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Am J Physiol Cell Physiol (October 31, 2001). doi:10.1152/ajpcell.00343.2001
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Articles in PresS, published online ahead of print October 31, 2001
Am J Physiol Cell Physiol, 10.1152/ajpcell.00343.2001
Submitted on July 25, 2001
Accepted on October 24, 2001

Hyperglycemia Increases Superoxide Anion In Rabbit Endothelium Leading To Decreased Smooth Muscle Cell Na+-K+-ATPase Activity

Sandeep Gupta1, Eugene Chough1, Jennifer Daley1, Peter Oates2, Keith Tornheim1, Neil B Ruderman1, and John F Keaney3*

1 Diabetes and Metabolism Unit, Boston University School of Medicine, Boston, MA, USA
2 Pfizer Central Research, Pfizer Inc., Groton, CT, USA
3 Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA

* To whom correspondence should be addressed. E-mail: jkeaney{at}bu.edu.

Nitric oxide (NO) plays an important role in the control of numerous vascular functions including basal Na+-K+-adenosine triphosphatase (Na+-K+-ATPase) activity in arterial tissue. Hyperglycemia inhibits Na+-K+-ATPase activity in rabbit aorta, in part, through diminished bioactivity of NO. The precise mechanism(s) for such observations, however, are not yet clear. The purpose of this study was to examine the role of superoxide in modulating NO-mediated control of Na+-K+-ATPasein response to hyperglycemia. Rabbit aorta incubated with hyperglycemic glucose concentrations (44 mM) demonstrated a 50% reduction in Na+-K+-ATPase activity that was abrogated by superoxide dismutase (SOD). Hyperglycemia also produced a 50% increase in steady-state vascular superoxide measured by lucigenin-enhanced chemiluminescence that was closely associated with reduced Na+-K+-ATPase activity. Specifically, the hyperglycemia-induced increase in vascular superoxide was endothelium-dependent, inhibited by L-arginine, and stimulated by N{omega}-nitro-L-arginine. Aldose reductase inhibition with zopolrestat also inhibited the hyperglycemia-induced increase in vascular superoxide. In each manipulation of vascular superoxide, a reciprocal change in Na+-K+-ATPase activity was observed. Finally, a commercially available preparation of Na+-K+-ATPase was inhibited by pyrogallol, a superoxide generator. These data suggest that hyperglycemia induces an increase in endothelial superoxide that inhibits the stimulatory effect of NO on vascular Na+-K+-ATPase activity.




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