Voltage-gated Na+ channels (VGSCs) in nociceptive neurons are the molecular targets for local anaesthetics. However, due to the ubiquity of VGSCs in excitable tissues, they are prone to inhibition by local anaesthetics, including the cardiac NaV1.5 subtype, which is also expressed in metastatic breast and colon cancer cells. The expression and function of NaV1.5 facilitate invasion and migration of colon cancer cells. Local anaesthetics inhibit metastatic cancer cell invasion in vitro by inhibiting NaV1.5 VGSCs, which may contribute to a direct mechanism by which regional anaesthesia during tumour resection reduces subsequent cancer recurrence. Metastatic colon cancer cells express adult and neonatal NaV1.5 splice variants. Lidocaine and levobupivacaine are amide local anaesthetics that are widely used in the clinic. They have different physiochemical properties and thus differ in their pharmacokinetic and pharmacodynamic profile. We compared the mechanisms of action of these two local anaesthetics on adult and neonatal NaV1.5 channels recombinantly expressed in human embryonic kidney cells using whole cell voltage-clamp. Lidocaine and levobupivacaine inhibited adult and neonatal NaV1.5 in a state-dependent manner. Both drugs required the inactivated state of the channel for inhibition within the concentration range tested. Lidocaine and levobupivacaine stabilised the inactivated state, resulting in significant hyperpolarising shifts in the V1/2 of inactivation, while neither affected the V1/2 of activation. Levobupivacaine was approximately 10-fold more potent than lidocaine. The potency of both local anaesthetics was similar on adult and neonatal splice variants. The neonatal NaV1.5 variant recovered more readily than the adult from lidocaine blockade. On the other hand, blockade by levobupivacaine of both splice variants, upon recovery from inactivation, was irreversible within the time scale examined. These findings are discussed in the context of their implications for cardiac toxicity and putative antimetastatic effects of local anaesthetics.
|Date of Award||2016|
|Supervisor||Tim Hales (Supervisor)|