The kallikrein-kinin system as mediator in vasogenic brain edema

✓ Plasma and bradykinin were perfused into the ventricular system of mongrel dogs to investigate whether either or both induce brain edema. Formation of cerebral edema was determined by measurement of cerebral water and electrolytes in periventricular white matter, cerebral cortex, and caudate nucleus. The response of cerebral tissue to exposure to bradykinin or to plasma, as a carrier of kininogens, was analyzed by assessment of the perfusate composition after ventricle passage. The authors report that cerebral administration of bradykinin induces cerebral edema. Ventricular perfusion with plasma also led to an increase of cerebral water content which was restricted to the white matter, but involved all brain tissue areas, if bradykinin was used. Ventricular perfusion with plasma was associated with consumption of the kinin precursor (kininogens) indicative of formation of kinins. Significant consumption of the precursor was found in five out of nine animals subjected to plasma perfusion of the ventricular system. In these animals a close correlation between the increase of white matter water content and kininogen-consumption as a measure of kinin-formation was obtained. Marked kinin-degrading activity was observed during ventricular perfusion with bradykinin as concluded from a considerable decrease of bradykinin concentration in the cisternal effluent compared to the inflowing perfusate concentration. Ventricular perfusion with plasma was associated with a decrease of K+ clearance capacity with continued duration, and in two animals with a release of glutamate into the plasma perfusate, suggesting an involvement of cytotoxic mechanisms. These findings provide support for the hypothesis of a mediator function of the kallikrein-kinin (KK) system in vasogenic brain edema. The next question that needs to be answered to complete the picture — does spontaneous activation of the KK system occur in conditions leading to vasogenic edema? — is studied in a subsequent report.</jats:p

Mechanisms of glial swelling induced by glutamate

The mechanisms of glutamate-induced glial swelling have been studied using an in vitro model that permits detection of cell volume changes with high accuracy. The model allows for a close control of the extracellular environment to study in isolation the effect of defined extracellular alterations occurring in brain under pathophysiologic conditions. Glutamate was applied in concentrations between 50 μM and 10 mM to either C6 glioma cells or astrocytes from primary culture. Glutamate uptake was assessed by HPLC measurements of amino acids in the extracellular medium. Glutamate at all concentrations tested caused glial swelling, which, however, was moderate, with maximal average volume increases between 5.0 ± 1.92 and 18.38 ± 1.6% of control at 50 μM and 5 mM glutamate, respectively. Swelling was concentration dependent and correlated with glutamate uptake. After removal of all extracellular glutamate by glial uptake, cell volume spontaneously normalized. Pretreatment of the cells for 90 min with ouabain (1 mM) to abolish the extracellular/intracellular Na+ gradient, prevented glutamate-induced swelling. It is concluded that while glial cells readily accumulate glutamate from the extracellular environment to protect neurons from excitotoxic effects, swelling results from the increase of intracellular osmotic activity due to the uptake of Na+ and glutamate.Key words: glia, glutamate uptake, cell volume, ouabain. </jats:p

Bradykinin antagonists reduce leukocyte-endothelium interactions after global cerebral ischemia

The aim of the present study was to evaluate the influence of bradykinin on microcirculatory changes and outcome after global cerebral ischemia (15 minute) in Mongolian gerbils. The cerebral microcirculation was investigated by fluorescent intravital microscopy. Survival and functional outcome was evaluated up to 4 d after ischemia. Animals were treated with the selective B1 and B2 receptor antagonists B 9858 and CP 0597, respectively, and the nonselective B1/B2 receptor antagonist B 9430. Leukocyte activation was significantly reduced by all antagonists as indicated by a significant decrease in the number of rolling (33 ± 20, 6 ± 8, 9 ± 10, and 13 ± 10) and adherent leukocytes (9 ± 7, 3 ± 4, 1 ± 1, and 2 ± 3 · 100 μm–1 · min–1 in controls and in animals treated with B1, B2, and B1/B2 antagonist, respectively). Arteriolar diameters were significantly reduced during reperfusion (35 ± 11 before and 27 ± 8 μm 40 minutes after ischemia) in animals treated with the B2 antagonist. The postischemic hypoperfusion, however, was not affected. Mortality was significantly higher in animals treated with the B1 and the B1/B2 antagonist. The authors concluded that bradykinin is involved in postischemic disturbances of cerebral microcirculation. The therapeutic effect of specific bradykinin receptor antagonists on functional outcome, however, remains unclear. </jats:p