title: Hyperglycemia increases endothelial superoxide that impairs smooth muscle cell Na+-K+-ATPase activity.
abstract: Nitric oxide (NO) plays an important role in the control of numerous vascular functions including basal 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+-ATPase in 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. 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.
authors.affiliation: Diabetes and Metabolism Unit, Evans Memorial Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Gupta
authors.forename: Eugene
authors.initials: E
authors.lastname: Chough
authors.forename: Jennifer
authors.initials: J
authors.lastname: Daley
authors.forename: Peter
authors.initials: P
authors.lastname: Oates
authors.forename: Keith
authors.initials: K
authors.lastname: Tornheim
authors.forename: Neil B
authors.initials: NB
authors.lastname: Ruderman
authors.forename: John F
authors.initials: JF
authors.lastname: Keaney
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001120:Arginine / Q000494:pharmacology; D052160:Benzothiazoles; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000378:metabolism*; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D010793:Phthalazines / Q000494:pharmacology; D011748:Pyrogallol / Q000494:pharmacology; D011817:Rabbits; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013012:Sorbitol / Q000378:metabolism; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D010793:Phthalazines; D013844:Thiazoles; D011748:Pyrogallol; D013481:Superoxides; C067172:zopolrestat; D013012:Sorbitol; D001120:Arginine; D000449:Aldehyde Reductase; D013482:Superoxide Dismutase; D000254:Sodium-Potassium-Exchanging ATPase; D005947:Glucose