Cardiovascular resuscitation secondary to intoxication with lipophilic ion channel blocking agents has proven most difficult. Recently, favorable results have been reported when lipid rescue therapy is performed, i.e. the infusion of a lipid solution during resuscitation. However, the mechanism of action is poorly understood. Here we investigate the effects of a clinically employed lipid solution (Lipovenös® MCT 20%) on the block of the fast Na⁺ current (I_Na) induced by the lipophilic local anesthetic bupivacaine in adult rat left ventricular myocytes examined by the whole-cell patch-clamp technique. 10µM bupivacaine decreased I_Na by 54% (-19.3±1.9pApF^-1 vs. -42.3±4.3pApF^-1, n=17, p<0.001, V_Pip=-40mV, 1Hz). Addition of 10% lipid solution in the presence of bupivacaine resulted in a 37% increase in I_Na (-26.4±2.8pApF^-1, n=17, p<0.001). To test whether these results could be explained by a reduction of the free bupivacaine concentration by the lipid (lipid sink effect), we removed the lipid phase from the bupivacaine-lipid mixture by ultracentrifugation. The resulting water phase led to a smaller increase in I_Na than the complete lipid-bupivacaine mixture (+19%, n=17, p<0.001 vs. bupivacaine), demonstrating that a part of the bupivacaine had been removed during ultracentrifugation. The hydrophilic mepivacaine (40µM) reduced I_Na by 27% (p<0.001, n=24). The mepivacaine-lipid mixture caused a significant increase in I_Na (+17%, n=24, p<0.001). Also for mepivacaine a small lipid sink effect could be demonstrated (+8%, n=23, p<0.01), reflecting the relatively poor lipid solubility of mepivacaine. Taken together we demonstrate lipid rescue therapy on the single cell level and provide evidence for a lipid sink mechanism.