Abstract 15968: Rescue of Bupivacaine-induced Cardiac Arrest by Lipid Emulsion is Prevented by Inhibition of Free Fatty Acid Receptor GPR40

Abstract

Introduction: Bupivacaine overdose leads to lethal arrhythmias and cardiac arrest. Lipid emulsion (LE) is cardioprotective and rescues Bupivacaine toxicity. Although both lipid sink and metabolic theories have been proposed, yet the exact molecular mechanism is not known. G protein-coupled receptor 40 (GPR40), also known as free fatty acid receptor-1 is activated by medium and long chain fatty acids. Among free fatty acid receptors, GPR40 expression is one of the highest in heart. Hypothesis: As GPR40 is activated by medium and long chain fatty acids, we hypothesized that GPR40 may mediate LE’s rescue of Bupivacaine cardiotoxicity. Methods: Male Sprague-Dawley rats were used. Continuous Echocardiography and ECG were done. In protocol-1 (n=6), rats received Bupivacaine bolus (10mg/kg, IV) to induce asystole. Resuscitation with LE 20% (5ml/kg bolus, and 0.5ml/kg/min maintenance) and chest compressions were initiated. In Protocol-2 (n=6) rats were pre-treated with GPR40-antagonist GW1100 (200uM, IV) 30-min before inducing asystole. Heart rate (HR) and ejection-fraction (EF) were measured before and 30-min after GW1100. In both protocols, HR, EF and fractional shortening (FS) were measured before asystole (baseline) and at 1, 5 and 10-min after LE. Means±SEM are reported. Results: In protocol-1, baseline HR and EF were 321±21 beats/min and 72.3±4.6%. Bupivacaine resulted in asystole. LE improved HR gradually within 10min; HR was 86±13 at 1min (27% recovery), 216±10 at 5min (67% recovery), and 228±14 at 10min (71% recovery). LV function fully recovered within 5 min of LE treatment as EF and FS were similar to baseline (EF=72±5%, FS=42±4%). To test our hypothesis, rats were pretreated with GW1100, 30-min before inducing asystole. There were no significant differences between HR and EF before (HR=316.6±3.3, EF=68.0±2.3%) and 30-min after GW1100 (HR=330±5.7, EF=71.6±1.5%) excluding GW1100 effects on hemodynamics. GW1100 pre-treatment however prevented LE rescue, with no recovery of cardiac function even after 10min of LE. Conclusions: This is the first report of involvement of GPR40 in rescue of Bupivacaine-induced cardiac arrest by LE. Discovery of GPR40 as a potential receptor for effects of LE may help us understand LE-induced cardioprotection.