The Distinct Effects of Lipid Emulsions Used for “Lipid Resuscitation” on Gating and Bupivacaine-Induced Inhibition of the Cardiac Sodium Channel Nav1.5

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Systemic administration of lipid emulsions is an established treatment for local anesthetic intoxication. However, it is unclear by which mechanisms lipids achieve this function. The high cardiac toxicity of the lipophilic local anesthetic bupivacaine probably results from a long-lasting inhibition of the cardiac Na channel Nav1.5. In this study, we sought to determine whether lipid emulsions functionally interact with Nav1.5 or counteract inhibition by bupivacaine. Human embryonic kidney cells expressing human Nav1.5 were investigated by whole-cell patch clamp. The effects of Intralipid® and Lipofundin® were explored on functional properties and on bupivacaine-induced inhibition. Intralipid and Lipofundin did not affect the voltage dependency of activation, but induced a small hyperpolarizing shift of the steady-state fast inactivation and impaired the recovery from fast inactivation. Lipofundin, but not Intralipid, induced a concentration-dependent but voltage-independent tonic block (42% ± 4% by 3% Lipofundin). The half-maximal inhibitory concentration (IC50) values for tonic block by bupivacaine (50 ± 4 µM) were significantly increased when lipids were coapplied (5% Intralipid: 196 ± 22 µM and 5% Lipofundin: 103 ± 8 µM). Use-dependent block by bupivacaine at 10 Hz was also reduced by both lipid emulsions. Moreover, the recovery of inactivated channels from bupivacaine-induced block was faster in the presence of lipids. Our data indicate that lipid emulsions reduce rather than increase availability of Nav1.5. However, both Intralipid and Lipofundin partly relieve Nav1.5 from block by bupivacaine. These effects are likely to involve not only a direct interaction of lipids with Nav1.5 but also the ability of lipid emulsions to absorb bupivacaine and thus reduce its effective concentration.