L-arginine and Arginase Products Potentiate Dexmedetomidine-induced Contractions in the Rat Aorta

Abstract

Background The α2-adrenergic sedative/anesthetic agent dexmedetomidine exerts biphasic effects on isolated arteries, causing endothelium-dependent relaxations at concentrations at or below 30 nM, followed by contractions at higher concentrations. l-arginine is a common substrate of endothelial nitric oxide synthase and arginases. This study was designed to investigate the role of l-arginine in modulating the overall vascular response to dexmedetomidine. Methods Isometric tension was measured in isolated aortic rings of Sprague Dawley rats. Cumulative concentrations of dexmedetomidine (10 nM to 10 μM) were added to quiescent rings (with and without endothelium) after previous incubation with vehicle, Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME; nitric oxide synthase inhibitor), prazosin (α1-adrenergic antagonist), rauwolscine (α2-adrenergic antagonist), l-arginine, (S)-(2-boronethyl)-l-cysteine hydrochloride (arginase inhibitor), NG-hydroxy-l-arginine (arginase inhibitor), urea and/or ornithine. In some preparations, immunofluorescent staining, immunoblotting, or measurement of urea content were performed. Results Dexmedetomidine did not contract control rings with endothelium but evoked concentration-dependent increases in tension in such rings treated with l-NAME (Emax 50 ± 4%) or after endothelium-removal (Emax 74 ± 5%; N = 7 to 12). Exogenous l-arginine augmented the dexmedetomidine-induced contractions in the presence of l-NAME (Emax 75 ± 3%). This potentiation was abolished by (S)-(2-boronethyl)-l-cysteine hydrochloride (Emax 16 ± 4%) and NG-hydroxy-l-arginine (Emax 18 ± 4%). Either urea or ornithine, the downstream arginase products, had a similar potentiating effect as l-arginine. Immunoassay measurements demonstrated an upregulation of arginase I by l-arginine treatment in the presence of l-NAME (N = 4). Conclusions These results suggest that when vascular nitric oxide homeostasis is impaired, the potentiation of the vasoconstrictor effect of dexmedetomidine by l-arginine depends on arginase activity and the production of urea and ornithine.

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

“…Consistent with the findings of a previous report, the DMT-induced contraction was enhanced in the endothelium-denuded aorta than in the endothelium-intact aorta [13]. In agreement with the previous report's findings, L-NAME and MβCD augmented the DMT-induced contraction of the endothelium-intact aorta (Figure 1B,C), suggesting that the DMT-induced contraction was attenuated by the pathway involving caveolin and NOS [13,14]. It was reported that LE decreases acetylcholine-induced NO-mediated vasodilation and increases left ventricular systolic pressure via inhibition of NO synthesis [17,20].…”

“…Increased fatty acids, which are derived from LE, enhanced blood pressure and systemic vascular resistance, and inhibited flow-mediated vasodilation, which seems to be caused by the decreased NO release of intact artery [10][11][12]. DMT-induced contraction of vascular smooth muscle is attenuated by endothelial nitric oxide (NO) release of intact aorta [13][14][15]. The phosphorylation of caveolin-1, which is upstream to the cellular signal pathway of NO production, induces endothelial nitric oxide synthase (eNOS) phosphorylation and NO release of intact vessel [16].…”

“…LE inhibits acetylcholine-induced NO-mediated vasodilation [17]. Therefore, in terms of endothelial NO release, as LE attenuates NOinduced vasodilation and DMT-induced contraction is attenuated by endothelial NO release of intact aorta, LE may augment the DMT-induced contraction via inhibition of endothelial NO release of intact aorta [10][11][12][13][14]17]. The widely accepted underlying mechanism of LE treatment of local anesthetic systemic toxicity is lipid shuttling, wherein LE absorbs highly lipid-soluble drug (e.g., bupivacaine; log (octanol/water partition coefficient): 3.41) from vital organs, such as the heart, and subsequently, the LE containing the highly lipid-soluble drug is transported to the liver and adipose tissue for detoxification and storage [9,18].…”

Effects of dexmedetomidine combined with oxycodone on sedation effect, perioperative inflammatory response and immunity

“…In this study, TNF-α and IL-6 levels at T3, T4, and T5 were increased in the four groups, with the levels in the ODG being lower as compared with those in the OG, DG, and CG, while IL-2 levels at T3, T4, and T5 were decreased in the four groups, with the levels in the ODG being higher as compared with those in the OG, DG, and CG (p < 0.05), coinciding with prior reports (Mo and Qiu 2017). Among these records, the enhanced perioperative inflammation in patients receiving local anesthetized transforaminal endoscopic resection of nucleus pulposus was alleviated by the actions of dexmedetomidine combined with oxycodone, possibly through mechanisms related to dexmedetomidine suppressing stress reactions in such way that postsynaptic receptors were activated, sympathetic nerve activity was reduced, and the excitability in the sympathetic nervous system induced by the operative wound was blocked as well as related to oxycodone lowering the intracellular cyclic adenosine as well as disturbing the e synthesis, and release of inflammatory factors (Ok et al 2016;Wong et al 2018).…”

Structure‑activity associations in novel farrerol derivatives with vasorelaxant properties

“…The upper hook was connected to a force transducer and changes in isometric force were recorded using Chart 5.4 (PowerLab; ADInstruments Inc., Colorado Springs, CO, USA). According to a previous study, passive tension was adjusted to 2 g and all subsequent measurements representing the force were generated above this baseline (14). Integrity of the endothelium was assumed when 10 -6 M acetylcholine induced >70% relaxation of the aortic rings precontracted with 60 mM KCl.…”