Repolarization of the cardiac action potential. Does an increase in repolarization capacity constitute a new anti‐arrhythmic principle?

Grunnet, Morten

doi:10.1111/j.1748-1716.2009.02072.x

Cited by 36 publications

(26 citation statements)

References 407 publications

(758 reference statements)

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“…Delayed rectifier K ϩ current, I Kr, constitutes the predominant outward current in HL-1 cells (4,39). Moreover, I Kr , inactivation contributes to the extended duration of the cardiac action potential and release from inactivation contributes to its repolarization (12). By virtue of the rapid release of channel inactivation on partial repolarization of the plasma membrane, I Kr displays a resurgent outward tail current due to the relatively slow ion channel deactivation (33) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Lipopolysaccharide prolongs action potential duration in HL-1 mouse cardiomyocytes

Wondergem

Graves

et al. 2012

American Journal of Physiology-Cell Physiology

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Wondergem R, Graves BM, Li C, Williams DL. Lipopolysaccharide prolongs action potential duration in HL-1 mouse cardiomyocytes. Am J Physiol Cell Physiol 303: C825-C833, 2012. First published August 15, 2012; doi:10.1152/ajpcell.00173.2012.-Sepsis has deleterious effects on cardiac function including reduced contractility. We have shown previously that lipopolysaccharides (LPS) directly affect HL-1 cardiac myocytes by inhibiting Ca 2ϩ regulation and by impairing pacemaker "funny" current, I f. We now explore further cellular mechanisms whereby LPS inhibits excitability in HL-1 cells. LPS (1 g/ml) derived from Salmonella enteritidis decreased rate of firing of spontaneous action potentials in HL-1 cells, and it increased their pacemaker potential durations and decreased their rates of depolarization, all measured by whole cell current clamp. LPS also increased action potential durations and decreased their amplitude in cells paced at 1 Hz with 0.1 nA, and 20 min were necessary for maximal effect. LPS decreased the amplitude of a rapidly inactivating inward current attributed to Na ϩ and of an outward current attributed to K ϩ ; both were measured by whole cell voltage clamp. The K ϩ currents displayed a resurgent outward tail current, which is characteristic of the rapid delayed-rectifier K ϩ current, IKr. LPS accordingly reduced outward currents measured with pipette Cs ϩ substituted for K ϩ to isolate IKr. E-4031 (1 M) markedly inhibited IKr in HL-1 cells and also increased action potential duration; however, the direct effects of E-4031 occurred minutes faster than the slow effects of LPS. We conclude that LPS increases action potential duration in HL-1 mouse cardiomyocytes by inhibition of IKr and decreases their rate of firing by inhibition of INa. This protracted time course points toward an intermediary metabolic event, which either decreases available mouse ether-a-go-go (mERG) and Na ϩ channels or potentiates their inactivation.delayed rectifier K ϩ current; patch-clamp electrophysiology; Salmonella enteritidis; E-4031 SEPSIS IS A COMPLEX CLINICAL problem that can progress into multiorgan dysfunction syndrome (MODS) and death. At least one-half of the high mortality rates of severe-sepsis, sepsis, and MODS result from cardiovascular failure (27). Approximately 40% of patients in septic shock also experience myocardial dysfunction (36, 44), which comprises reduced systolic contractility, impaired diastolic relaxation, and ventricular dilatation. The initial clinical pattern, however, ironically is termed "hyperdynamic," because it often presents with high cardiac output, elevated heart rate, and vasodilatation of the dermis (27). This is attributable in part to the volume loading that is frequently the initial treatment for septic shock patients to maintain cardiac output and organ perfusion (15, 28). As is often the case in the complexity of sepsis, the prevailing symptoms can mask organ and system failure occurring at a deeper level in the clinical spectrum.The most prevalent sign of myocardial depressio...

