Nonselective cation channels as effecters of free radical-induced rat liver cell necrosis

Necrosis, as opposed to apoptosis, is recognized as a nonspecific cell deat h that induces tissue inflammation and is preceded by cell edema, In non-ne uronal cells, the latter has been explained by defective outward pumping of Na+ caused by metabolic depletion or by increased Na+ influx via membrane transporters, Here we describe a novel mechanism of swelling and necrosis; namely the influx of Na+ through oxidative stress-activated nonselective ca tion channels. Exposure of liver epithelial Clone 9 cells to the free-radic al donors calphostin C or menadione induced the rapid activation of an appr oximately 16-pS nonselective cation channel (NSCC), Blockage of this conduc tance with flufenamic acid protected the cells against swelling, calcium ov erload, and necrosis. Protection was also achieved by Gd3+, an inhibitor of stretch-activated cation channels, or by isosmotic replacement of extracel lular Na+ with N-methyl-D-glucamine, It is proposed that NSCCs, which are u biquitous although largely inactive in healthy cells, become activated unde r severe oxidative stress, The ensuing influx of Na+ initiates a positive f eedback of metabolic and electrolytic disturbances leading cells to their n ecrotic demise.