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Dexmedetomidine‐induced contraction involves c‐ Jun NH 2 ‐terminal kinase phosphorylation through activation of the 5‐lipoxygenase pathway in the isolated endothelium‐denuded rat aorta
Author(s) -
Ok SeongHo,
Byon HyoJin,
Jin Hana,
Kim Hye Jung,
Kim Woochan,
Nam InKoo,
Eun So Young,
Sohn JuTae
Publication year - 2014
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12307
Subject(s) - nordihydroguaiaretic acid , dexmedetomidine , cyclooxygenase , chemistry , pharmacology , arachidonic acid , chelerythrine , protein kinase c , phosphorylation , biochemistry , biology , sedation , enzyme
Summary Vasoconstriction induced by dexmedetomidine, a highly selective alpha‐2 adrenoceptor agonist, mainly involves c‐ Jun NH 2 ‐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 SP 600125, 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. SP 600125, 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. SP 600125, 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.