Nitration and functional loss of voltage-gated K+ channels in rat coronary microvessels exposed to high glucose.
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(+) (K(v)) 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 K(v) channels in rat small coronary arteries (RSCAs). Exposure to ONOO(-) reduced the dilator influence of K(v) channels in RSCAs. Patch-clamp studies revealed that ONOO(-) diminished whole-cell and unitary K(v) currents attributable to the K(v)1 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 K(v)1.2 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 K(v) channel dilator influence that also was partially restored by the ONOO(-) scavengers urate and ebselen. We conclude that ONOO(-) generated by HG impairs K(v) channel function in coronary microvessels, possibly by nitrating tyrosine residues in the pore-forming region of the K(v) channel protein.
Cardiovascular Center, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA. ypliu@mcw.edu
Hongwei
H
Li
David D
DD
Gutterman
Nancy J
NJ
Rusch
Aaron
A
Bubolz
Yanping
Y
Liu
D000818:Animals; D001393:Azoles / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D054833:Isoindoles; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008833:Microcirculation / Q000187:drug effects; D009584:Nitrogen / Q000378:metabolism*; D016566:Organoselenium Compounds / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D030421:Peroxynitrous Acid / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014527:Uric Acid / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D001393:Azoles; D016166:Free Radical Scavengers; D054833:Isoindoles; D016566:Organoselenium Compounds; D024642:Potassium Channels, Voltage-Gated; D030421:Peroxynitrous Acid; D014527:Uric Acid; C042986:ebselen; D005947:Glucose; D009584:Nitrogen