Nitric oxide-mediated alterations of protein tyrosine phosphatase activity and expression during hypoxia in the cerebral cortex of newborn piglets.

The present study tested the hypothesis that the hypoxia-induced decrease in protein tyrosine phosphatase (PTP) activity in the membranes and increased activity and expression of PTPs (PTP-1B, PTP-SH1 and 2) in the cytosol of the cerebral cortex of newborn piglets are mediated by nitric oxide (NO). To test this hypothesis, PTP activity in cell membranes and activity and expression were measured in the cytosol of normoxic (Nx, n = 5), hypoxic (Hx, n = 5), and 7-nitro-indazole sodium salt (7-NINA), a selective inhibitor of neuronal nitric oxide synthase (nNOS), pretreated hypoxic (7-NINA+Hx, n = 6) newborn piglets. PTP activity in cortical cell membranes was lower in the Hx group as compared to the Nx group and this decrease was prevented in the 7-NINA+Hx group. The density of cytosolic PTP-1B, cytosolic PTP-SH1 and PTP-SH2 was increased in the Hx group and this increase was prevented in the 7-NINA+Hx group. Immunohistochemistry results show an increased immunoreactivity to PTP-1B in the Hx as compared to Nx animals. The data show that pretreatment with 7-NINA, a selective inhibitor of nNOS, prevents the hypoxia-induced decrease in PTP activity in membranes. nNOS inhibition also prevented the hypoxia-induced increase in PTP activity and expression in cytosol, and therefore we conclude that modification of PTP during hypoxia is NO-mediated.