Abstract
Background: Cardiovascular resuscitation upon 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 triglyceride-rich lipid emulsion during resuscitation. However, the mechanism of action is poorly understood. Methods: The authors investigate the effects of ...
Abstract
Background: Cardiovascular resuscitation upon 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 triglyceride-rich lipid emulsion during resuscitation. However, the mechanism of action is poorly understood. Methods: The authors investigate the effects of a clinically used lipid emulsion (Lipovenos (R) MCT 20%; Fresenius Kabi AG, Bad Homburg, Germany) on the block of the fast Na+ current (I-Na) induced by the lipophilic local anesthetic bupivacaine in adult rat left ventricular myocytes by using the whole cell patch clamp technique. Results: Bupivacaine at 10 mu m decreased I-Na by 54% (-19.3 1.9 pApF(-1)vs. -42.3 +/- 4.3 pApF(-1); n = 17; P < 0.001; V-Pip = -40 mV, 1 Hz). Addition of 10% lipid emulsion in the presence of bupivacaine produced a 37% increase in I-Na (-26.4 +/- 2.8 pApF(-1); n = 17; P < 0.001 vs. bupivacaine alone). To test whether these results could be explained by a reduction in the free bupivacaine concentration by the lipid (lipid-sink effect), the authors removed the lipid phase from the bupivacaine-lipid mixture by ultracentrifugation. Also, the resulting water phase led to an increase in I-Na (+19%; n = 17; P < 0.001 vs. bupivacaine), demonstrating that part of the bupivacaine had been removed during ultracentrifugation. The substantially less lipophilic mepivacaine (40 mu m) reduced I-Na by 27% (n = 24; P < 0.001). The mepivacaine-lipid mixture caused a significant increase in I-Na (+17%; n = 24; P < 0.001). For mepivacaine, only a small lipid-sink effect could be demonstrated (+8%; n = 23; P < 0.01), reflecting its poor lipid solubility. Conclusion: The authors demonstrate lipid rescue on the single-cell level and provide evidence for a lipid-sink mechanism.
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