Voltage-Dependent Effects of Volatile Anesthetics on Cardiac Sodium Current

Abstract

Cardiac dysrhythmias during inhaled anesthesia are well documented and may, in part, involve depression of the fast inward Na+ current (INa) during the action potential upstroke. In this study, we examined the effects of halothane, isoflurane, and sevoflurane at clinically relevant concentrations on INa in single ventricular myocytes isolated enzymatically from adult guinea pig hearts. INa was recorded using standard whole-cell configuration of the patch clamp technique. Halothane at 0.6 mM and 1.2 mM produced significant (P < 0.05) depressions of peak INa of 12.3% +/- 1.8% and 24.4% +/- 4.1% (mean +/- SEM, n = 12), respectively. Isoflurane (0.5 mM, n = 12; 1.0 mM, n = 15) and sevoflurane (0.6 mM, n = 14; 1.2 mM, n = 12) were less potent than halothane, decreasing peak INa by 4.8% +/- 1.1% and 11.4% +/- 1.4% (isoflurane) and 3.0% +/- 0.7% and 10.7% +/- 3.9% (sevoflurane). The depressant effects on INa were reversible in all cases. For all anesthetics tested, the degree of block increased at more depolarizing potentials. Anesthetics induced significant shifts in the steady-state inactivation and activation of the channel toward more hyperpolarizing potentials. The present findings indicate that volatile anesthetics at clinical concentrations decrease the cardiac INa in a dose- and voltage-dependent manner. At approximately equianesthetic concentrations, the decrease of INa caused by halothane was twice that observed with isoflurane or sevoflurane.

Comparative Effects of Halogenated Inhaled Anesthetics on Voltage-gated Na+Channel Function

“…Our results are comparable to those reported for the cardiac isoform Na v 1.5, for which equi-anesthetic concentrations of halothane are more potent than isoflurane in tonic blockade of human9 and guinea pig23 cardiac I Na . Isoflurane, halothane and desflurane, which were analyzed in more detail, exhibited state-dependent block and a negative shift in the voltage dependence of inactivation, consistent with enhancement of inactivation at physiological holding potentials.…”

“…Isoflurane, halothane and desflurane, which were analyzed in more detail, exhibited state-dependent block and a negative shift in the voltage dependence of inactivation, consistent with enhancement of inactivation at physiological holding potentials. State-dependent block has been reported previously for isoflurane effects on I Na in rat neurohypophysial nerve terminals,7 guinea pig cardiomyocytes,23 and heterologously expressed Na v 1.2, Na v 1.4, Na v 1.5 and Na v 1.6 8–11. Moreover, isoflurane and halothane affected channel gating evident as accelerated current decay and use-dependent block (halothane > isoflurane).…”

Isoflurane and Propofol Inhibit Voltage-Gated Sodium Channels in Isolated Rat Neurohypophysial Nerve Terminals

“…The actions of isoflurane on the voltage dependence of activation were unremarkable, and the small effect of propofol was evident only at a holding potential of Ϫ70 mV. In a previous report, volatile anesthetics shifted the voltage dependence of both activation and steady-state inactivation of cardiac Na ϩ currents toward more hyperpolarized potentials (Weigt et al, 1997). This may represent a subtle difference in anesthetic actions on neuronal (Nav1.2, Nav1.3, and Nav1.6) versus cardiac (Nav1.5) voltage-gated Na ϩ channels.…”

A possible mechanism of halocarbon-induced cardiac sensitization arrhythmias

“…Studies implicate halocarbons in alterations of a number of ion channels, and these changes may contribute to their arrhythmic effect. Halocarbon effects include activation of hyperpolarizing, background potassium channels [37,38], reduction of gap junction conductance between cells [39], alterations of voltagegated calcium channel activity [40], increases in calcium release from the sarcoplasmic reticulum [41][42][43][44] and depression of the sodium current [36,[45][46][47].…”