Voltage-dependent blockade by bupivacaine of cardiac sodium channels expressed in Xenopus oocytes

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. Na v 1.5 is the dominant isoform of VGSCs expressed in cardiac myocytes, and its dysfunction may be the cause of bupivacainetriggered arrhythmia. Here, we investigated the effect of bupivacaine on Na v 1.5 within the clinical concentration range. The electrophysiological measurements on Na v 1.5 expressed in Xenopus oocytes showed that bupivacaine induced a voltageand 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 Na v 1.5 currents. The underlying mechanisms of this blockade may contribute to the fact that bupivacaine not only dose-dependently affected the gating kinetics of Na v 1.5 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.

In VitroNegative Inotropic Effect of Low Concentrations of Bupivacaine Relates to Diminished Ca2+ Sensitivity but Not to Ca2+ Handling or β-Adrenoceptor Signaling

“…Potency values for bupivacaine to block cardiac sodium channels vary widely and are hard to interpret since drug binding depends on resting membrane potential, stimulation rate, and extracellular sodium concentration. 17,18 Since there is an almost linear relation between sodium currents and upstroke velocity, 19 we simultaneously measured action potential and force in intact muscle preparations of guinea pig ventricles exposed to a wide range of bupivacaine concentrations.…”

A New Strategy for Multitarget Drug Discovery/Repositioning Through the Identification of Similar 3D Amino Acid Patterns Among Proteins Structures: The Case of Tafluprost and its Effects on Cardiac Ion Channels

“…The differential activity of tafluprost upon both ion channels (as well as its higher potency as compared with the local anesthetic bupivacaine (Stoetzer et al, 2016)) roughly agrees with the theoretical binding energies predicted by the docking simulations. Noteworthy, although tafluprost was clearly less active in NaV1.5 than in TASK-1, it still shows a potency in a similar range as that shown by the well-known sodium channel blocker bupivacaine (Zhang et al, 2014). Even though this is the first time that an activity of tafluprost on cardiac channels is described, it should be noted that it had been reported that the drug is able to induce a relaxation of rabbit ciliary arteries precontracted with a high-potassium solution (Dong et al, 2008).…”

Local Anesthetic Like Inhibition of the Cardiac Na+ Channel Nav1.5 by Chloroquine and Hydroxychloroquine

“…Nevertheless, both agents induce less use-dependent block compared to bupivacaine and other LAs but showing similar effects to methadone which was reported to have relevant LA-like properties. 28 , 29 , 67 In addition to the use-dependent block as a surrogate for an increasing affinity of Nav1.5 channels towards an agent as a response to repetitive depolarizations, substance-specific kinetics are responsible for the duration of their blocking capabilities. Fast onset of inhibition and slow dissociation from inactivated cardiac Na + channels of bupivacaine and amitriptyline led to the generally used classification of “fast in” and “slow out” blockers.…”