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(Hypertension. 2008;52:507.)
© 2008 American Heart Association, Inc.

Original Articles

Roles of Phosphatidylinositol 3-Kinase-Akt and NADPH Oxidase in Adenosine 5'-Triphosphate–Sensitive K⁺ Channel Function Impaired by High Glucose in the Human Artery

Hiroyuki Kinoshita; Naoyuki Matsuda; Hikari Kaba; Noboru Hatakeyama; Toshiharu Azma; Katsutoshi Nakahata; Yasuhiro Kuroda; Kazuaki Tange; Hiroshi Iranami; Yoshio Hatano

From the Department of Anesthesiology (H. Kinoshita, K.N., K.T., Y.H.), Wakayama Medical University, Wakayama; Departments of Primary Care and Emergency Medicine (N.M.), Graduate School of Medicine, Kyoto University, Kyoto; Departments of Molecular Medical Pharmacology (H. Kaba) and Anesthesiology (N.H.), Toyama University School of Medicine, Toyama; Department of Anesthesiology (T.A.), Saitama Medical University, Moroyama; Department of Emergency Medical Center (Y.K.), Kagawa University Hospital, Miki-cho; Department of Anesthesia (H.I.), Japanese Red Cross Society, Wakayama Medical Center, Wakayama, Japan.

Correspondence to Hiroyuki Kinoshita, Department of Anesthesiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-0012, Japan. E-mail hkinoshi{at}pd5.so-net.ne.jp

The present study was designed to examine roles of the phosphatidylinositol 3-kinase-Akt pathway and reduced nicotinamide-adenine dinucleotide phosphate oxidases in the reduced ATP-sensitive K⁺ channel function via superoxide produced by high glucose in the human artery. We evaluated the activity of the phosphatidylinositol 3-kinase-Akt pathway, as well as reduced nicotinamide-adenine dinucleotide phosphate oxidases, the intracellular levels of superoxide and ATP-sensitive K⁺ channel function in the human omental artery without endothelium. Levels of the p85- subunit and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits, including p47phox, p22phox, and Rac-1, increased in the membrane fraction from arteries treated with D-glucose (20 mmol/L) accompanied by increased intracellular superoxide production. High glucose simultaneously augmented Akt phosphorylation at Ser 473, as well as Thr 308 in the human vascular smooth muscle cells. A phosphatidylinositol 3-kinase inhibitor LY294002, as well as tiron and apocynin, restored vasorelaxation and hyperpolarization in response to an ATP-sensitive K⁺ channel opener levcromakalim. Therefore, it can be concluded that the activation of the phosphatidylinositol 3-kinase-Akt pathway, in combination with the translocation of p47phox, p22phox, and Rac-1, contributes to the superoxide production induced by high glucose, resulting in the impairment of ATP-sensitive K⁺ channel function in the human visceral artery.

Key Words: ATP-sensitive K⁺ channels • human artery • hyperglycemia • NADPH oxidase • phosphatidylinositol 3-kinase