Inhibition of Na+/H+ exchange by 5-(N-ethyl-N-isopropyl)-amiloride reducesfree fatty acid efflux from the ischemic reperfused rat cerebral cortex

Brain tissue acidosis is considered to be a contributor to ischemic brain i njury. The deleterious effects of marked acidosis may be associated with re perfusion and an excessive entry of Na+ into cerebral neurons and glia as i ntracellular pH is restored by Na+/H+ exchange. Normalization of pH, with a ctivation of many calcium-dependent and other phospholipases and proteases with pH optima in the neutral or alkaline range, could account for the pron ounced elevation in extracellular levels of free fatty acids which occurs d uring reperfusion following cerebral ischemia. In the present investigation we evaluated the effects of inhibition of Na+/H+ exchange with N-(N-ethyl- N-isopropyl)-amiloride (EIPA; 25 muM) applied topically onto the rat cerebr al cortex prior to and during ischemia. Free fatty acid levels in cortical superfusates, withdrawn at 10-min intervals from bilateral cortical windows , were analyzed by high pressure liquid chromatography. EIPA application ef fectively inhibited the increases in arachidonic and linoleic acid release observed in the control rats during reperfusion, and non-significantly depr essed that of palmitic and oleic acids. Superfusate levels of glucose, whic h decline to near zero levels during ischemia and then rebound during reper fusion, were not affected by EIPA administration. Lactate levels in cortica l superfusates from EIPA-treated animals rose more rapidly during reperfusi on than did those in the control rats and then significantly declined towar ds basal levels. The data indicate that inhibition of Na+/H+ exchange preve nted the activation of phospholipases that usually occurs during reperfusio n following a cerebral ischemic episode. These results are the first demons tration of such an effect and may provide an explanation for the cerebropro tective effects that have been observed in stroked animals following admini stration of Na+/H+ exchange inhibitors. (C) 2000 Elsevier Science B.V. All rights reserved.