Angiotensin II inhibits the Na+-K+ pump via PKC-dependent activation of NADPH oxidase.

The sarcolemmal Na+-K+ pump, pivotal in cardiac myocyte function, is inhibited by angiotensin II (ANG II). Since ANG II activates NADPH oxidase, we tested the hypothesis that NADPH oxidase mediates the pump inhibition. Exposure to 100 nmol/l ANG II increased superoxide-sensitive fluorescence of isolated rabbit ventricular myocytes. The increase was abolished by pegylated superoxide dismutase (SOD), by the NADPH oxidase inhibitor apocynin, and by myristolated inhibitory peptide to e-protein kinase C (ePKC), previously implicated in ANG II-induced Na+-K+ pump inhibition. A role for ePKC was also supported by an ANG II-induced increase in coimmunoprecipitation of ePKC with the receptor for the activated kinase and with the cytosolic p47phox subunit of NADPH oxidase. ANG II decreased electrogenic Na+-K+ pump current in voltage-clamped myocytes. The decrease was abolished by SOD, by the gp91ds inhibitory peptide that blocks assembly and activation of NADPH oxidase, and by ePKC inhibitory peptide. Since colocal...