Abstract 287: 5-Hydroxydecanoate, a Mitochondrial Selective KATP Antagonist, Blocks the Rescue Action of Lipid Emulsion in Bupivacaine-Induced Cardiotoxicity

Abstract

Introduction: Lipid emulsion (intralipid) rescues Bupivacaine-induced cardiac toxicity. We have shown previously that glibenclamide, a non selective ATP potassium channel blocker abolishes the rescue action of intralipid. Here we explored the role of 5-Hydroxydecanoate (5-HD), a mitochondrial selective KATP antagonist in the intralipid-mediated rescue of bupivacaine overdose. Methods: Young male Sprague-Dawley rats (300-350 g) were anesthetized intraperitoneally with a mixture of ketamine (80 mg/kg) and xylazine (8 mg/kg), and ventilated with a ventilator. M-mode echocardiography were acquired throughout the experiment. In protocol-1 (n=5), asystole was induced by a single injection of bupivacaine (10mg/kg over 20 seconds, intravenously) and resuscitation with Intralipid 20% (5ml/kg bolus, and 0.5ml/kg/min maintenance) with chest compression was started immediately. In protocol-2 (n=8) rats were pre-treated with 5-HD (5 mg/kg, IV) 30 minutes prior to inducing asystole with bupivacaine. In both protocols the heart rate (HR), ejection fraction (EF) and fractional shortening (FS) were measured before inducing asystole (baseline), and at 1, 5 and 10 min after lipid treatment. A two way repeated measure analysis of variance (ANOVA) model was used for comparison of means. Values are mean ± SEM, n=5 rats/group, p<0.05 significant. Results: In protocol-1, the baseline HR and EF were 321±21 and 72.3±4.6%. Bupivacaine resulted in asystole and intralipid therapy improved the heart rate and cardiac function within 10 min(HR=86±13beats/min at 1min, 216±10beats/min at 5 min, and 228±14beats/min at 10 min). The left ventricular systolic function fully recovered in all rats within 5 min of intralipid treatment (EF=72±5%, FS=42±4%). In protocol-2, there were no significant differences between HR and EF before (HR=324.6±16.5 beats/min, EF=78.0±2.8%) and 30 min after (HR=340.9±15.6 beats/min, EF=83.3±2.0%) 5-HD adminstration. However, 5-HD (5mg/kg), prevented the intralipid-induced rescue of bupivacaine overdose, as there was no recovery within 10 min of intralipid therapy. Conclusions: Pre-treatment with 5-HD prevents the lipid rescue of bupivacaine-induced cardiotoxicity suggesting that mitochondrial KATP channels are involved.