The present study investigated whether oxidative stress plays a role in ischemia-reperfusion-induced changes in cardiac gene expression of Na+-K+ ATPase isoforms. The levels of mRNA for Na+-K+ ATPase isoforms were assessed in the isolated rat heart subjected to global ischemia (30 min) followed by reperfusion (60 min) in the presence or absence of superoxide dismutase (5 x 10(4) U/L) plus catalase (7.5 x 10(4) U/L), an antioxidant mixture. The levels of mRNA for the alpha(2), alpha(3), and beta(1) isoforms of Na+-K+ ATPase were significantly reduced in the ischemia-reperfusion hearts, unlike the alpha(1) isoform. Pretreatment with superoxide dismutase + catalase preserved the ischemia-reperfusion-induced changes in alpha(2), alpha(3), and beta(1) isoform mRNA levels of the Na+-K+ ATPase, whereas the alpha(1) mRNA levels were unaffected. In order to test if oxidative stress produced effects similar to those seen with ischemia-reperfusion, hearts were perfused with an oxidant, H2O2 (300 muM), or a free radical generator, xanthine (2 mM) plus xanthine oxidase (0.03 U/ml) for 20 min. Perfusion of hearts with H2O2 or xanthine/xanthine oxidase depressed the alpha(2), alpha(3), and beta(1) isoform mRNA levels of the Na+-K+ ATPase, but had lesser effects on alpha(1) mRNA levels. These results indicate that Na+-K+ ATPase isoform gene expression is altered differentially in the ischemia-reperfusion hearts and that antioxidant treatment appears to attenuate these changes. It is suggested that alterations in Na+-K+ ATPase isoform gene expression by ischemia-reperfusion may be mediated by oxidative stress. (C) 2003 Elsevier Science (USA). All rights reserved.