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Elevated glucose impairs cAMP-mediated dilation by reducing K_v channel activity in rat small coronary smooth muscle cells

Departments of Internal Medicine and Cardiovascular Center, Medical College of Wisconsin, and Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin 53226

Submitted 14 March 2003 ; accepted in final form 20 May 2003

Hyperglycemia impairs endothelium-dependent vasodilation. In this study, we examined the effect of high glucose (HG) on vascular smooth muscle function. Rat small coronary arteries were freshly isolated or incubated for 24 h with normal glucose (NG; 5.5 mmol/l) or HG (23 mmol/l). In freshly isolated arteries, dilation to isoproterenol (Iso) was reduced by 3 mmol/l 4-aminopyridine (4-AP; 44 ± 10% vs. 77 ± 4%; P < 0.05) and further reduced by 4-AP + iberiotoxin (IbTX; 100 nmol/l; 17 ± 2%). Dilation to forskolin was abolished by 4-AP (–3 ± 17 vs. 73 ± 9%). cAMP production was similar in NG and HG vessels. Dilations to Iso and forskolin were significantly reduced in HG arteries (Iso, 41 ± 5% vs. 70 ± 6%; forskolin, 40 ± 4% vs. 75 ± 4%) compared with NG arteries. A similar reduction was also observed to the dilation to papaverine. Endothelial denudation had no effect on Iso-induced dilation. In HG vessels, the reduced 4-AP-sensitive component of Iso-induced dilation was greater compared with the IbTX-sensitive component. Iso increased whole cell K⁺ current in NG cells but had little effect in HG cells. Similarly, 4-AP-, but not IbTX-sensitive, K⁺ currents were reduced in HG cells. These results suggest that HG impairs cAMP-mediated dilation primarily by reducing K_v channel function. We speculate that in addition to the endothelial dysfunction, altered smooth muscle function may also contribute to the reduced coronary vasodilation in diabetes.

coronary circulation; potassium channel; hyperglycemia

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