Inhibition of Na(+)/H(+) exchange by 5-(N-ethyl-N-isopropyl)-amiloride reduces free fatty acid efflux from the ischemic reperfused rat cerebral cortex.
Brain tissue acidosis is considered to be a contributor to ischemic brain injury. The deleterious effects of marked acidosis may be associated with reperfusion and an excessive entry of Na(+) into cerebral neurons and glia as intracellular pH is restored by Na(+)/H(+) exchange. Normalization of pH, with activation of many calcium-dependent and other phospholipases and proteases with pH optima in the neutral or alkaline range, could account for the pronounced elevation in extracellular levels of free fatty acids which occurs during 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 microM) applied topically onto the rat cerebral 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 Free fatty acid levels in cortical superfusates, withdrawn at 10-min intervals from bilateral cortical windows, were analyzed by high pressure liquid chromatography.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 effectively inhibited the increases in arachidonic and linoleic acid release observed in the control rats during reperfusion, and non-significantly depressed that of palmitic and oleic acids. Superfusate levels of glucose, which decline to near zero levels during ischemia and then rebound during reperfusion, were not affected by EIPA administration. Lactate levels in cortical superfusates from EIPA-treated animals rose more rapidly during reperfusion than did those in the control rats and then significantly declined towards basal levels. The data indicate that inhibition of Na(+)/H(+) exchange prevented the activation of phospholipases that usually occurs during reperfusion following a cerebral ischemic episode. These results are the first demonstration of such an effect and may provide an explanation for the cerebroprotective effects that have been observed in stroked animals following administration of Na(+)/H(+) exchange inhibitors.
Phillis
J W
JW
Department of Physiology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201-1928, USA. jphillis@med.wayne.edu
Ren
J
J
O'Regan
M H
MH
D000138:Acidosis / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control*; D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004569:Electroencephalography / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010740:Phospholipases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D017923:Sodium-Hydrogen Exchangers / Q000187:drug effects* / Q000378:metabolism
D005230:Fatty Acids, Nonesterified; D018696:Neuroprotective Agents; D017923:Sodium-Hydrogen Exchangers; D019344:Lactic Acid; D000584:Amiloride; D010740:Phospholipases; D005947:Glucose; C039614:ethylisopropylamiloride