ANTIOXIDANTS PREVENT HIGH-D-GLUCOSE-ENHANCED ENDOTHELIAL CA2+ CGMP RESPONSE BY SCAVENGING SUPEROXIDE ANIONS/

Very recently we proposed that hyperactivity of endothelial Ca2+/cGMP signaling under hyperglycemic conditions is due to superoxide anion (O -2(-)) release. The present study was designed to investigate changes in endothelial glutathione (GSH) levels in response to high D-glucose and possible prevention of the high-D-glucose-initiated changes in Ca2 +/cGMP signal by antioxidants. Under hyperglycemic conditions, GSH con tent increased by 29% within 4 h. Co-incubation with 10 mM GSH during high-D-glucose treatment normalized the Ca2+/cCMP response associated with an increase in GSH content by 222%. Vitamin C (250 mu M) markedly diminished the high-D-glucose-mediated hyperreactivity of endothelial Ca2+ entry (by 40%) and Ca2+ release (by 52%). Similar to GSH, co-inc ubation with vitamin E (alpha-tocopherol; 50 mu g/ml) and probucol (50 mu M) completely prevented the high-D-glucose-inititiated hyperreacti vity of the endothelial Ca2+/cGMP response. Vitamin E, probucol, GSH a nd vitamin C diminished the high-D-glucose-mediated O-2(-) release by 78, 65, 89 and 46%, respectively. These data suggest that antioxidants prevent high-D-glucose-initiated changes in endothelial Ca2+/cGMP res ponse by scavenging the overshoot of O-2(-). (C) 1997 Elsevier Science B.V.