid mobility through the small diameter extracellular channels and the counteracting resistance of the intermingled structures of brain parenchyma to be separated. Once the IFP exceeds these opposing forces, the ECS dilates, fluid mobility increases, and the edema front advances.