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Multiple targets for flecainide action: implications for cardiac arrhythmogenesis
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| Zeitschriftentitel: | British Journal of Pharmacology |
|---|---|
| Personen und Körperschaften: | , , , , , , |
| In: | British Journal of Pharmacology, 175, 2018, 8, S. 1260-1278 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Wiley
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| Schlagwörter: |
| author_facet |
Salvage, Samantha C Chandrasekharan, Karthik H Jeevaratnam, Kamalan Dulhunty, Angela F Thompson, Andrew J Jackson, Antony P Huang, Christopher L‐H Salvage, Samantha C Chandrasekharan, Karthik H Jeevaratnam, Kamalan Dulhunty, Angela F Thompson, Andrew J Jackson, Antony P Huang, Christopher L‐H |
|---|---|
| author |
Salvage, Samantha C Chandrasekharan, Karthik H Jeevaratnam, Kamalan Dulhunty, Angela F Thompson, Andrew J Jackson, Antony P Huang, Christopher L‐H |
| spellingShingle |
Salvage, Samantha C Chandrasekharan, Karthik H Jeevaratnam, Kamalan Dulhunty, Angela F Thompson, Andrew J Jackson, Antony P Huang, Christopher L‐H British Journal of Pharmacology Multiple targets for flecainide action: implications for cardiac arrhythmogenesis Pharmacology |
| author_sort |
salvage, samantha c |
| spelling |
Salvage, Samantha C Chandrasekharan, Karthik H Jeevaratnam, Kamalan Dulhunty, Angela F Thompson, Andrew J Jackson, Antony P Huang, Christopher L‐H 0007-1188 1476-5381 Wiley Pharmacology http://dx.doi.org/10.1111/bph.13807 <jats:sec><jats:label /><jats:p>Flecainide suppresses cardiac tachyarrhythmias including paroxysmal atrial fibrillation, supraventricular tachycardia and arrhythmic long QT syndromes (LQTS), as well as the Ca<jats:sup>2+</jats:sup>‐mediated, catecholaminergic polymorphic ventricular tachycardia (CPVT). However, flecainide can also exert pro‐arrhythmic effects most notably following myocardial infarction and when used to diagnose Brugada syndrome (BrS). These divergent actions result from its physiological and pharmacological actions at multiple, interacting levels of cellular organization. These were studied in murine genetic models with modified Na<jats:sub>v</jats:sub> channel or intracellular ryanodine receptor (RyR2)‐Ca<jats:sup>2+</jats:sup> channel function. Flecainide accesses its transmembrane Na<jats:sub>v</jats:sub>1.5 channel binding site during activated, open, states producing a use‐dependent antagonism. Closing either activation or inactivation gates traps flecainide within the pore. An early peak <jats:italic>I</jats:italic><jats:sub>Na</jats:sub> related to activation of Na<jats:sub>v</jats:sub> channels followed by rapid de‐activation, drives action potential (AP) upstrokes and their propagation. This is diminished in pro‐arrhythmic conditions reflecting loss of function of Na<jats:sub>v</jats:sub>1.5 channels, such as BrS, accordingly exacerbated by flecainide challenge. Contrastingly, pro‐arrhythmic effects attributed to prolonged AP recovery by abnormal late I<jats:sub>NaL</jats:sub> following gain‐of‐function modifications of Na<jats:sub>v</jats:sub>1.5 channels in LQTS3 are reduced by flecainide. Anti‐arrhythmic effects of flecainide that reduce triggering in CPVT models mediated by sarcoplasmic reticular Ca<jats:sup>2+</jats:sup> release could arise from its primary actions on Na<jats:sub>v</jats:sub> channels indirectly decreasing [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> through a reduced [Na<jats:sup>+</jats:sup>]<jats:sub>i</jats:sub> and/or direct open‐state RyR2‐Ca<jats:sup>2+</jats:sup> channel antagonism. The consequent [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> alterations could also modify AP propagation velocity and therefore arrhythmic substrate through its actions on Na<jats:sub>v</jats:sub>1.5 channel function. This is consistent with the paradoxical differences between flecainide actions upon Na<jats:sup>+</jats:sup> currents, AP conduction and arrhythmogenesis under circumstances of normal and increased RyR2 function.</jats:p></jats:sec><jats:sec><jats:title>Linked Articles</jats:title><jats:p>This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc">http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc</jats:ext-link></jats:p></jats:sec> Multiple targets for flecainide action: implications for cardiac arrhythmogenesis British Journal of Pharmacology |
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2018 |
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Wiley |
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British Journal of Pharmacology |
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| title |
Multiple targets for flecainide action: implications for cardiac arrhythmogenesis |
| title_unstemmed |
Multiple targets for flecainide action: implications for cardiac arrhythmogenesis |
| title_full |
Multiple targets for flecainide action: implications for cardiac arrhythmogenesis |
| title_fullStr |
Multiple targets for flecainide action: implications for cardiac arrhythmogenesis |
| title_full_unstemmed |
Multiple targets for flecainide action: implications for cardiac arrhythmogenesis |
| title_short |
