Abstract
Bupivacaine ranks as the most potent and efficient drug among class I local anesthetics, but its high potential for toxic reactions severely limits its clinical use. Although bupivacaine-induced toxicity is mainly caused by substantial blockade of voltage-gated sodium channels (VGSCs), how these hydrophobic molecules interact with the receptor sites to which they bind remains unclear. Nav1.5 is the dominant isoform of VGSCs expressed in cardiac myocytes, and its dysfunction may be the cause of bupivacaine-triggered arrhythmia. Here, we investigated the effect of bupivacaine on Nav1.5 within the clinical concentration range. The electrophysiological measurements on Nav1.5 expressed in Xenopus oocytes showed that bupivacaine induced a voltage- and concentration-dependent blockade on the peak of I Na and the half-maximal inhibitory dose was 4.51 μmol/L. Consistent with other local anesthetics, bupivacaine also induced a use-dependent blockade on Nav1.5 currents. The underlying mechanisms of this blockade may contribute to the fact that bupivacaine not only dose-dependently affected the gating kinetics of Nav1.5 but also accelerated the development of its open-state slow inactivation. These results extend our knowledge of the action of bupivacaine on cardiac sodium channels, and therefore contribute to the safer and more efficient clinical use of bupivacaine.