Abstract
The goal of this in vitro study was to examine the effect of a lipid emulsion on toxic-dose bupivacaine-induced vasodilation in a model of tyrosine phosphatase inhibitor sodium orthovanadate-induced contraction in endothelium-denuded rat aortae and to elucidate the associated cellular mechanism. The effect of a lipid emulsion on vasodilation induced by a toxic dose of a local anesthetic during sodium orthovanadate-induced contraction was examined. In addition, the effects of various inhibitors, either bupivacaine alone or a lipid emulsion plus bupivacaine, on protein kinase phosphorylation induced by sodium orthovanadate in rat aortic vascular smooth muscle cells was examined. A lipid emulsion reversed the vasodilation induced by bupivacaine during sodium orthovanadate-induced contraction. The lipid emulsion attenuated the bupivacaine-mediated inhibition of the sodium orthovanadate-induced phosphorylation of protein tyrosine, c-Jun NH2-terminal kinase (JNK), myosin phosphatase target subunit 1 (MYPT1), phospholipase C (PLC) γ-1 and extracellular signal-regulated kinase (ERK). These results suggest that a lipid emulsion reverses toxic-dose bupivacaine-induced vasodilation during sodium orthovanadate-induced contraction via the activation of a pathway involving either tyrosine kinase, JNK, Rho-kinase and MYPT1 or tyrosine kinase, PLC γ-1 and ERK, and this reversal is associated with the lipid solubility of the local anesthetic and the induction of calcium sensitization.
Highlights
Lipid emulsions are widely used to mitigate systemic toxicity induced by local anesthetics or lipid-soluble non-local anesthetic drugs [1]
Bupivacaine (10−3 M), lidocaine (3 × 10−3 M) and mepivacaine (10−2 M) produced vasodilation in isolated endothelium-denuded rat aortae precontracted with sodium orthovanadate (10−3 M) (Figure 1)
The magnitude of the lipid emulsion (0.5% to 2%)-mediated reversal of vasodilation induced by local anesthetics was as follows: bupivacaine, lidocaine and mepivacaine (Figure S1)
Summary
Lipid emulsions are widely used to mitigate systemic toxicity induced by local anesthetics or lipid-soluble non-local anesthetic drugs [1]. Tyrosine kinase-induced protein tyrosine phosphorylation in vascular smooth muscle contributes to contraction by both calcium sensitization, which is mediated by the regulation of phospholipase C and D and mitogen-activated protein kinase (MAPK) activity, and the regulation of voltage-operated calcium channels [4]. The effect of lipid emulsions on toxic-dose bupivacaine-induced vasodilation during protein tyrosine phosphorylation-mediated contraction, which is associated with a mechanism of agonist-induced contraction, including norepinephrine released from sympathetic nerve endings in vivo, remains unknown [5,10]. The goal of this in vitro study was to investigate the effect of lipid emulsion on vasodilation induced by a toxic dose of bupivacaine during sodium orthovanadate-induced protein tyrosine phosphorylation-mediated contraction of isolated endothelium-denuded rat aortae and to elucidate the associated cellular mechanism, with a particular focus on the signaling pathways downstream of sodium orthovanadate-induced protein tyrosine phosphorylation in vascular smooth muscle
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