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• W2912395711 endingPage "230" @default.
• W2912395711 startingPage "214" @default.
• W2912395711 abstract "Drug-induced block of the cardiac rapid delayed rectifying potassium current (IKr), carried by the human ether-a-go-go-related gene (hERG) channel, is the most common cause of acquired long QT syndrome. Indeed, some, but not all, drugs that block hERG channels cause fatal cardiac arrhythmias. However, there is no clear method to distinguish between drugs that cause deadly arrhythmias and those that are clinically safe. Here we propose a mechanism that could explain why certain clinically used hERG blockers are less proarrhythmic than others. We demonstrate that several drugs that block hERG channels, but have favorable cardiac safety profiles, also evoke another effect; they facilitate the hERG current amplitude in response to low-voltage depolarization. To investigate how hERG facilitation impacts cardiac safety, we develop computational models of IKr block with and without this facilitation. We constrain the models using data from voltage clamp recordings of hERG block and facilitation by nifekalant, a safe class III antiarrhythmic agent. Human ventricular action potential simulations demonstrate the ability of nifekalant to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive IKr block evokes early afterdepolarizations, which cause lethal arrhythmias. When facilitation is introduced, early afterdepolarizations are prevented at the same degree of block. Facilitation appears to prevent early afterdepolarizations by increasing IKr during the repolarization phase of action potentials. We empirically test this prediction in isolated rabbit ventricular myocytes and find that action potential prolongation with nifekalant is less likely to induce early afterdepolarization than action potential prolongation with dofetilide, a hERG channel blocker that does not induce facilitation. Our data suggest that hERG channel blockers that induce facilitation increase the repolarization reserve of cardiac myocytes, rendering them less likely to trigger lethal ventricular arrhythmias." @default.
• W2912395711 created "2019-02-21" @default.
• W2912395711 creator A5004667194 @default.
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• W2912395711 creator A5088588845 @default.
• W2912395711 date "2019-01-23" @default.
• W2912395711 modified "2023-10-14" @default.
• W2912395711 title "Facilitation of <i>I</i>Kr current by some hERG channel blockers suppresses early afterdepolarizations" @default.
• W2912395711 cites W1517378034 @default.
• W2912395711 cites W1597781658 @default.
• W2912395711 cites W1905285594 @default.
• W2912395711 cites W1965674048 @default.
• W2912395711 cites W1966544083 @default.
• W2912395711 cites W1967151871 @default.
• W2912395711 cites W1968098810 @default.
• W2912395711 cites W1969927082 @default.
• W2912395711 cites W1970391136 @default.
• W2912395711 cites W1970868441 @default.
• W2912395711 cites W1975869151 @default.
• W2912395711 cites W1975903898 @default.
• W2912395711 cites W1980538198 @default.
• W2912395711 cites W1985032406 @default.
• W2912395711 cites W1988498011 @default.
• W2912395711 cites W1991902077 @default.
• W2912395711 cites W1991992462 @default.
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• W2912395711 cites W2002314174 @default.
• W2912395711 cites W2007448071 @default.
• W2912395711 cites W2009667219 @default.
• W2912395711 cites W2013875064 @default.
• W2912395711 cites W2015426350 @default.
• W2912395711 cites W2019973925 @default.
• W2912395711 cites W2021438486 @default.
• W2912395711 cites W2024287748 @default.
• W2912395711 cites W2025002813 @default.
• W2912395711 cites W2030074596 @default.
• W2912395711 cites W2032268067 @default.
• W2912395711 cites W2037860525 @default.
• W2912395711 cites W2038131479 @default.
• W2912395711 cites W2040165185 @default.
• W2912395711 cites W2040826404 @default.
• W2912395711 cites W2047620467 @default.
• W2912395711 cites W2052993276 @default.
• W2912395711 cites W2056347060 @default.
• W2912395711 cites W2059798273 @default.
• W2912395711 cites W2060320617 @default.
• W2912395711 cites W2060489949 @default.
• W2912395711 cites W2067584517 @default.
• W2912395711 cites W2070703456 @default.
• W2912395711 cites W2073921281 @default.
• W2912395711 cites W2074527519 @default.
• W2912395711 cites W2077113957 @default.
• W2912395711 cites W2077424966 @default.
• W2912395711 cites W2082072065 @default.
• W2912395711 cites W2084265884 @default.
• W2912395711 cites W2085048839 @default.
• W2912395711 cites W2086084827 @default.
• W2912395711 cites W2088417119 @default.
• W2912395711 cites W2088469773 @default.
• W2912395711 cites W2090122064 @default.
• W2912395711 cites W2093186412 @default.
• W2912395711 cites W2109622977 @default.
• W2912395711 cites W2113927644 @default.
• W2912395711 cites W2115765852 @default.
• W2912395711 cites W2121217634 @default.
• W2912395711 cites W2130321115 @default.
• W2912395711 cites W2130405400 @default.
• W2912395711 cites W2137618884 @default.
• W2912395711 cites W2147857057 @default.
• W2912395711 cites W2154246975 @default.
• W2912395711 cites W2163071496 @default.
• W2912395711 cites W2163332866 @default.
• W2912395711 cites W2164379882 @default.
• W2912395711 cites W2168806904 @default.
• W2912395711 cites W2261271378 @default.
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• W2912395711 doi "https://doi.org/10.1085/jgp.201812192" @default.
• W2912395711 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6363420" @default.
• W2912395711 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30674563" @default.
• W2912395711 hasPublicationYear "2019" @default.
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