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.

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We would like to thank Tomoki Katome, Yuri Asano, Akari Ishibiki, Saya Imamura, Myu Kozakai, Kana Saegusa, Kanako Takimoto, Takeru Toda, Yuka Hayashida, Taiga Yoshida, Marina Ito, Yurika Ezaki, Amane Kurakata, Yuzuki Sato, Tamayo Hashimoto, Yurina Mae, and Hiyori Yokoyama for the excellent technical assistance. We also thank Enago ( for the English language review.


This work was supported in part by grants JSPS KAKENHI grant numbers JP18K06861 (to Takayuki Matsumoto), JP17K08318 (to Kumiko Taguchi), and JP18K06974 (to Tsuneo Kobayashi).

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T.M. and T.K. conceived and designed the research; T.M., K.T., and M.K. performed the experiments; T.M., K.T., M.K., T.K, and K.T. analyzed the data; T.M., K.T., M.K., T.K., K.T., and T.K. interpreted the results; T.M. prepared the figures; T.M. drafted the manuscript; T.M. and T.K. edited and revised the manuscript; T.M., K.T., M.K., T.K., K.T., and T.K. approved the final version of the manuscript.

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Correspondence to Takayuki Matsumoto or Tsuneo Kobayashi.

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Matsumoto, T., Takayanagi, K., Kojima, M. et al. Mechanisms underlying suppression of noradrenaline-induced contraction by prolonged treatment with advanced glycation end-products in organ-cultured rat carotid artery. Pflugers Arch - Eur J Physiol 472, 355–366 (2020).

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  • Advanced glycation end-products
  • Carotid artery
  • Contraction
  • Noradrenaline
  • Vascular smooth muscle