Modulation of the Cardiac Sodium Current by Inhalational Anesthetics in the Absence and Presence of β-Stimulation

Weigt, Henry U.; Kwok, Wai‐Meng; Rehmert, Georg C.; Bošnjak, Željko J.

doi:10.1097/00000542-199801000-00019

Cited by 19 publications

(21 citation statements)

References 33 publications

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“…Furthermore, inactivation of the inhibitory G iα protein as demonstrated previously (Böhm et al, 1994) appears to be involved in the facilitation of halothane-, but not isoflurane-associated cardiac dysrhythmias (Weigt et al, 1998b). Similarly, I Na was reduced upon β-adrenergic stimulation by isoproterenol (1 μmol/L), and this inhibition was potentiated by halothane and somewhat less by isoflurane (Weigt et al, 1998a). In case of halothane, this synergistic effect was reduced in the presence of the G protein inhibitor GDPβS and a specific PKA inhibitor, whereas PKA inhibition had no effect in case of isoflurane (Weigt et al, 1998a).…”

supporting

confidence: 60%

“…Interestingly, coexpression experiments of Na + channel α-subunits from skeletal muscle, brain, and cardiac muscle with PKC in Xenopus oocytes have shown that halothane (1 mmol/L) was without effect on any of the three isoforms when expressed alone, but reduced Na + current after PKC coexpression, with skeletal and neuronal isoforms being markedly more sensitive than the cardiac one (Patel et al, 2000). Potential synergistic effects of volatile anesthetics with PKC and PKA pathways on cardiac Na + current have been investigated in guinea pig ventricular myocytes using the α 1 -and β-adrenoceptor agonists methoxamine and isoproterenol, respectively, and other tools interfering with G proteins and kinases (Weigt et al, 1997b(Weigt et al, , 1998a(Weigt et al, , 1998b. Methoxamine decreased I Na in a concentration-and voltage-dependent manner, being more potent at depolarized potentials, and halothane (1.2 mmol/L) and isoflurane (1.0 mmol/L) interacted synergistically with methoxamine to reduce I Na around the physiologic cardiac resting potential (Weigt et al, 1997b).…”

Section: Cardiac Sodium Channelsmentioning

confidence: 99%

“…Similarly, I Na was reduced upon β-adrenergic stimulation by isoproterenol (1 μmol/L), and this inhibition was potentiated by halothane and somewhat less by isoflurane (Weigt et al, 1998a). In case of halothane, this synergistic effect was reduced in the presence of the G protein inhibitor GDPβS and a specific PKA inhibitor, whereas PKA inhibition had no effect in case of isoflurane (Weigt et al, 1998a).…”

mentioning

confidence: 96%

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Mechanisms Involved in Cardiac Sensitization by Volatile Anesthetics: General Applicability to Halogenated Hydrocarbons?

Himmel

2008

Critical Reviews in Toxicology

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An increased sensitivity of the heart to catecholamines or cardiac sensitization is a recognized risk during acute human exposure to halogenated hydrocarbons used as solvents, foam-blowing or fire-extinguishing agents, refrigerants, and aerosol propellants. Although cardiac sensitization to such "industrial" halocarbons can result in serious arrhythmia and death, research into its mechanistic basis has been limited, whereas the literature on volatile anesthetics (e.g., halothane, chloroform) is comparably extensive. A review of the literature on halocarbons and related volatile anesthetics was conducted. The available experimental evidence suggests that volatile anesthetics at physiologically relevant concentrations interact predominantly with the main repolarizing cardiac potassium channels hERG and I Ks , as well as with calcium and sodium channels at slightly higher concentrations. On the level of the heart, inhibition of these ion channels is prone to alter both action potential shape (triangulation) and electrical impulse conduction, which may facilitate arrhythmogenesis by volatile anesthetics per se and is potentiated by catecholamines. Action potential triangulation by regionally heterogeneous inhibition of calcium and potassium channels will facilitate catecholamine-induced afterdepolarizations, triggered activity, and enhanced automaticity. Inhibition of cardiac sodium channels will reduce conduction velocity and alter refractory period; this is potentiated by catecholamines and promotes reentry arrhythmias. Other cardiac and/or neuronal mechanisms might also contribute to arrhythmogenesis. The few scattered in vitro data available for halocarbons (e.g., FC-12, halon 1301, trichloroethylene) suggest inhibition of cardiac sodium (conduction), calcium and potassium channels (triangulation), extraneuronal catecholamine reuptake, and various neuronal ion channels. Therefore, it is hypothesized that halocarbons promote cardiac sensitization by similar mechanisms as volatile anesthetics. Experimental approaches for further investigation of these sensitization mechanisms by selected halocarbons are suggested.

