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(Circulation Research. 2001;0:hh1401.093294.)
© 2001 American Heart Association, Inc.

Article

High Glucose Impairs Voltage-Gated K⁺ Channel Current in Rat Small Coronary Arteries

Yanping Liu, Ken Terata, Nancy J. Rusch David D. Gutterman

From the Departments of Internal Medicine (Y.L., K.T., D.D.G.) and Pharmacology and Toxicology (N.J.R.), Cardiovascular Center, Medical College of Wisconsin, and Zablocki VA Medical Center (Y.L., K.T., D.D.G.), Milwaukee, Wis.

Correspondence to Yanping Liu, MD, PhD, Assistant Professor, Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail ypliu{at}mcw.edu

Abstract

Abstract—Hyperglycemia is associated with impaired endothelium-dependent dilation that is due to quenching of NO by superoxide (O₂ ^{· -}). In small coronary arteries (CAs), dilation depends more on smooth muscle hyperpolarization, such as that mediated by voltage-gated K⁺ (Kv) channels. We determined whether high glucose enhances O₂^·- production and reduces microvascular Kv channel current and functional responses. CAs from Sprague-Dawley rats were incubated 24 hours in medium containing either normal glucose (NG, 5.5 mmol/L D-glucose), high glucose (HG, 23 mmol/L D-glucose), or L-glucose (LG, 5.5 mmol/L D-glucose and 17 mmol/L L-glucose). O₂^·- production was increased in HG arteries. Whole-cell patch clamping showed a reduction of 4-aminopyridine (4-AP)–sensitive current (Kv current) from smooth muscle cells of HG CAs versus NG CAs or versus LG CAs (peak density was 9.95±5.3 pA/pF for HG versus 27.8±6.8 pA/pF for NG and 28.5±5.2 pA/pF for LG; P<0.05). O₂^·- generation (xanthine+xanthine oxidase) decreased K⁺ current density, with no further reduction by 4-AP. Partial restoration was observed with superoxide dismutase and catalase. Constriction to 3 mmol/L 4-AP was reduced in vessels exposed to HG (13±5%, P<0.05) versus NG (30±7%) or LG (34±4%). Responses to KCl and nifedipine were not different among groups. Superoxide dismutase and catalase increased contraction to 4-AP in HG CAs. This is the first direct evidence that exposure of CAs to HG impairs Kv channel activity. We speculate that this O₂^·--induced impairment may reduce vasodilator responsiveness in the coronary circulation of subjects with coronary disease or its risk factors.

Key Words: K⁺ channels • superoxide • coronary circulation • vascular smooth muscle

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