title: Mechanisms underlying increased serotonin-induced contraction in carotid arteries from chronic type 2 diabetic Goto-Kakizaki rats.
abstract: Serotonin (5-hydroxytryptamine; 5-HT) plays important roles in the cardiovascular system; however, the relationship between 5-HT-induced vasocontraction and the arterial 5-HT system including metabolism and signal transduction, in the presence of chronic type 2 diabetes (T2D) remains unclear. Therefore, we investigated 5-HT-induced contraction and associated mechanisms in carotid arteries from chronic T2D Goto-Kakizaki (GK) rats. Contractions in response to 5-HT were examined in carotid arteries from GK rats (42-46 weeks old). To investigate the response mechanisms of arterial smooth muscle, we constructed concentration-response curves for TCB2 (5-HT2A-receptor agonist), BW723C86 (5-HT2B-receptor agonist), and 5-HT in the presence of various inhibitors using endothelium-denuded preparations. Carotid arterial expressions of monoamine oxidase-A (MAO-A), serotonin transporter (SERT), and 5-HT2A were detected by immunoblotting. 5-HT-induced contraction was increased in carotid arteries from GK compared to control Wistar rats in both endothelium-intact and -denuded preparations. In denuded preparations, we found that: (1) TCB2-induced contraction was increased in GK rat arteries (vs. Wistar); (2) MAO-A inhibitor did not affect 5-HT-induced contraction, whereas SERT inhibitor augmented such contractions in both groups; and (3) differences in 5-HT-induced contractions were abolished by p38 MAPK, PI3K, and Rho kinase inhibitors. Carotid arterial expressions of MAO-A, SERT, and 5-HT2A remained unchanged in the groups. The results suggest that 5-HT-induced contraction is augmented in T2D GK rat carotid arteries. This augmentation is due to smooth muscle activation partly mediated by p38 MAPK, PI3K, and Rho kinases, and may also be partly due to arterial SERT activity.
authors.affiliation: Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Taguchi
authors.affiliation: Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan. Electronic address: tkoba@hoshi.ac.jp.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000502:physiology*; D003010:Clorgyline / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000502:physiology; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D012701:Serotonin / Q000502:physiology*; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D008996:Monoamine Oxidase Inhibitors; D047428:Protein Kinase Inhibitors; D016601:RNA-Binding Proteins; D044402:Receptor, Serotonin, 5-HT2A; C482440:Sert1 protein, rat; D012701:Serotonin; D008995:Monoamine Oxidase; D011494:Protein Kinases; D003010:Clorgyline
keywords: Carotid artery; Contraction; Diabetes; Kinase; Serotonin transporter; Vascular smooth muscle