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Int J Med Sci 2015; 12(9):727-736. doi:10.7150/ijms.11952

Research Paper

Dexmedetomidine-Induced Contraction in the Isolated Endothelium-Denuded Rat Aorta Involves PKC-δ-mediated JNK Phosphorylation

Jongsun Yu1*, Seong-Ho Ok1*, Won Ho Kim2, Hyunhoo Cho3, Jungchul Park3, il-Woo Shin1, Heon Keun Lee1, Young-Kyun Chung1, Mun-Jeoung Choi4, Seong-Chun Kwon5, Ju-Tae Sohn1,6✉

1. Department of Anesthesiology and Pain Medicine, Gyeongsang National University School of Medicine and Gyeongsang National University Hospital, Jinju-si, 52727, Republic of Korea
2. Department of Anesthesiology and Pain Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
3. Department of Anesthesiology and Pain Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
4. Department of Oral and Maxillofacial Surgery, Gyeongsang National University Hospital, Jinju, Republic of Korea
5. Department of Physiology, Institute for Clinical and Translational Research, Catholic Kwandong University College of Medicine, Gangneung, 25601, Korea
6. Institute of Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
* These authors contributed equally to this study as co-first authors.

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.

Keywords: dexmedetomidine, protein kinase C, aorta, protein kinase C-δ, vasoconstriction, c-Jun NH2-terminal kinase

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How to cite this article:
Yu J, Ok SH, Kim WH, Cho H, Park J, Shin iW, Lee HK, Chung YK, Choi MJ, Kwon SC, Sohn JT. Dexmedetomidine-Induced Contraction in the Isolated Endothelium-Denuded Rat Aorta Involves PKC-δ-mediated JNK Phosphorylation. Int J Med Sci 2015; 12(9):727-736. doi:10.7150/ijms.11952. Available from http://www.medsci.org/v12p0727.htm