C-JunNH₂-Terminal Kinase Contributes to Dexmedetomidine-Induced Contraction in Isolated Rat Aortic Smooth Muscle

Abstract

PurposeDexmedetomidine, a full agonist of α2B-adrenoceptors, is used for analgesia and sedation in the intensive care units. Dexmedetomidine produces an initial transient hypertension due to the activation of post-junctional α2B-adrenoceptors on vascular smooth muscle cells (SMCs). The aims of this in vitro study were to identify mitogen-activated protein kinase (MAPK) isoforms that are primarily involved in full, α2B-adrenoceptor agonist, dexmedetomidine-induced contraction of isolated rat aortic SMCs.Materials and MethodsRat thoracic aortic rings without endothelium were isolated and suspended for isometric tension recording. Cumulative dexmedetomidine (10-9 to 10-6 M) dose-response curves were generated in the presence or absence of extracellular signal-regulated kinase (ERK) inhibitor PD 98059, p38 MAPK inhibitor SB 203580, c-Jun NH2-terminal kinase (JNK) inhibitor SP 600125, L-type calcium channel blocker (verapamil and nifedipine), and α2-adrenoceptor inhibitor atipamezole. Dexmedetomidine-induced phosphorylation of ERK, JNK, and p38 MAPK in rat aortic SMCs was detected using Western blotting.ResultsSP 600125 (10-6 to 10-5 M) attenuated dexmedetomidine-evoked contraction in a concentration-dependent manner, whereas PD 98059 had no effect on dexmedetomidine-induced contraction. SB 203580 (10-5 M) attenuated dexmedetomidine-induced contraction. Dexmedetomidine-evoked contractions were both abolished by atipamezole and attenuated by verapamil and nifedipine. Dexmedetomidine induced phosphorylation of JNK and p38 MAPK in rat aortic SMCs, but did not induce phosphorylation of ERK.ConclusionDexmedetomidine-induced contraction involves a JNK- and p38 MAPK-mediated pathway downstream of α2-adrenoceptor stimulation in rat aortic SMCs. In addition, dexmedetomidine-induced contractions are primarily dependent on calcium influx via L-type calcium channels.

Hydrogen sulphide induces vasoconstriction of rat coronary artery via activation of Ca2+ influx

“…Rho kinase and MAPK pathways play essential roles in vascular smooth muscle contraction (Ok et al . , Matsumoto et al . ).…”

“…Rho kinase and MAPK pathways play essential roles in vascular smooth muscle contraction (Ok et al 2011, Matsumoto et al 2014. H 2 S-induced vasoconstriction occurs via a reduction in cAMP accumulation .…”

Multiple activation mechanisms of serotonin-mediated contraction in the carotid arteries obtained from spontaneously hypertensive rats

“…Concentrationresponse curves for 5-HT (1 nmol L −1 -30 μmol L −1 ) and norepinephrine (100 pmol L −1 -10 μmol L −1 ) in endotheliumintact carotid arterial rings were measured. To investigate the signaling pathways of 5-HT-mediated contraction, we examined 5-HT-mediated contraction in the absence or presence of various inhibitors as follows: (1) 10 μmol L −1 PD98059 (MEK/ERK pathway inhibitor [20,28,29,34,39]), (2) 10 μmol L −1 SB203580 (p38 MAPK inhibitor [19,34]), (3) 1 μmol L −1 SP600125 (c-Jun N-terminal kinase (JNK) inhibitor [14,49]), (4) 10 μmol L −1 LY294002 (PI3K inhibitor [34,58]), (5) 1 μmol L −1 Y27632 (Rho kinase inhibitor [29,34]), and (6) 10 μmol L −1 GSK2334470 (PDK1 inhibitor [58]). …”

Dexmedetomidine-induced contraction involves c-JunNH2-terminal kinase phosphorylation through activation of the 5-lipoxygenase pathway in the isolated endothelium-denuded rat aorta

“…Dexmedetomidine‐induced contraction mainly involves activation of the lipoxygenase (LOX) pathway among the arachidonic acid metabolic pathways . In addition, vasoconstriction produced by dexmedetomidine mainly involves c‐ Jun NH 2 ‐terminal kinase (JNK) activation among the mitogen‐activated protein kinase (MAPK) isoforms in the isolated endothelium‐denuded aorta . JNK in vascular smooth muscle cells is activated by the arachidonic acid and LOX metabolite, 12‐hydroperoxyeicosatetraenoic acid .…”