Medical Physiology Commons^™

Na/K-Atpase Amplification Of Oxidant Stress; A Universal But Unrecognized Clinical Target?, Zijian Xie, Phd, Joseph I. Shapiro, Md

Joseph I Shapiro MD

The Na/K-ATPase has a signaling function which appears to be separate from its ion pumping function. This signaling function refers to the transduction of conformational changes in the Na/K-ATPase alpha1 subunit into activating Src’s tyrosine kinase activity, triggering a cascade which generates reactive oxygen species (ROS), modulates other signaling pathways, and causes many physiological and pathophysiological effects. We have recently observed that ROS themselves as well as cardiotonic steroids can actually initiate the signal by directly inducing conformational changes in alpha1. It therefore appears that the Na/K-ATPase signal cascade can serve as a feed forward amplification for ROS with circulating …

Effects Of Uremic Serum On Isolated Cardiac Myocyte Calcium Cycling And Contractile Function, Sankaridrug Periyasamy, Jie Chen, Derek Cooney, Patricia Carter, Eiad Omran, Jiang Tian, Snigdha Priyadarshi, Alexei Bagrov, Olga Fedorova, Deepak Malhotra, Zijian Xie, Joseph Shapiro

Zijian Xie

Background: Diastolic dysfunction occurs in patients with chronic renal failure. Moreover, serum from uremic patients contains one or more inhibitors of the plasmalemmal Na,K-ATPase (sodium pump). We hypothesized that a circulating substance present in uremic sera contributes to both sodium pump inhibition and diastolic dysfunction.

Methods: Serum samples were obtained from six patients with chronic renal failure and diastolic dysfunction.

Results: Their serum samples caused marked inhibition of Na,K-ATPase purified from dog kidney at all concentrations studied (all P < 0.01) and also impaired ouabain-sensitive rubidium uptake by myocytes isolated from Sprague-Dawley rats (P < 0.01). These cardiac myocytes were studied for their contractile function with video-edge detection and calcium metabolism with indo-1 fluorescence spectroscopy after exposure to these uremic sera. These uremic sera caused increases in myocyte fractional shortening (P < 0.01) as well as an increase in the time constant of relengthening (P < 0.01). Examining the calcium transient, the time constant for calcium recovery was also increased (P < 0.01). Exposure of these cells to sera from age- and sex-matched healthy subjects did not result in significant changes in contraction or calcium cycling. Extracts of uremic serum samples inhibited isolated Na,K-ATPase whereas extracts of normal serum samples did not. The effect of uremic serum extracts on contractile function and calcium cycling were quite similar to that of intact serum or the addition of ouabain. Co-incubation of uremic serum extract with an antibody fragment directed against digoxin markedly attenuated the inhibition of Na,K-ATPase activity and completely prevented any effects on calcium cycling or contractile function.

Conclusion: These data show that one or more substances are present in uremic sera that acutely cause increased force of contraction …