Abstract 19275: T-type Calcium Channel Overexpression in Mice Attenuates Recovery from Bupivacaine-Induced Cardiac Arrest

Abstract

Background _ The cardiotoxicity from the local anesthetic bupivacaine is predominantly a result of sodium channel blockade, though calcium channel inhibition has been implicated as well. Mechanisms of reversal of this cardiotoxicity are unclear. We investigated the toxicity of bupivacaine on FVB isolated mouse hearts that were either wild type (WT) or overexpressors for T-type calcium channel (TTCC). We subsequently attempted reversal of cardiotoxicity with a combination of intralipid and epinephrine. We hypothesized that the increased calcium metabolism of the transgenic hearts would augment the adverse effects of bupivacaine. Methods and Results _ Hearts from anesthetized WT and transgenic FVB mice aged 4 months were excised and placed on a Langendorff perfusion apparatus. The left atrial auricle was excised, the mitral valve was perforated, and a fluid-filled balloon was placed in the left ventricle to capture left ventricular pressure and heart rate data. After 10 min of baseline perfusion at an EDP of 10mmHg, bupivacaine was added at 100μM, causing arrest of cardiac activity for both mouse lines. After 3 min of cardiac arrest, the heart was perfused with a solution of bupivacaine (30μM), intralipid (0.2%) and epinephrine (0.15μg/ml) with cardiac recovery following. At baseline, there were no differences in left ventricle function between WT and transgenic mice. After recovery, the left ventricle end diastolic pressure in the transgenic mice was significantly higher (29.18 ± 4.05 mm Hg) than in the WT mice (17.15 ± 0.83 mmHg), P=0.02). Furthermore, the left ventricle developed pressure was significantly reduced (P=0.03) in the transgenic mice (28.61 ± 5.966 mmHg) when compared to WT (57.17 ± 8.052 mmHg). When incorporating heart rate, the Rate Pressure Product (HR x LVESP) was significantly decreased (P=0.03) in the transgenic mice (6455 ± 748.3) versus the WT (11396 ± 1646). Electrophysiological analysis revealed significantly increased suppression of calcium current in the L Type Calcium Channel (P=0.03) Conclusions _ These data show that bupivacaine-induced cardiotoxicity is more difficult to reverse in hearts overexpressing TTCC, possibly reflecting a stronger inhibition of Calcium release from the Sarcoplasmic Reticulum in them.