title: Dexmedetomidine-Induced Contraction in the Isolated Endothelium-Denuded Rat Aorta Involves PKC-δ-mediated JNK Phosphorylation.
abstract: Vasoconstriction mediated by the highly selective alpha-2 adrenoceptor agonist dexmedetomidine leads to transiently increased blood pressure and severe hypertension. The dexmedetomidine-induced contraction involves the protein kinase C (PKC)-mediated pathway. However, the main PKC isoform involved in the dexmedetomidine-induced contraction remains unknown. The goal of this in vitro study was to examine the specific PKC isoform that contributes to the dexmedetomidine-induced contraction in the isolated rat aorta. The endothelium-denuded rat aorta was suspended for isometric tension recording. Dexmedetomidine dose-response curves were generated in the presence or absence of the following inhibitors: the pan-PKC inhibitor, chelerythrine; the PKC-α and -β inhibitor, Go6976; the PKC-α inhibitor, safingol; the PKC-β inhibitor, ruboxistaurin; the PKC-δ inhibitor, rottlerin; the c-Jun NH2-terminal kinase (JNK) inhibitor, SP600125; and the myosin light chain kinase inhibitor, ML-7 hydrochloride. Western blot analysis was used to examine the effect of rottlerin on dexmedetomidine-induced PKC-δ expression and JNK phosphorylation in rat aortic vascular smooth muscle cells (VSMCs) and to investigate the effect of dexmedetomidine on PKC-δ expression in VSMCs transfected with PKC-δ small interfering RNA (siRNA) or control siRNA. Chelerythrine as well as SP600125 and ML-7 hydrochloride attenuated the dexmedetomidine-induced contraction. Go6976, safingol, and ruboxistaurin had no effect on the dexmedetomidine-induced contraction, whereas rottlerin inhibited the dexmedetomidine-induced contraction. Dexmedetomidine induced PKC-δ expression, whereas rottlerin and PKC-δ siRNA transfection inhibited dexmedetomidine-induced PKC-δ expression. Dexmedetomidine also induced JNK phosphorylation, which was inhibited by rottlerin. Taken together, these results suggest that the dexmedetomidine-induced contraction involves PKC-δ-dependent JNK phosphorylation in the isolated rat aorta.
authors.affiliation: 1. Department of Anesthesiology and Pain Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju-si, 52727, Republic of Korea.
authors.forename: Jongsun
authors.initials: J
authors.lastname: Yu
authors.affiliation: 1. Department of Anesthesiology and Pain Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju-si, 52727, Republic of Korea.
authors.forename: Seong-Ho
authors.initials: SH
authors.lastname: Ok
authors.affiliation: 2. Department of Anesthesiology and Pain Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea.
authors.forename: Won Ho
authors.initials: WH
authors.lastname: Kim
authors.affiliation: 3. Department of Anesthesiology and Pain Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea.
authors.forename: Hyunhoo
authors.initials: H
authors.lastname: Cho
authors.affiliation: 3. Department of Anesthesiology and Pain Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea.
authors.forename: Jungchul
authors.initials: J
authors.lastname: Park
authors.affiliation: 1. Department of Anesthesiology and Pain Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju-si, 52727, Republic of Korea.
authors.forename: Il-Woo
authors.initials: IW
authors.lastname: Shin
authors.affiliation: 1. Department of Anesthesiology and Pain Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju-si, 52727, Republic of Korea.
authors.forename: Heon Keun
authors.initials: HK
authors.lastname: Lee
authors.affiliation: 1. Department of Anesthesiology and Pain Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju-si, 52727, Republic of Korea.
authors.forename: Young-Kyun
authors.initials: YK
authors.lastname: Chung
authors.affiliation: 4. Department of Oral and Maxillofacial Surgery, Gyeongsang National University Hospital, Jinju, Republic of Korea.
authors.forename: Mun-Jeoung
authors.initials: MJ
authors.lastname: Choi
authors.affiliation: 5. Department of Physiology, Institute for Clinical and Translational Research, Catholic Kwandong University College of Medicine, Gangneung, 25601, Korea.
authors.forename: Seong-Chun
authors.initials: SC
authors.lastname: Kwon
authors.affiliation: 1. Department of Anesthesiology and Pain Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju-si, 52727, Republic of Korea ; 6. Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Ju-Tae
authors.initials: JT
authors.lastname: Sohn
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology; D053119:Benzophenanthridines / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D020927:Dexmedetomidine / Q000494:pharmacology*; D004730:Endothelium, Vascular; D007211:Indoles / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D001381:Azepines; D053119:Benzophenanthridines; D002227:Carbazoles; D007211:Indoles; D008301:Maleimides; D009281:Naphthalenes; C070571:ML 7; C081021:Go 6976; D020927:Dexmedetomidine; C099154:ruboxistaurin; C016299:chelerythrine; D051745:Protein Kinase C-delta; D048670:MAP Kinase Kinase 4
keywords: aorta; c-Jun NH2-terminal kinase; dexmedetomidine; protein kinase C; protein kinase C-δ; vasoconstriction