The plateau outward current in canine ventricle, sensitive to 4‐aminopyridine, is a constitutive contributor to ventricular repolarization

Background and purpose: IKur (Ultra‐rapid delayed rectifier current) has μM sensitivity to 4‐aminopyridine (4‐AP) and is an important modulator of the plateau amplitude and action potential duration in canine atria. Kv1.5 encodes IKur and is present in both atria and ventricles in canines and humans...

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Published in:British journal of pharmacology 2007-11, Vol.152 (6), p.870-879
Main Authors: Sridhar, A, Cunha, D N Q, Lacombe, V A, Zhou, Q, Fox, J J, Hamlin, R L, Carnes, C A
Format: Article
Language:English
Subjects:
4-Aminopyridine - pharmacology
4‐aminopyridine
action potential
Action Potentials - drug effects
Algorithms
Animals
canine
Computer Simulation
Delayed Rectifier Potassium Channels - drug effects
Delayed Rectifier Potassium Channels - physiology
Dogs
Dose-Response Relationship, Drug
Electrophysiology
Heart - drug effects
Heart Ventricles - drug effects
In Vitro Techniques
Markov Chains
Myocardium - cytology
Myocardium - metabolism
Myocytes, Cardiac - drug effects
Patch-Clamp Techniques
Potassium Channel Blockers - pharmacology
potassium current
Receptors, Adrenergic, beta - drug effects
Receptors, Adrenergic, beta - physiology
repolarization
Research Papers
Solutions
ventricle
ventricular myocyte
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container_title British journal of pharmacology
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creator Sridhar, A
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Lacombe, V A
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Fox, J J
Hamlin, R L
Carnes, C A
description Background and purpose: IKur (Ultra‐rapid delayed rectifier current) has μM sensitivity to 4‐aminopyridine (4‐AP) and is an important modulator of the plateau amplitude and action potential duration in canine atria. Kv1.5 encodes IKur and is present in both atria and ventricles in canines and humans. We hypothesized that a similar plateau outward current with μM sensitivity to 4‐AP is present in canine ventricle. Experimental approach: We used established voltage clamp protocols and used 4‐AP (50 and 100 μM) to measure a plateau outward current in normal canine myocytes isolated from the left ventricular mid‐myocardium. Key results: Action potential recordings in the presence of 4‐AP showed significant prolongation of action potential duration at 50 and 90% repolarization at 0.5 and 1 Hz (P
doi_str_mv 10.1038/sj.bjp.0707403
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Kv1.5 encodes IKur and is present in both atria and ventricles in canines and humans. We hypothesized that a similar plateau outward current with μM sensitivity to 4‐AP is present in canine ventricle. Experimental approach: We used established voltage clamp protocols and used 4‐AP (50 and 100 μM) to measure a plateau outward current in normal canine myocytes isolated from the left ventricular mid‐myocardium. Key results: Action potential recordings in the presence of 4‐AP showed significant prolongation of action potential duration at 50 and 90% repolarization at 0.5 and 1 Hz (P&lt;0.05), while no prolongation occurred at 2 Hz. Voltage clamp experiments revealed a rapidly activating current, similar to current characteristics of canine atrial IKur, in ∼70% of left ventricular myocytes. The IC50 of 4‐AP for this current was 24.2 μM. The concentration of 4‐AP used in our experiments resulted in selective blockade of an outward current that was not Ito or IKr. β‐Adrenergic stimulation with isoprenaline significantly increased the 4‐AP sensitive outward current density (P&lt;0.05), suggesting a role for this current during increased sympathetic stimulation. In silico incorporation into a canine ventricular cell model revealed selective AP prolongation after current blockade. Conclusions and implications: Our results support the existence of a canine ventricular plateau outward current sensitive to micromolar 4‐AP and its constitutive role in ventricular repolarization. British Journal of Pharmacology (2007) 152, 870–879; doi:10.1038/sj.bjp.0707403; published online 13 August 2007</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1038/sj.bjp.0707403</identifier><identifier>PMID: 17700726</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>4-Aminopyridine - pharmacology ; 4‐aminopyridine ; action potential ; Action Potentials - drug effects ; Algorithms ; Animals ; canine ; Computer Simulation ; Delayed Rectifier Potassium Channels - drug effects ; Delayed Rectifier Potassium Channels - physiology ; Dogs ; Dose-Response Relationship, Drug ; Electrophysiology ; Heart - drug effects ; Heart Ventricles - drug effects ; In Vitro Techniques ; Markov Chains ; Myocardium - cytology ; Myocardium - metabolism ; Myocytes, Cardiac - drug effects ; Patch-Clamp Techniques ; Potassium Channel Blockers - pharmacology ; potassium current ; Receptors, Adrenergic, beta - drug effects ; Receptors, Adrenergic, beta - physiology ; repolarization ; Research Papers ; Solutions ; ventricle ; ventricular myocyte</subject><ispartof>British journal of pharmacology, 2007-11, Vol.152 (6), p.870-879</ispartof><rights>2007 British Pharmacological Society</rights><rights>Copyright Nature Publishing Group Nov 2007</rights><rights>Copyright 2007, Nature Publishing Group 2007 Nature Publishing Group</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4587-30c854328689355fce63a649e681e2cefcf8fb747f4105fc6dd08fd3a2a52e393</citedby><cites>FETCH-LOGICAL-c4587-30c854328689355fce63a649e681e2cefcf8fb747f4105fc6dd08fd3a2a52e393</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2078232/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2078232/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17700726$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sridhar, A</creatorcontrib><creatorcontrib>Cunha, D N Q</creatorcontrib><creatorcontrib>Lacombe, V A</creatorcontrib><creatorcontrib>Zhou, Q</creatorcontrib><creatorcontrib>Fox, J J</creatorcontrib><creatorcontrib>Hamlin, R L</creatorcontrib><creatorcontrib>Carnes, C A</creatorcontrib><title>The plateau outward current in canine ventricle, sensitive to 4‐aminopyridine, is a constitutive contributor to ventricular repolarization</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>Background and purpose: IKur (Ultra‐rapid delayed rectifier current) has μM sensitivity to 4‐aminopyridine (4‐AP) and is an important modulator of the plateau amplitude and action potential duration in canine atria. 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The concentration of 4‐AP used in our experiments resulted in selective blockade of an outward current that was not Ito or IKr. β‐Adrenergic stimulation with isoprenaline significantly increased the 4‐AP sensitive outward current density (P&lt;0.05), suggesting a role for this current during increased sympathetic stimulation. In silico incorporation into a canine ventricular cell model revealed selective AP prolongation after current blockade. Conclusions and implications: Our results support the existence of a canine ventricular plateau outward current sensitive to micromolar 4‐AP and its constitutive role in ventricular repolarization. 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Kv1.5 encodes IKur and is present in both atria and ventricles in canines and humans. We hypothesized that a similar plateau outward current with μM sensitivity to 4‐AP is present in canine ventricle. Experimental approach: We used established voltage clamp protocols and used 4‐AP (50 and 100 μM) to measure a plateau outward current in normal canine myocytes isolated from the left ventricular mid‐myocardium. Key results: Action potential recordings in the presence of 4‐AP showed significant prolongation of action potential duration at 50 and 90% repolarization at 0.5 and 1 Hz (P&lt;0.05), while no prolongation occurred at 2 Hz. Voltage clamp experiments revealed a rapidly activating current, similar to current characteristics of canine atrial IKur, in ∼70% of left ventricular myocytes. The IC50 of 4‐AP for this current was 24.2 μM. The concentration of 4‐AP used in our experiments resulted in selective blockade of an outward current that was not Ito or IKr. β‐Adrenergic stimulation with isoprenaline significantly increased the 4‐AP sensitive outward current density (P&lt;0.05), suggesting a role for this current during increased sympathetic stimulation. In silico incorporation into a canine ventricular cell model revealed selective AP prolongation after current blockade. Conclusions and implications: Our results support the existence of a canine ventricular plateau outward current sensitive to micromolar 4‐AP and its constitutive role in ventricular repolarization. British Journal of Pharmacology (2007) 152, 870–879; doi:10.1038/sj.bjp.0707403; published online 13 August 2007</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>17700726</pmid><doi>10.1038/sj.bjp.0707403</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record>
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subjects 4-Aminopyridine - pharmacology
4‐aminopyridine
action potential
Action Potentials - drug effects
Algorithms
Animals
canine
Computer Simulation
Delayed Rectifier Potassium Channels - drug effects
Delayed Rectifier Potassium Channels - physiology
Dogs
Dose-Response Relationship, Drug
Electrophysiology
Heart - drug effects
Heart Ventricles - drug effects
In Vitro Techniques
Markov Chains
Myocardium - cytology
Myocardium - metabolism
Myocytes, Cardiac - drug effects
Patch-Clamp Techniques
Potassium Channel Blockers - pharmacology
potassium current
Receptors, Adrenergic, beta - drug effects
Receptors, Adrenergic, beta - physiology
repolarization
Research Papers
Solutions
ventricle
ventricular myocyte
title The plateau outward current in canine ventricle, sensitive to 4‐aminopyridine, is a constitutive contributor to ventricular repolarization
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