Multiple targets for flecainide action: implications for cardiac arrhythmogenesis |
| title_sort |
multiple targets for flecainide action: implications for cardiac arrhythmogenesis |
| topic |
Pharmacology |
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http://dx.doi.org/10.1111/bph.13807 |
| publishDate |
2018 |
| physical |
1260-1278 |
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<jats:sec><jats:label /><jats:p>Flecainide suppresses cardiac tachyarrhythmias including paroxysmal atrial fibrillation, supraventricular tachycardia and arrhythmic long QT syndromes (LQTS), as well as the Ca<jats:sup>2+</jats:sup>‐mediated, catecholaminergic polymorphic ventricular tachycardia (CPVT). However, flecainide can also exert pro‐arrhythmic effects most notably following myocardial infarction and when used to diagnose Brugada syndrome (BrS). These divergent actions result from its physiological and pharmacological actions at multiple, interacting levels of cellular organization. These were studied in murine genetic models with modified Na<jats:sub>v</jats:sub> channel or intracellular ryanodine receptor (RyR2)‐Ca<jats:sup>2+</jats:sup> channel function. Flecainide accesses its transmembrane Na<jats:sub>v</jats:sub>1.5 channel binding site during activated, open, states producing a use‐dependent antagonism. Closing either activation or inactivation gates traps flecainide within the pore. An early peak <jats:italic>I</jats:italic><jats:sub>Na</jats:sub> related to activation of Na<jats:sub>v</jats:sub> channels followed by rapid de‐activation, drives action potential (AP) upstrokes and their propagation. This is diminished in pro‐arrhythmic conditions reflecting loss of function of Na<jats:sub>v</jats:sub>1.5 channels, such as BrS, accordingly exacerbated by flecainide challenge. Contrastingly, pro‐arrhythmic effects attributed to prolonged AP recovery by abnormal late I<jats:sub>NaL</jats:sub> following gain‐of‐function modifications of Na<jats:sub>v</jats:sub>1.5 channels in LQTS3 are reduced by flecainide. Anti‐arrhythmic effects of flecainide that reduce triggering in CPVT models mediated by sarcoplasmic reticular Ca<jats:sup>2+</jats:sup> release could arise from its primary actions on Na<jats:sub>v</jats:sub> channels indirectly decreasing [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> through a reduced [Na<jats:sup>+</jats:sup>]<jats:sub>i</jats:sub> and/or direct open‐state RyR2‐Ca<jats:sup>2+</jats:sup> channel antagonism. The consequent [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> alterations could also modify AP propagation velocity and therefore arrhythmic substrate through its actions on Na<jats:sub>v</jats:sub>1.5 channel function. This is consistent with the paradoxical differences between flecainide actions upon Na<jats:sup>+</jats:sup> currents, AP conduction and arrhythmogenesis under circumstances of normal and increased RyR2 function.</jats:p></jats:sec><jats:sec><jats:title>Linked Articles</jats:title><jats:p>This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc">http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc</jats:ext-link></jats:p></jats:sec> |
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| author | Salvage, Samantha C, Chandrasekharan, Karthik H, Jeevaratnam, Kamalan, Dulhunty, Angela F, Thompson, Andrew J, Jackson, Antony P, Huang, Christopher L‐H |
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| description | <jats:sec><jats:label /><jats:p>Flecainide suppresses cardiac tachyarrhythmias including paroxysmal atrial fibrillation, supraventricular tachycardia and arrhythmic long QT syndromes (LQTS), as well as the Ca<jats:sup>2+</jats:sup>‐mediated, catecholaminergic polymorphic ventricular tachycardia (CPVT). However, flecainide can also exert pro‐arrhythmic effects most notably following myocardial infarction and when used to diagnose Brugada syndrome (BrS). These divergent actions result from its physiological and pharmacological actions at multiple, interacting levels of cellular organization. These were studied in murine genetic models with modified Na<jats:sub>v</jats:sub> channel or intracellular ryanodine receptor (RyR2)‐Ca<jats:sup>2+</jats:sup> channel function. Flecainide accesses its transmembrane Na<jats:sub>v</jats:sub>1.5 channel binding site during activated, open, states producing a use‐dependent antagonism. Closing either activation or inactivation gates traps flecainide within the pore. An early peak <jats:italic>I</jats:italic><jats:sub>Na</jats:sub> related to activation of Na<jats:sub>v</jats:sub> channels followed by rapid de‐activation, drives action potential (AP) upstrokes and their propagation. This is diminished in pro‐arrhythmic conditions reflecting loss of function of Na<jats:sub>v</jats:sub>1.5 channels, such as BrS, accordingly exacerbated by flecainide challenge. Contrastingly, pro‐arrhythmic effects attributed to prolonged AP recovery by abnormal late I<jats:sub>NaL</jats:sub> following gain‐of‐function modifications of Na<jats:sub>v</jats:sub>1.5 channels in LQTS3 are reduced by flecainide. Anti‐arrhythmic effects of flecainide that reduce triggering in CPVT models mediated by sarcoplasmic reticular Ca<jats:sup>2+</jats:sup> release could arise from its primary actions on Na<jats:sub>v</jats:sub> channels indirectly decreasing [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> through a reduced [Na<jats:sup>+</jats:sup>]<jats:sub>i</jats:sub> and/or direct open‐state RyR2‐Ca<jats:sup>2+</jats:sup> channel antagonism. The consequent [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> alterations could also modify AP propagation velocity and therefore arrhythmic substrate through its actions on Na<jats:sub>v</jats:sub>1.5 channel function. This is consistent with the paradoxical differences between flecainide actions upon Na<jats:sup>+</jats:sup> currents, AP conduction and arrhythmogenesis under circumstances of normal and increased RyR2 function.