Permeability and vasomotor response of cerebral vessels during exposure to arachidonic acid

Summary

Release of arachidonic acid (AA) in brain tissue is found in various cerebral insults. Blood-brain barrier function and vasomotor response were studied during cerebral administration of the fatty acid to obtain further evidence on its role as mediator of secondary brain damage under pathological conditions. Na⁺-fluorescein or fluorescein isothiocyanate (FITC)-dextran were i.v. administered as low- and high-molecular weight blood-brain barrier indicators. Cortical superfusion of arachidonic acid led to moderate constriction of ca. 90% of normal of pial arteries of 60–220 μm Ø, whereas the venous diameters remained unaffected. On the other hand, AA caused opening of the blood-brain barrier not only for Na⁺-fluorescein but also for FITC-dextran (mol.wt. 62,000). Extravasation of Na⁺-fluorescein started at AA concentrations of 3×10⁻⁵ M. Concentrations of 3×10⁻⁴ to 3×10⁻³ M always sufficed to induce barrier opening for fluorescein, whereas 3×10⁻³ M was required for FITC-dextran. Leakage of the blood-brain barrier indicators started around venules. Pretreatment with indomethacin, or with BW 755 C, a dual inhibitor of both the cyclo- and lipoxygenase pathway did not prevent barrier opening by arachidonate for Na⁺-fluorescein. However, in the presence of indomethacin higher concentrations of AA were required to open the barrier for Na⁺-fluorescein, whereas BW 755 C did not influence the dose-effect relationship of AA and barrier opening observed in untreated animals. The latter findings imply that the pathophysiological effects induced by AA are likely to be attributed to the acid itself, rather than to its metabolites, a conclusion which might be in conflict with earlier observations reported in the literature. Electron microscopy revealed marked alterations of the venous endothelium, such as an attachment and eventual penetration of polymorphonuclear granulocytes through the endothelial barrier, while the small arteries and arterioles were unaffected. The findings may indicate that opening of the barrier by AA is mediated by granulocytes and/or their products. Taken together, our findings support the concept that release of AA in primarily damaged brain tissue enhances secondary processes, such as a failure of the blood-brain barrier function. The limited potency or even ineffectiveness, respectively, of indomethacin or BW 755 C provides evidence for a direct involvement of the fatty acid rather than of its metabolic degradation products. Therefore, therapeutic prevention of AA formation under these circumstances might be superior to mere inhibition of its metabolism.