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Section: Resultsmentioning

confidence: 99%

Lipopolysaccharide prolongs action potential duration in HL-1 mouse cardiomyocytes

Wondergem

Graves

et al. 2012

American Journal of Physiology-Cell Physiology

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“…The cardiac action potential is composed of five distinct phases that are designated phases 0-4 [1] . The precise shape of the action potential is determined by the coordinated activity of many various ion channels.…”

Section: Introductionmentioning

confidence: 99%

Effects of the histamine H1 receptor antagonist hydroxyzine on hERG K+ channels and cardiac action potential duration

Lee

Chu

et al. 2011

Acta Pharmacol Sin

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Aim: To investigate the effects of hydroxyzine on human ether-a-go-go-related gene (hERG) channels to determine the electrolphysiological basis for its proarrhythmic effects. Methods: hERG channels were expressed in Xenopus oocytes and HEK293 cells, and the effects of hydroxyzine on the channels were examined using two-microelectrode voltage-clamp and patch-clamp techniques, respectively. The effects of hydroxyzine on action potential duration were examined in guinea pig ventricular myocytes using current clamp. Results: Hydroxyzine (0.2 and 2 μmol/L) significantly increased the action potential duration at 90% repolarization (APD 90 ) in both concentration-and time-dependent manners. Hydroxyzine (0.03-3 μmol/L) blocked both the steady-state and tail hERG currents. The block was voltage-dependent, and the values of IC 50 for blocking the steady-state and tail currents at +20 mV was 0.18±0.02 μmol/L and 0.16±0.01 μmol/L, respectively, in HEK293 cells. Hydroxyzine (5 μmol/L) affected both the activated and the inactivated states of the channels, but not the closed state. The S6 domain mutation Y652A attenuated the blocking of hERG current by ~6-fold. Conclusion:The results suggest that hydroxyzine could block hERG channels and prolong APD. The tyrosine at position 652 in the channel may be responsible for the proarrhythmic effects of hydroxyzine.

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“…NS1643 significantly reduced the amount of ectopic activity and torsades de pointes [32]. Drug-induced QT prolongation was reverted by application of NS3623 in guinea pigs [37]. These results point to in vivo anti-arrhythmic properties of hERG1 channel activation under certain settings.…”

Section: In Vitro and In Vivo Effects Of Potassium Channel Activatorsmentioning

confidence: 69%

“…In vivo effect of potassium channel activators was reported: NS1643 has demonstrated anti-arrhythmic properties in rabbit models favoring Torsades de Pointes arrhythmias [37]. NS1643 significantly reduced the amount of ectopic activity and torsades de pointes [32].…”

Section: In Vitro and In Vivo Effects Of Potassium Channel Activatorsmentioning

confidence: 99%

“…These data provided proof of principle of the concept that the combined knowledge of an inherited gene variant in an ion channel gene and the binding site of a drug in the respective channel could be used to predict a possible drug resistance by mutational disruption of the molecular binding site in the ion channel protein. The specific activation of cardiac potassium channels may therefore represent a novel anti-arrhythmic principle [37].…”

Section: In Vitro and In Vivo Effects Of Potassium Channel Activatorsmentioning

confidence: 99%

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K Channel Openers as New Anti-arrhythmic Agents

Strutz‐Seebohm

Seebohm

2011

Heart Rate and Rhythm

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Ion channels are membrane integral proteins that allow controlled passage of ions through cellular membranes. Cation-selective channels play key roles in physiological processes such as control of ion homeostasis and cell volume, vesicle trafficking, neurotransmitter and hormone secretion, and electrical control of excitable tissues. Many therapeutic drugs mediate their effects by targeting cation channel proteins. Potassium-selective channels are the most genetically and functionally diverse family of cation channels. After the cloning of the first potassium-selective ion channel, Shaker from Drosophila, several hundred potassium channel genes have been identified in the human genome. The number of functionally distinct channels in native tissues is further increased by heteromultimeric coassembly of potassium channel a-subunits with other a-and b-subunits and by posttranscriptional or posttranslational modifications such as alternative splicing of mRNAs, glycosylation, sumoylation, and phosphorylation. In light of the broad range of physiological roles of K channels it is not surprising that channel impairment results in a variety of pathophysiological conditions.The following text will give an overview of molecular details and availability of potassium channel modulators and try to address their potential as anti-arrhythmic drugs.

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Repolarization of the cardiac action potential. Does an increase in repolarization capacity constitute a new anti‐arrhythmic principle?

Cited by 36 publications

References 407 publications

Lipopolysaccharide prolongs action potential duration in HL-1 mouse cardiomyocytes

Lipopolysaccharide prolongs action potential duration in HL-1 mouse cardiomyocytes

Effects of the histamine H1 receptor antagonist hydroxyzine on hERG K+ channels and cardiac action potential duration

K Channel Openers as New Anti-arrhythmic Agents

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