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confidence: 60%

Section: Cardiac Sodium Channelsmentioning

confidence: 99%

mentioning

confidence: 96%

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Mechanisms Involved in Cardiac Sensitization by Volatile Anesthetics: General Applicability to Halogenated Hydrocarbons?

Himmel

2008

Critical Reviews in Toxicology

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“…As has been discussed for L-type Ca 2þ channels, it is important to consider interference of anesthetics with regulatory pathways. Halothane evoked an attenuation of Na þ currents by complex interactions with pathways involving G proteins and cAMP (115). For isoflurane, pharmacological evidence has been presented showing that it interacted with G proteins (partly distinct from those affected by halothane) and with protein kinase C (116).…”

Section: Na + Channelsmentioning

confidence: 99%

Effects of volatile anesthetics on cardiac ion channels

Hüneke¹,

Fassl²,

Rossaint³

et al. 2004

Acta Anaesthesiol Scand

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The focus of the present review is on how interference with various ion channels in the heart may be the molecular basis for cardiac side-effects of gaseous anesthetics. Electrophysiological studies in isolated animal and human cardiomyocytes have identified the L-type Ca(2+) channel as a prominent target of anesthetics. Since this ion channel is of fundamental importance for the plateau phase of the cardiac action potential as well as for Ca(2+)-mediated electromechanical coupling, its inhibition may facilitate arrhythmias by shortening the refractory period and may decrease the contractile force. Effective inhibition of this ion channel has been shown for clinically used concentrations of halothane and, to a lesser extent, of isoflurane and sevoflurane, whereas xenon was without effect. Anesthetics furthermore inhibit several types of voltage-gated K(+) channels. Thereby, they may disturb the repolarization and bear a considerable risk for the induction of ventricular tachycardia in predisposed patients. In future, an advanced understanding of cardiac side-effects of anesthetics will derive from more detailed analyses of how and which channels are affected as well as from a better comprehension of how altered channel function influences heart function.

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“…Pathophysiological implications have been described: PKC modulation is at least partially responsible for the modulatory action of lysophosphatidylcholine, which has been implicated in arrhythmogenesis during ischemia [134][135][136]. Furthermore, cardiac dysrhythmias during inhalation anesthesia by halothane and isoflurane are also related to PKA-and PKC-mediated phosphorylation of cardiac sodium channels [137,138]. …”

Section: Cardiac Sodium Channelmentioning

confidence: 99%

Isoform Diversity and Modulation of Sodium Channels by Protein Kinases

Schultze-Seemann¹

1999

Cell Physiol Biochem

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Although voltage-dependent sodium channels from the brain have been realized as targets for regulatory protein phosphorylation since the first isolation of sodium channels as proteins, the functional role of phosphoprotein formation has been obscured until recently. The review summarizes progress on the modulation of voltage-dependent sodium channels by serine/threonine protein kinases, i.e. PKA and PKC. Divergent modulation is discussed in context with divergent primary structure of the α-subunit.

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Modulation of the Cardiac Sodium Current by Inhalational Anesthetics in the Absence and Presence of β-Stimulation

Cited by 19 publications

References 33 publications

Mechanisms Involved in Cardiac Sensitization by Volatile Anesthetics: General Applicability to Halogenated Hydrocarbons?

Mechanisms Involved in Cardiac Sensitization by Volatile Anesthetics: General Applicability to Halogenated Hydrocarbons?

Effects of volatile anesthetics on cardiac ion channels

Isoform Diversity and Modulation of Sodium Channels by Protein Kinases

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