Pharmacological block of the slow component of the outward delayed rectifier current (IKs) fails to lengthen rabbit ventricular muscle QTc and action potential duration
The effects of IKs block by chromanol 293B and L‐735,821 on rabbit QT‐interval, action potential duration (APD), and membrane current were compared to those of E‐4031, a recognized IKr blocker. Measurements were made in rabbit Langendorff‐perfused whole hearts, isolated papillary muscle, and single...
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| Veröffentlicht in: | British journal of pharmacology 2001-01, Vol.132 (1), p.101-110 |
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| creator | Lengyel, Csaba Iost, Norbert Virág, László Varró, András Lathrop, David A Papp, Julius Gy |
| description | The effects of IKs block by chromanol 293B and L‐735,821 on rabbit QT‐interval, action potential duration (APD), and membrane current were compared to those of E‐4031, a recognized IKr blocker. Measurements were made in rabbit Langendorff‐perfused whole hearts, isolated papillary muscle, and single isolated ventricular myocytes.
Neither chromanol 293B (10 μM) nor L‐735,821 (100 nM) had a significant effect on QTc interval in Langendorff‐perfused hearts. E‐4031 (100 nM), on the other hand, significantly increased QTc interval (35.6±3.9%, n=8, P |
| doi_str_mv | 10.1038/sj.bjp.0703777 |
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| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_1572535</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>958979411</sourcerecordid><originalsourceid>FETCH-LOGICAL-j3288-161ec1646edb5512fb31b1383208a180bb6925330021b162e6649b9acd905c83</originalsourceid><addsrcrecordid>eNpVkU1vEzEYhC1ERUPhytmCCxw29buOP3JBggpoRaUWKXfL9noTL971Yu82yj_qz8RRQyVOlmYej0cehN4BWQKh8jJ3S9ONSyIIFUK8QAtYCV4xKuElWhBCRAUg5Tl6nXNHSDEFe4XOAYBxxvkCPd7vdOq1jSFuvdUBmxDtbxxbPO0cziHusY39GAc3TP_UOE97nRrcuKAPrsHJ2cm33iVs55SO4Mebn_kTbrUPGU8RBzdsy8UBJ22Mn_BDYZK3c9AJ93O2weFfG4v10GBdouKAxzgVxpc-zZz0UXqDzlodsnt7Oi_Q5vu3zdV1dXv34-bqy23V0VrKCjg4C3zFXWMYg7o1FAxQSWsiNUhiDF_XjFJC6qLz2nG-Wpu1ts2aMCvpBfr8FDvOpneNPTbVQY3J9zodVNRe_e8Mfqe28UEBEyWXlYD3p4AU_8wuT6qLcxpKZVWDAEkJrQv04QTpXD69TXqwPj-_IqWQwAtFn6i9D-7w7AJRx-lV7lSZXp2mV1_vr0FySf8CciOmPg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>217183032</pqid></control><display><type>article</type><title>Pharmacological block of the slow component of the outward delayed rectifier current (IKs) fails to lengthen rabbit ventricular muscle QTc and action potential duration</title><source>Access via Wiley Online Library</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Wiley Online Library (Open Access Collection)</source><source>PubMed Central</source><source>Alma/SFX Local Collection</source><creator>Lengyel, Csaba ; Iost, Norbert ; Virág, László ; Varró, András ; Lathrop, David A ; Papp, Julius Gy</creator><creatorcontrib>Lengyel, Csaba ; Iost, Norbert ; Virág, László ; Varró, András ; Lathrop, David A ; Papp, Julius Gy</creatorcontrib><description>The effects of IKs block by chromanol 293B and L‐735,821 on rabbit QT‐interval, action potential duration (APD), and membrane current were compared to those of E‐4031, a recognized IKr blocker. Measurements were made in rabbit Langendorff‐perfused whole hearts, isolated papillary muscle, and single isolated ventricular myocytes.
Neither chromanol 293B (10 μM) nor L‐735,821 (100 nM) had a significant effect on QTc interval in Langendorff‐perfused hearts. E‐4031 (100 nM), on the other hand, significantly increased QTc interval (35.6±3.9%, n=8, P<0.05).
Similarly both chromanol 293B (10 μM) and L‐735,821 (100 nM) produced little increase in papillary muscle APD (less than 7%) while pacing at cycle lengths between 300 and 5000 ms. In contrast, E‐4031 (100 nM) markedly increased (30 – 60%) APD in a reverse frequency‐dependent manner.
In ventricular myocytes, the same concentrations of chromanol 293B (10 μM), L‐735,821 (100 nM) and E‐4031 (1 μM) markedly or totally blocked IKs and IKr, respectively.
IKs tail currents activated slowly (at +30 mV, τ=888.1±48.2 ms, n=21) and deactivated rapidly (at −40 mV, τ=157.1±4.7 ms, n=22), while IKr tail currents activated rapidly (at +30 mV, τ=35.5±3.1 ms, n=26) and deactivated slowly (at −40 mV, τ1=641.5±29.0 ms, τ2=6531±343, n=35). IKr was estimated to contribute substantially more to total current density during normal ventricular muscle action potentials (i.e., after a 150 ms square pulse to +30 mV) than does IKs.
