Mechanisms underlying suppression of noradrenaline-induced contraction by prolonged treatment with advanced glycation end-products in organ-cultured rat carotid artery.

We investigated the direct effects of prolonged exposure to advanced glycation end-products (AGEs) on noradrenaline-induced contraction of rat carotid artery smooth muscle. Noradrenaline-induced contraction of endothelium-denuded carotid artery rings was suppressed by AGE-bovine serum albumin (AGE-BSA) pretreatment (0.01 and 0.1 mg/mL for 23 ± 1 h) compared with vehicle pretreatment (control), whereas isotonic-K+-induced contraction was not significantly altered by AGE-BSA pretreatment. This reduction in noradrenaline-induced contraction by AGE-BSA (0.1 mg/mL) was reversed by iberiotoxin, an inhibitor of large-conductance calcium-activated potassium (BKCa) channels, but not by inhibitors of other K channels [4-AP (Kv inhibitor), TRAM-34 (IKCa inhibitor), or glibenclamide (KATP inhibitor)]. Acute incubation of carotid arterial rings with H2O2 had also reduced noradrenaline-induced contraction in control arteries, but it had no effect on noradrenaline-induced contraction in AGE-BSA-pretreated arteries. Alternatively, acute incubation with the H2O2 scavenger catalase increased noradrenaline-induced contraction of AGE-BSA-pretreated arteries but had no effect on noradrenaline-induced contraction of control arteries. Noradrenaline-induced contraction in the presence of H2O2 was increased by co-treatment with iberiotoxin. The AGE-BSA-mediated suppression of noradrenaline-induced contraction was prevented by the organic cation transporter 3 (OCT3) inhibitor corticosterone, whereas the expression of OCT3 protein was similar between control and AGE-BSA-treated endothelium-denuded carotid arteries. These findings suggest that noradrenaline-induced arterial contraction is reduced by prolonged AGE-BSA exposure due to activation of BKCa channels via H2O2 generation and increased OCT3-mediated noradrenaline transport activity.