High glucose impairs voltage-gated K+ channel current in rat small coronary arteries

Hyperglycemia is associated with impaired endothelium-dependent dilation th at is due to quenching of NO by superoxide (O(2)radical anion). In small co ronary arteries (CAs), dilation depends more on smooth muscle hyperpolariza tion, such as that mediated by voltage-gated K+ (Kv) channels. We determine d whether high glucose. enhances O(2)radical anion production and reduces m icrovascular Kv channel current and functional responses. CAs from Sprague- Dawley rats were incubated 24 hours in medium containing either normal gluc ose (NG, 5.5 mmol/L D-glucose), high glucose (HG, 23 mmol/L D-glucose), or L-lucose (LG, 5.5 mmol/L D-glucose and 17 mmol/L L-glucose). O(2)radical an ion production was increased in HG arteries. Whole-cell patch clamping show ed a reduction of 4-aminopyridine (4-AP)-sensitive current (Kv current) fro m smooth muscle cells of HG CAs versus NG CAs or versus LG CAs (peak densit y 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). O(2)radical anion generation (xanthine+xanthine oxidase) decreased K+ current density, with no further reduction by 4-AP. P artial restoration was observed with superoxide dismutase and catalase. Con striction to 3 mmol/L 4-AP was reduced in vessels exposed to HG (13<plus/mi nus>5%, P<0.05) versus NG (30<plus/minus>7%) or LG (34 +/-4%). Responses to KCI and nifedipine were, not different among groups. Superoxide dismutase and catalase increased contraction to 4-AP in HG CAs. This is the first dir ect evidence that exposure of CAs to HG impairs Kv channel activity. We spe culate that this O(2)radical anion-induced impairment may reduce vasodilato r responsiveness in the coronary circulation of subjects with coronary dise ase or its risk factors.