BACKGROUND: It is unclear whether improved metabolism or a "lipid sink" effect of lipid infusion is responsible for the positive effects in local anesthetic-induced myocardial depression. METHODS: We used an isolated rat heart, constant-pressure perfused, nonrecirculating Langendorff preparation and exposed hearts to 5 μg/mL l-bupivacaine and 9 μL/mL lipid emulsion. Hearts were freeze-clamped and energy was charge measured by HPLC. In a second experiment the effects of pacing hearts was evaluated. The effects of lipid addition on local anesthetic concentrations in Krebs-Henseleit buffer and human plasma were examined by using a mass spectrometer. RESULTS: With spontaneously beating hearts l-bupivacaine led to a significant decrease in heart rate (to 74% ± 7% of baseline), +dP/dt (69% ± 7%), systolic pressure (78% ± 6%), coronary flow (61% ± 8%), and to an increase in PR (177% ± 52%) and QRS intervals (166% ± 36%). Lipid infusion exerted a positive inotropic effect, significantly augmenting +dP/dt and systolic pressure back to 94% ± 11% and 102% ± 16% of baseline in l-bupivacaine-treated hearts. Heart rate, coronary flow, PR, and QRS intervals remained unchanged after lipid intervention. Lipid infusion in paced hearts had a significant effect on +dP/dt, systolic pressure, and Mvo2. Neither l-bupivacaine nor lipids had an effect on energy charge. A lipid concentration of 500 μL/mL plasma was necessary to effect changes in the plasma concentration of local anesthetics. CONCLUSION: Lipid application in l-bupivacaine-induced cardiac depression had a significant positive inotropic effect, which we would attribute to a direct inotropic effect. However, in an isolated heart model, indirect, local anesthetic plasma-binding effect of lipids cannot be excluded.