Abstract
The goal of this study was to investigate the effect of lipid emulsion on a toxic dose of local anesthetic-mediated reduction of vasodilation evoked by the ATP-sensitive potassium (KATP) channel agonist levcromakalim. The effect of lipid emulsion (LE) and linoleic acid on the local anesthetic-mediated reduction of vasodilation and membrane hyperpolarization evoked by levcromakalim was assessed in isolated endothelium-denuded vessels (rat aorta and mesenteric artery) and aortic vascular smooth muscle cells. The effect of LE and linoleic acid on KATP channel activity in transfected HEK-293 cells was investigated, as was the effect of LE on bupivacaine concentration. The efficacy of LE in attenuating the local anesthetic-mediated reduction of vasodilation evoked by levcromakalim was correlated with the lipid solubility of the local anesthetic. Linoleic acid attenuated the bupivacaine-mediated reduction of vasodilation evoked by levcromakalim. LE decreased the bupivacaine-mediated reduction of membrane hyperpolarization evoked by levcromakalim but did not significantly alter the mepivacaine-mediated reduction. LE and linoleic acid both reversed the bupivacaine-mediated decrease of KATP activity and enhanced KATP activity. LE decreased the bupivacaine concentration. Linoleic acid may be the major contributor to LE-induced attenuation of bupivacaine-mediated reduction of vasodilation evoked by levcromakalim via the direct activation of KATP channels and indirect effects.
Highlights
Lipid emulsions effectively treat cardiovascular depression evoked by a toxic dose of local anesthetics [1]
A toxic dose of bupivacaine (10−5 M), ropivacaine (5 × 10−5 M) and mepivacaine (3 × 10−4 M) decreased vasodilation evoked by levcromakalim in the isolated endothelium-denuded rat aorta and mesenteric artery (Figure 1A–F)
Lipid emulsion (0.25% and 1%) significantly attenuated the toxic dose of bupivacaine-mediated reduction of maximal vasodilation evoked by levcromakalim (10−5 M) in isolated endothelium-denuded rat aorta (Figure 1A, p < 0.001), and the highest concentration of lipid emulsion (1%) only significantly attenuated the ropivacaine-mediated reduction of maximal vasodilation evoked by levcromakalim (10−5 M) (Figure 1B, p < 0.001)
Summary
Lipid emulsions effectively treat cardiovascular depression evoked by a toxic dose of local anesthetics [1]. Decreased blood flow evoked by the systemic toxicity of local anesthetics produces pathophysiologic states, including ischemia, hypoxia and acidosis, which cause adenosine triphosphate-sensitive potassium (KATP) channel-evoked vasodilation of the vascular smooth muscle as a protective response [7,8]. Local anesthetics such as lidocaine, R-(+)-bupivacaine, and mepivacaine decrease the vasodilation evoked by the KATP channel agonist levcromakalim in isolated vessels [9,10,11,12]. The objective of this study was to examine the effect of a lipid emulsion and linoleic acid on the toxic dose of local anesthetic-mediated reduction of levcromakalim-evoked vasodilation in isolated vessels, including rat aorta and mesenteric artery, and to examine the underlying mechanism
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