Abstract
Dexmedetomidine, a highly selective α-2 adrenoceptor agonist, produces vasoconstriction, which leads to transiently increased blood pressure. The goal of this study was to investigate specific protein kinases and the associated cellular signal pathways responsible for the increased calcium sensitization induced by dexmedetomidine in isolated rat aortas, with a particular focus on phosphorylation-dependent inhibitory protein of myosin phosphatase (CPI-17). The effect of Y-27632 and chelerythrine on the dexmedetomidine-induced intracellular calcium concentration ([Ca2+]i) and tension were assessed using fura-2-loaded aortic strips. The effects of rauwolscine, Y-27632, chelerythrine, and ML-7 hydrochloride on the dexmedetomidine-induced phosphorylation of CPI-17 or of the 20-kDa regulatory light chain of myosin (MLC20) were investigated in rat aortic vascular smooth muscle cells. The effects of rauwolscine, Y-27632, and chelerythrine on the membrane translocation of Rho-kinase and protein kinase C (PKC) phosphorylation induced by dexmedetomidine were assessed. Y-27632 and chelerythrine each reduced the slopes of the [Ca2+]i-tension curves of dexmedetomidine-induced contraction, and Y-27632 more strongly reduced these slopes than did chelerythrine. Rauwolscine, Y-27632, chelerythrine, and ML-7 hydrochloride attenuated the dexmedetomidine-induced phosphorylation of CPI-17 and MLC20. Taken together, these results suggest that dexmedetomidine-induced contraction involves calcium sensitization, which appears to be mediated by CPI-17 phosphorylation via Rho-kinase or PKC.
Highlights
As a highly selective α-2 adrenoceptor agonist, dexmedetomidine induces sedation, reduces the opioid analgesic requirement, and attenuates the hemodynamic response to anesthesia and surgery [1,2]
A previous study demonstrated that the slope of the [Ca2+ ]i -tension curve induced by dexmedetomidine is steeper than the slope of the [Ca2+ ]i -tension curve induced by high KCl, suggesting that dexmedetomidine-induced α-2 adrenoceptor-mediated contraction would be mediated by calcium sensitization [15]
The downstream cellular signal pathways associated with specific protein kinases that contribute to calcium sensitization remain unknown
Summary
As a highly selective α-2 adrenoceptor agonist, dexmedetomidine induces sedation, reduces the opioid analgesic requirement, and attenuates the hemodynamic response to anesthesia and surgery [1,2]. Blood pressure response, which consists of transient hypertension followed by decreased blood This initial hypertension is due to α-2 adrenoceptor stimulation of vascular smooth pressure [3]. This initial transient hypertension is due to α-2 adrenoceptor stimulation of vascular muscle, muscle, whereas whereas the observed decrease indecrease blood pressure is associated a centralwith sympatholytic smooth the observed in blood pressure iswith associated a central effect evoked by dexmedetomidine [4,5,6,7,8]. The goal of this in vitro study investigatecellular the specific protein kinase and contribute cellular to the increased sensitization induced a particular focus associated signalingcalcium pathways that contribute to by thedexmedetomidine, increased calcium with sensitization induced ondexmedetomidine, CPI-17 phosphorylation.
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