</jats:p></jats:sec><jats:sec><jats:title>Linked Articles</jats:title><jats:p>This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc">http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc</jats:ext-link></jats:p></jats:sec> |
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| spelling | Salvage, Samantha C Chandrasekharan, Karthik H Jeevaratnam, Kamalan Dulhunty, Angela F Thompson, Andrew J Jackson, Antony P Huang, Christopher L‐H 0007-1188 1476-5381 Wiley Pharmacology http://dx.doi.org/10.1111/bph.13807 <jats:sec><jats:label /><jats:p>Flecainide suppresses cardiac tachyarrhythmias including paroxysmal atrial fibrillation, supraventricular tachycardia and arrhythmic long QT syndromes (LQTS), as well as the Ca<jats:sup>2+</jats:sup>‐mediated, catecholaminergic polymorphic ventricular tachycardia (CPVT). However, flecainide can also exert pro‐arrhythmic effects most notably following myocardial infarction and when used to diagnose Brugada syndrome (BrS). These divergent actions result from its physiological and pharmacological actions at multiple, interacting levels of cellular organization. These were studied in murine genetic models with modified Na<jats:sub>v</jats:sub> channel or intracellular ryanodine receptor (RyR2)‐Ca<jats:sup>2+</jats:sup> channel function. Flecainide accesses its transmembrane Na<jats:sub>v</jats:sub>1.5 channel binding site during activated, open, states producing a use‐dependent antagonism. Closing either activation or inactivation gates traps flecainide within the pore. An early peak <jats:italic>I</jats:italic><jats:sub>Na</jats:sub> related to activation of Na<jats:sub>v</jats:sub> channels followed by rapid de‐activation, drives action potential (AP) upstrokes and their propagation. This is diminished in pro‐arrhythmic conditions reflecting loss of function of Na<jats:sub>v</jats:sub>1.5 channels, such as BrS, accordingly exacerbated by flecainide challenge. Contrastingly, pro‐arrhythmic effects attributed to prolonged AP recovery by abnormal late I<jats:sub>NaL</jats:sub> following gain‐of‐function modifications of Na<jats:sub>v</jats:sub>1.5 channels in LQTS3 are reduced by flecainide. Anti‐arrhythmic effects of flecainide that reduce triggering in CPVT models mediated by sarcoplasmic reticular Ca<jats:sup>2+</jats:sup> release could arise from its primary actions on Na<jats:sub>v</jats:sub> channels indirectly decreasing [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> through a reduced [Na<jats:sup>+</jats:sup>]<jats:sub>i</jats:sub> and/or direct open‐state RyR2‐Ca<jats:sup>2+</jats:sup> channel antagonism. The consequent [Ca<jats:sup>2+</jats:sup>]<jats:sub>i</jats:sub> alterations could also modify AP propagation velocity and therefore arrhythmic substrate through its actions on Na<jats:sub>v</jats:sub>1.5 channel function. This is consistent with the paradoxical differences between flecainide actions upon Na<jats:sup>+</jats:sup> currents, AP conduction and arrhythmogenesis under circumstances of normal and increased RyR2 function.</jats:p></jats:sec><jats:sec><jats:title>Linked Articles</jats:title><jats:p>This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc">http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc</jats:ext-link></jats:p></jats:sec> Multiple targets for flecainide action: implications for cardiac arrhythmogenesis British Journal of Pharmacology |
| spellingShingle | Salvage, Samantha C, Chandrasekharan, Karthik H, Jeevaratnam, Kamalan, Dulhunty, Angela F, Thompson, Andrew J, Jackson, Antony P, Huang, Christopher L‐H, British Journal of Pharmacology, Multiple targets for flecainide action: implications for cardiac arrhythmogenesis, Pharmacology |
| title | Multiple targets for flecainide action: implications for cardiac arrhythmogenesis |
| title_full | Multiple targets for flecainide action: implications for cardiac arrhythmogenesis |
| title_fullStr | Multiple targets for flecainide action: implications for cardiac arrhythmogenesis |
| title_full_unstemmed | Multiple targets for flecainide action: implications for cardiac arrhythmogenesis |
| title_short | Multiple targets for flecainide action: implications for cardiac arrhythmogenesis |
| title_sort | multiple targets for flecainide action: implications for cardiac arrhythmogenesis |
| title_unstemmed | Multiple targets for flecainide action: implications for cardiac arrhythmogenesis |
| topic | Pharmacology |
| url | http://dx.doi.org/10.1111/bph.13807 |