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Diabetes 53:2436-2442, 2004
© 2004 by the American Diabetes Association, Inc.

Nitration and Functional Loss of Voltage-Gated K+ Channels in Rat Coronary Microvessels Exposed to High Glucose

Hongwei Li1, David D. Gutterman2,3, Nancy J. Rusch3,4, Aaron Bubolz2,3, and Yanping Liu2,3

1 Heart and Vessel Diseases Center, Beijing Friendship Hospital, Affiliate of Capital University of Medical Sciences, Beijing, People’s Republic of China
2 Department of Medicine, The Medical College of Wisconsin and The Veterans Administration Medical Center, Milwaukee, Wisconsin
3 Cardiovascular Center, The Medical College of Wisconsin and The Veterans Administration Medical Center, Milwaukee, Wisconsin
4 Department of Pharmacology & Toxicology, The Medical College of Wisconsin and The Veterans Administration Medical Center, Milwaukee, Wisconsin

Coronary microvessels generate reactive oxygen species in response to high glucose (HG), resulting in vasodilator defects involving an impaired function of vascular K+ channels. Inhibition of voltage-gated K+ (Kv) channels by peroxynitrite (ONOO–), formed by the interaction of superoxide and nitric oxide, may contribute to impaired dilation. The present study investigated whether HG induces ONOO– formation to mediate nitration and impairment of Kv channels in rat small coronary arteries (RSCAs). Exposure to ONOO– reduced the dilator influence of Kv channels in RSCAs. Patch-clamp studies revealed that ONOO– diminished whole-cell and unitary Kv currents attributable to the Kv1 gene family in smooth muscle cells. Subsequently, immunohistochemically detected enhancement of nitrotyrosine residues in RSCAs that were cultured in HG (23 mmol/l) compared with normal glucose (5.5 mmol/l) for 24 h correlated with the nitration of Kv1.2 channel {alpha}-subunits. HG-induced nitrotyrosine formation was partially reversed by scavenging ONOO–. Finally, RSCAs that were exposed to HG for 24 h showed a loss of Kv channel dilator influence that also was partially restored by the ONOO– scavengers urate and ebselen. We conclude that ONOO– generated by HG impairs Kv channel function in coronary microvessels, possibly by nitrating tyrosine residues in the pore-forming region of the Kv channel protein.

Address correspondence and reprint requests to Yanping Liu, MD, PhD, Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. E-mail: ypliu{at}mcw.edu


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Copyright © 2004 by the American Diabetes Association.