Advanced Glycation End Products Impair Voltage-Gated K+ Channels-Mediated Coronary Vasodilation in Diabetic Rats

BACKGROUND: We have previously reported that high glucose impairs coronary vasodilation by reducing voltage-gated K(+) (K(v)) channel activity. However, the underlying mechanisms remain unknown. Advanced glycation end products (AGEs) are potent factors that contribute to the development of diabetic vasculopathy. The aim of this study was to investigate the role of AGEs in high glucose-induced impairment of K(v) channels-mediated coronary vasodilation. METHODS: Patch-clamp recording and molecular biological techniques were used to assess the function and expression of K(v) channels. Vasodilation of isolated rat small coronary arteries was measured using a pressurized myograph. Treatment of isolated coronary vascular smooth muscle cells (VSMCs) and streptozotocin-induced diabetic rats with aminoguanidine, the chemical inhibitor of AGEs formation, was performed to determine the contribution of AGEs. RESULTS: Incubation of VSMCs with high glucose reduced K(v) current density by 60.4 ± 4.8%, and decreased expression of K(v)1.2 and K(v)1.5 both at the gene and protein level, whereas inhibiting AGEs formation or blocking AGEs interacting with their receptors prevented high glucose-induced impairment of K(v) channels. In addition, diabetic rats manifested reduced K(v) channels-mediated coronary dilation (9.3 ± 1.4% vs. 36.9 ± 1.4%, P < 0.05), which was partly corrected by the treatment with aminoguanidine (24.4 ± 2.2% vs. 9.3 ± 1.4%, P < 0.05). CONCLUSIONS: Excessive formation of AGEs impairs K(v) channels in VSMCs, then leading to attenuation of K(v) channels-mediated coronary vasodilation.