Lipid Emulsion Enhances Vasoconstriction Induced by Dexmedetomidine in the Isolated Endothelium-Intact Aorta.

Soo Hee Lee,Seung Hyun Ahn,Ji-Yoon Kim,Yeran Hwang,Kyeong-Eon Park,Sung Il Bae,Seong-Ho Ok,Hyun-Jin Kim,Ju-Tae Sohn

doi:10.3390/ijms22073309

Abstract

This study aimed to examine the effect of lipid emulsion (LE) on the vasoconstriction induced by dexmedetomidine (DMT) in the isolated rat aorta and elucidate the associated cellular mechanism. The effect of LE, NW-nitro-L-arginine methyl ester (L-NAME), and methyl-β-cyclodextrin (MβCD) on the DMT-induced contraction was examined. We investigated the effect of LE on the DMT-induced cyclic guanosine monophosphate (cGMP) formation and DMT concentration. The effect of DMT, LE, 4-Amino-3-(4-chlorophenyl)-1-(t-butyl)-1H-pyrazolo[3,4-d]pyrimidine,4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), and rauwolscine on the phosphorylation of endothelial nitric oxide synthase (eNOS), caveolin-1, and Src kinase was examined in the human umbilical vein endothelial cells. L-NAME, MβCD, and LE (1%, standardized mean difference (SMD): 2.517) increased the DMT-induced contraction in the endothelium-intact rat aorta. LE (1%) decreased the DMT (10−6 M) concentration (SMD: −6.795) and DMT-induced cGMP formation (SMD: −2.132). LE (1%) reversed the DMT-induced eNOS (Ser1177 and Thr496) phosphorylation. PP2 inhibited caveolin-1 and eNOS phosphorylation induced by DMT. DMT increased the Src kinase phosphorylation. Thus, LE (1%) enhanced the DMT-induced contraction by inhibition of NO synthesis, which may be caused by the decreased DMT concentration. DMT-induced NO synthesis may be caused by the increased eNOS (Ser1177) phosphorylation and decreased eNOS (Thr495) phosphorylation potentially mediated by Src kinase-induced caveolin-1 phosphorylation.

Highlights

Dexmedetomidine (DMT), which is a highly selective alpha-2 adrenoceptor agonist (α2 :α1 = 1620:1), is widely used for sedation [1,2]
Low concentration (1%) of lipid emulsion (LE) did not significantly alter the DMTinduced contraction of the endothelium-intact aorta pretreated with L-NAME (10−4 M)
Seems to be due to inverse agonism [28]. These results suggest that an increased stimulatory endothelial nitric oxide synthase (eNOS) (Ser1177) phosphorylation and reduced inhibitory eNOS (Thr495) phosphorylation by DMT are mediated by the pathway involving caveolin-1 and Src kinase via alpha-2 adrenoceptor (Figure 10) [16,25,26,27]

Summary

Introduction

Dexmedetomidine (DMT), which is a highly selective alpha-2 adrenoceptor agonist (α2 :α1 = 1620:1), is widely used for sedation [1,2]. A small dose of DMT (0.2 μg/kg/h and 0.6 μg/kg/h) causes a slightly decreased mean arterial blood pressure, whereas a high dose of DMT (1.25 μg/kg and 2.5 μg/kg) causes an initial increase in mean arterial 4.0/). A high dose of DMT used for sedation in pediatric patients causes hypertension, which is mediated by alpha-2 adrenoceptor stimulation of the vascular smooth muscles [5,6,7,8]. Lipid emulsion (LE) was originally developed for parenteral nutrition. LE is used for parenteral nutrition, and for treatment of systemic toxicity of local anesthetic or non-local anesthetic drugs [9]. DMT can be used to sedate patients receiving

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