These findings indicate that block of IKs is not likely to provide antiarrhythmic benefit by lengthening normal ventricular muscle QTc, APD, and refractoriness over a wide range of frequencies.
British Journal of Pharmacology (2001) 132, 101–110; doi:10.1038/sj.bjp.0703777</description><identifier>ISSN: 0007-1188</identifier><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1038/sj.bjp.0703777</identifier><identifier>PMID: 11156566</identifier><identifier>CODEN: BJPCBM</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Antiarythmic agents ; arrhythmia ; Biological and medical sciences ; Cardiovascular system ; chromanol 293B ; IKs, action potential duration ; L‐735,821 ; Medical sciences ; Pharmacology. Drug treatments ; rabbit heart</subject><ispartof>British journal of pharmacology, 2001-01, Vol.132 (1), p.101-110</ispartof><rights>2001 British Pharmacological Society</rights><rights>2001 INIST-CNRS</rights><rights>Copyright Nature Publishing Group Jan 2001</rights><rights>Copyright 2001, Nature Publishing Group 2001 Nature Publishing Group</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1572535/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1572535/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,1417,1433,4024,27923,27924,27925,45574,45575,46409,46833,53791,53793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=887816$$DView record in Pascal Francis$$Hfree_for_read</backlink></links><search><creatorcontrib>Lengyel, Csaba</creatorcontrib><creatorcontrib>Iost, Norbert</creatorcontrib><creatorcontrib>Virág, László</creatorcontrib><creatorcontrib>Varró, András</creatorcontrib><creatorcontrib>Lathrop, David A</creatorcontrib><creatorcontrib>Papp, Julius Gy</creatorcontrib><title>Pharmacological block of the slow component of the outward delayed rectifier current (IKs) fails to lengthen rabbit ventricular muscle QTc and action potential duration</title><title>British journal of pharmacology</title><description>The effects of IKs block by chromanol 293B and L‐735,821 on rabbit QT‐interval, action potential duration (APD), and membrane current were compared to those of E‐4031, a recognized IKr blocker. Measurements were made in rabbit Langendorff‐perfused whole hearts, isolated papillary muscle, and single isolated ventricular myocytes.
Neither chromanol 293B (10 μM) nor L‐735,821 (100 nM) had a significant effect on QTc interval in Langendorff‐perfused hearts. E‐4031 (100 nM), on the other hand, significantly increased QTc interval (35.6±3.9%, n=8, P<0.05).
Similarly both chromanol 293B (10 μM) and L‐735,821 (100 nM) produced little increase in papillary muscle APD (less than 7%) while pacing at cycle lengths between 300 and 5000 ms. In contrast, E‐4031 (100 nM) markedly increased (30 – 60%) APD in a reverse frequency‐dependent manner.
In ventricular myocytes, the same concentrations of chromanol 293B (10 μM), L‐735,821 (100 nM) and E‐4031 (1 μM) markedly or totally blocked IKs and IKr, respectively.
IKs tail currents activated slowly (at +30 mV, τ=888.1±48.2 ms, n=21) and deactivated rapidly (at −40 mV, τ=157.1±4.7 ms, n=22), while IKr tail currents activated rapidly (at +30 mV, τ=35.5±3.1 ms, n=26) and deactivated slowly (at −40 mV, τ1=641.5±29.0 ms, τ2=6531±343, n=35). IKr was estimated to contribute substantially more to total current density during normal ventricular muscle action potentials (i.e., after a 150 ms square pulse to +30 mV) than does IKs.
These findings indicate that block of IKs is not likely to provide antiarrhythmic benefit by lengthening normal ventricular muscle QTc, APD, and refractoriness over a wide range of frequencies.
