Dexmedetomidine-induced contraction involves c-Jun NH2-terminal kinase phosphorylation through activation of the 5-lipoxygenase pathway in the isolated endothelium-denuded rat aorta
- Authors
- Ok, Seong-Ho; Byon, Hyo-Jin; Jin, Hana; Kim, Hye Jung; Kim, Woochan; Nam, In-Koo; Eun, So Young; Sohn, Ju-Tae
- Issue Date
- Dec-2014
- Publisher
- WILEY
- Keywords
- alpha-2 adrenoceptor; aorta; c-Jun NH2-terminal kinase; contraction; dexmedetomidine; lipoxygenase
- Citation
- CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, v.41, no.12, pp.1014 - 1022
- Indexed
- SCIE
SCOPUS
- Journal Title
- CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
- Volume
- 41
- Number
- 12
- Start Page
- 1014
- End Page
- 1022
- URI
- https://scholarworks.bwise.kr/gnu/handle/sw.gnu/18615
- DOI
- 10.1111/1440-1681.12307
- ISSN
- 0305-1870
- Abstract
- Vasoconstriction induced by dexmedetomidine, a highly selective alpha-2 adrenoceptor agonist, mainly involves c-Jun NH2-terminal kinase (JNK) phosphorylation in the isolated endothelium-denuded aorta. We carried out an in vitro study to determine the main arachidonic acid metabolic pathway that is involved in dexmedetomidine-induced JNK activation. Cumulative dexmedetomidine concentration-contractile response curves were generated in the endothelium-denuded rat aorta in the presence or absence of the following inhibitors: the JNK inhibitor SP600125, the phospholipase A(2) inhibitor quinacrine dihydrochloride, the non-specific lipoxygenase (LOX) inhibitor nordihydroguaiaretic acid, the 5-LOX inhibitor AA-861, the dual 5-LOX and cyclooxygenase (COX) inhibitor phenidone, the non-specific COX inhibitor indomethacin, the cytochrome p450 epoxygenase inhibitor fluconazole, the COX-1 inhibitor SC-560, and the COX-2 inhibitor NS-398. The effect of the alpha-2 adrenoceptor inhibitor rauwolscine and other inhibitors, such as quinacrine dihydrochloride, nordihydroguaiaretic acid, AA-861, phenidone, indomethacin and the protein kinase C inhibitor GF 109203X, on dexmedetomidine-induced JNK phosphorylation was investigated in rat aortic vascular smooth muscle cells with western blotting. The effect of dexmedetomidine on 5-LOX and COX-2 expression was investigated in vascular smooth muscle cells. SP600125, quinacrine dihydrochloride, nordihydroguaiaretic acid, AA-861, phenidone, rauwolscine and chelerythrine attenuated dexmedetomidine-induced contraction. Indomethacin slightly attenuated dexmedetomidine-induced contraction. Fluconazole and SC-560 had no effect on dexmedetomidine-induced contraction, whereas NS-398 attenuated contraction. SP600125, rauwolscine, quinacrine dihydrochloride, nordihydroguaiaretic acid, AA-861, phenidone and GF 109203X attenuated dexmedetomidine-induced JNK phosphorylation. 5-LOX and COX-2 were upregulated by dexmedetomidine. Thus, dexmedetomidine-induced alpha-2 adrenoceptor-mediated contraction is mediated mainly by 5-LOX and partially by COX-2, which leads to JNK phosphorylation.
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