Lipid emulsions enhance the norepinephrine-mediated reversal of local anesthetic-induced vasodilation at toxic doses

Abstract

Purpose: Intravenous lipid emulsions have been used to treat the systemic toxicity of local anesthetics. The goal of this in vitro study was to examine the effects of lipid emulsions on the norepinephrine-mediated reversal of vasodilation induced by high doses of levobupivacaine, ropivacaine, and mepivacaine in isolated endothelium-denuded rat aorta, and to determine whether such effects are associated with the lipid solubility of local anesthetics.

Materials and methods: The effects of lipid emulsions (0.30, 0.49, 1.40, and 2.61%) on norepinephrine concentration-responses in high-dose local anesthetic (6×10(-4) M levobupivacaine, 2×10(-3) M ropivacaine, and 7×10(-3) M mepivacaine)-induced vasodilation of isolated aorta precontracted with 60 mM KCl were assessed. The effects of lipid emulsions on local anesthetic- and diltiazem-induced vasodilation in isolated aorta precontracted with phenylephrine were also assessed.

Results: Lipid emulsions (0.30%) enhanced norepinephrine-induced contraction in levobupivacaine-induced vasodilation, whereas 1.40 and 2.61% lipid emulsions enhanced norepinephrine-induced contraction in both ropivacaine- and mepivacaine-induced vasodilation, respectively. Lipid emulsions (0.20, 0.49 and 1.40%) inhibited vasodilation induced by levobupivacaine and ropivacaine, whereas 1.40 and 2.61% lipid emulsions slightly attenuated mepivacaine (3×10(-3) M)-induced vasodilation. In addition, lipid emulsions attenuated diltiazem-induced vasodilation. Lipid emulsions enhanced norepinephrine-induced contraction in endothelium-denuded aorta without pretreatment with local anesthetics.

Conclusion: Taken together, these results suggest that lipid emulsions enhance the norepinephrine-mediated reversal of local anesthetic-induced vasodilation at toxic anesthetic doses and inhibit local anesthetic-induced vasodilation in a manner correlated with the lipid solubility of a particular local anesthetic.

Keywords: Lipid emulsion; local anesthetic-induced vasodilation; norepinephrine; systemic toxicity of local anesthetic.

Fig. 1

Effects of lipid emulsions (LEs: 0.30, 0.49, 1.40, and 2.61%) on the norepinephrine concentration-response curves in high-dose levobupivacaine (LBV, A)-, ropivacaine (RPV, B)-, and mepivacaine (MPV, C)-induced vasodilation of isolated endothelium-denuded aorta precontracted with 60 mM KCl. Data are the means±SD expressed as the percentage of the maximal contraction induced by isotonic 60 mM KCl [100%=3.20±0.30 g (n=6) and 100%=2.96±0.35 g (n=6) for endothelium-denuded rings with control and 0.30% LE, respectively, in A; 100%=3.44±0.26 g (n=7), 100%=3.35±0.36 g (n=5), and 100%=3.30±0.22 g (n=7) for endothelium-denuded rings with control, 0.49% LE and 1.40% LE, respectively, in B; 100%=3.29±0.50 g (n=5), 100%=3.00±0.56 g (n=5), and 100%=3.08±0.19 g (n=5) for endothelium-denuded rings with control, 1.40% LE and 2.61% LE, respectively, in C]. N indicates the number of rats from which descending thoracic aortic rings were derived. ^*p<0.05, ^†p<0.01, and ^‡p<0.001 versus control. SD, standard deviation.

Fig. 2

Effects of lipid emulsions (LEs: 0.30 and 0.49%) on the norepinephrine concentration-response curves of isolated endothelium-denuded aorta without local anesthetics. Data are the means±SD expressed as the percentage of the maximal contraction induced by isotonic 60 mM KCl [100%=2.93±0.36 g (n=5), 100%=3.00±0.42 g (n=5), and 100%=2.74±0.44 g (n=5) for endothelium-denuded rings with control, 0.30% LE and 0.49% LE, respectively]. N indicates the number of rats from which descending thoracic aortic rings were derived. ^*p<0.001 and ^†p<0.01 versus control. SD, standard deviation.

Fig. 3

The effects of lipid emulsions (LEs: 0.20, 0.49, 1.40, and 2.61%) on local anesthetic (levobupivacaine: A, ropivacaine: B, and mepivacaine: C)-induced concentration-response curves in isolated endothelium-denuded aorta precontracted with 10^-7 M phenylephrine. Data are the means±SD expressed as the percentage of the maximal contraction induced by phenylephrine [10^-7 M; 100%=2.99±0.34 g (n=7), 100%=3.09±0.35 g (n=5), and 100%=3.11±0.49 g (n=7) for endothelium-denuded rings with control, 0.20% LE and 0.49% LE, respectively, in A; 100%=3.42±0.43 g (n=6), 100%=3.30±0.38 g (n=5), 100%=3.50±0.40 g (n=6), and 100%=3.30±0.29 g (n=5) for endothelium-denuded rings with control, 0.20% LE, 0.49% LE, and 1.40% LE, respectively, in B; 100%=3.43±0.20 g (n=5), 100%=3.48±0.77 g (n=5), 100%=3.54±0.40 g (n=5), and 100%=3.46±0.36 g (n=5) for endothelium-denuded rings with control, 0.49% LE, 1.40% LE, and 2.61% LE, respectively, in C]. N indicates the number of rats from which descending thoracic aortic rings were derived. ^*p<0.05, ^†p<0.01, and ^‡p<0.001 versus control. A: ^§p<0.001 versus 0.2% LE. B: ^§p<0.001 versus 0.49% LE. C: ^§p<0.001 versus 0.49% LE. SD, standard deviation.

Fig. 4

The lipid emulsion concentration-response curves in endothelium-denuded aorta precontracted with 10^-7 M phenylephrine. Data are the means±SD expressed as the percentage of the maximal contraction induced by 10^-7 M phenylephrine [100%=2.78±0.46 g (n=8) and 100%=2.68±0.45 g (n=8) for endothelium-denuded aortic rings with time-matched control and lipid emulsion, respectively]. N indicates the number of isolated descending thoracic aortic rings. SD, standard deviation.

Fig. 5

Effects of lipid emulsions (LEs: 1.40 and 2.61%) on diltiazem concentration-response curves in endothelium-denuded aorta precontracted with 10^-7 M phenylephrine. Data are the means±SD expressed as the percentage of the maximal contraction induced by phenylephrine [10^-7 M; 100%=2.64±0.44 g (n=6), 100%=2.51±0.22 g (n=5), and 100%=2.59±0.46 g (n=5) for endothelium-denuded rings with control, 1.40% LE, and 2.61% LE, respectively]. N indicates the number of rats from which descending thoracic aortic rings were derived. ^*p<0.05, ^†p<0.01 and ^‡p<0.001 versus control. ^§p<0.05 and ^∥p<0.01 versus 1.40% LE. SD, standard deviation.