Bupivacaine destabilizes action potential duration in cellular and computational models of long QT syndrome 1

Background: The effects of the local anesthetic bupivacaine on cardiac action potentials (APs) are mainly attributed to inhibition of cardiac Na ⁺ channels. The relevance of its ability to also induce high-affinity blockade of human ether-à-gogo-related gene (hERG) channels is unclear. We investigated whether this interaction may functionally become more significant in cellular and computational models of long (L)QT syndromes. Methods: Left ventricular cardiomyocytes were isolated from adult guinea pig hearts, and bupivacaine-induced effects on APs were investigated using the patch-clamp technique. LQT-like states were pharmacologically induced by either blocking IKs (LQT1-like, 10 μmol/L chromanol 293B), or IKr (LQT2-like, 10 μmol/L E4031). Computational analysis of bupivacaine's effects was based on the Luo-Rudy dynamic model. Results: Bupivacaine induced dose-dependent AP shortening in control myocytes. However, in the presence of 1 to 30 μmol/L bupivacaine, a high variability in AP duration with AP prolongations of up to 40% was observed. This destabilizing effect on AP duration was significantly increased in LQT1-like but not in LQT2-like myocytes. Similarly, the incidence of AP prolongations in the presence of 3 μmol/L bupivacaine was significantly increased from 6% in control myocytes to 24% in LQT1-like but not in LQT2-like myocytes. Computational modeling supported the concept that this bupivacaine-induced AP instability and the AP prolongations in the control and LQT1-like myocytes were caused by inhibition of hERG channels. CONCLUSIONS:: This study provides evidence that bupivacaine induces inhibition of hERG channels, which is functionally silent under normal conditions but will become more relevant in LQT1-like states in which repolarization relies to a larger degree on hERG channels. Interactions with ion channels other than cardiac Na channels may, therefore, determine the net cardiac effects of bupivacaine when the normal balance of ionic currents is altered.