British Journal of Pharmacology (2001) 132, 101–110; doi:10.1038/sj.bjp.0703777</description><subject>Antiarythmic agents</subject><subject>arrhythmia</subject><subject>Biological and medical sciences</subject><subject>Cardiovascular system</subject><subject>chromanol 293B</subject><subject>IKs, action potential duration</subject><subject>L‐735,821</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>rabbit heart</subject><issn>0007-1188</issn><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNpVkU1vEzEYhC1ERUPhytmCCxw29buOP3JBggpoRaUWKXfL9noTL971Yu82yj_qz8RRQyVOlmYej0cehN4BWQKh8jJ3S9ONSyIIFUK8QAtYCV4xKuElWhBCRAUg5Tl6nXNHSDEFe4XOAYBxxvkCPd7vdOq1jSFuvdUBmxDtbxxbPO0cziHusY39GAc3TP_UOE97nRrcuKAPrsHJ2cm33iVs55SO4Mebn_kTbrUPGU8RBzdsy8UBJ22Mn_BDYZK3c9AJ93O2weFfG4v10GBdouKAxzgVxpc-zZz0UXqDzlodsnt7Oi_Q5vu3zdV1dXv34-bqy23V0VrKCjg4C3zFXWMYg7o1FAxQSWsiNUhiDF_XjFJC6qLz2nG-Wpu1ts2aMCvpBfr8FDvOpneNPTbVQY3J9zodVNRe_e8Mfqe28UEBEyWXlYD3p4AU_8wuT6qLcxpKZVWDAEkJrQv04QTpXD69TXqwPj-_IqWQwAtFn6i9D-7w7AJRx-lV7lSZXp2mV1_vr0FySf8CciOmPg</recordid><startdate>200101</startdate><enddate>200101</enddate><creator>Lengyel, Csaba</creator><creator>Iost, Norbert</creator><creator>Virág, László</creator><creator>Varró, András</creator><creator>Lathrop, David A</creator><creator>Papp, Julius Gy</creator><general>Blackwell Publishing Ltd</general><general>Nature Publishing</general><scope>IQODW</scope><scope>3V.</scope><scope>7QP</scope><scope>7RV</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>200101</creationdate><title>Pharmacological block of the slow component of the outward delayed rectifier current (IKs) fails to lengthen rabbit ventricular muscle QTc and action potential duration</title><author>Lengyel, Csaba ; Iost, Norbert ; Virág, László ; Varró, András ; Lathrop, David A ; Papp, Julius Gy</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-j3288-161ec1646edb5512fb31b1383208a180bb6925330021b162e6649b9acd905c83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Antiarythmic agents</topic><topic>arrhythmia</topic><topic>Biological and medical sciences</topic><topic>Cardiovascular system</topic><topic>chromanol 293B</topic><topic>IKs, action potential duration</topic><topic>L‐735,821</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>rabbit heart</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lengyel, Csaba</creatorcontrib><creatorcontrib>Iost, Norbert</creatorcontrib><creatorcontrib>Virág, László</creatorcontrib><creatorcontrib>Varró, András</creatorcontrib><creatorcontrib>Lathrop, David A</creatorcontrib><creatorcontrib>Papp, Julius Gy</creatorcontrib><collection>Pascal-Francis</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lengyel, Csaba</au><au>Iost, Norbert</au><au>Virág, László</au><au>Varró, András</au><au>Lathrop, David A</au><au>Papp, Julius Gy</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacological block of the slow component of the outward delayed rectifier current (IKs) fails to lengthen rabbit ventricular muscle QTc and action potential duration</atitle><jtitle>British journal of pharmacology</jtitle><date>2001-01</date><risdate>2001</risdate><volume>132</volume><issue>1</issue><spage>101</spage><epage>110</epage><pages>101-110</pages><issn>0007-1188</issn><eissn>1476-5381</eissn><coden>BJPCBM</coden><abstract>The effects of IKs block by chromanol 293B and L‐735,821 on rabbit QT‐interval, action potential duration (APD), and membrane current were compared to those of E‐4031, a recognized IKr blocker. Measurements were made in rabbit Langendorff‐perfused whole hearts, isolated papillary muscle, and single isolated ventricular myocytes.
Neither chromanol 293B (10 μM) nor L‐735,821 (100 nM) had a significant effect on QTc interval in Langendorff‐perfused hearts. E‐4031 (100 nM), on the other hand, significantly increased QTc interval (35.6±3.9%, n=8, P<0.05).
Similarly both chromanol 293B (10 μM) and L‐735,821 (100 nM) produced little increase in papillary muscle APD (less than 7%) while pacing at cycle lengths between 300 and 5000 ms. In contrast, E‐4031 (100 nM) markedly increased (30 – 60%) APD in a reverse frequency‐dependent manner.
In ventricular myocytes, the same concentrations of chromanol 293B (10 μM), L‐735,821 (100 nM) and E‐4031 (1 μM) markedly or totally blocked IKs and IKr, respectively.
IKs tail currents activated slowly (at +30 mV, τ=888.1±48.2 ms, n=21) and deactivated rapidly (at −40 mV, τ=157.1±4.7 ms, n=22), while IKr tail currents activated rapidly (at +30 mV, τ=35.5±3.1 ms, n=26) and deactivated slowly (at −40 mV, τ1=641.5±29.0 ms, τ2=6531±343, n=35). IKr was estimated to contribute substantially more to total current density during normal ventricular muscle action potentials (i.e., after a 150 ms square pulse to +30 mV) than does IKs.
These findings indicate that block of IKs is not likely to provide antiarrhythmic benefit by lengthening normal ventricular muscle QTc, APD, and refractoriness over a wide range of frequencies.
British Journal of Pharmacology (2001) 132, 101–110; doi:10.1038/sj.bjp.0703777</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>11156566</pmid><doi>10.1038/sj.bjp.0703777</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Antiarythmic agents arrhythmia Biological and medical sciences Cardiovascular system chromanol 293B IKs, action potential duration L‐735,821 Medical sciences Pharmacology. Drug treatments rabbit heart |
| title | Pharmacological block of the slow component of the outward delayed rectifier current (IKs) fails to lengthen rabbit ventricular muscle QTc and action potential duration |
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