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Mechanism of inhibition of the Na current by tocainide in guinea-pig isolated ventricular cells
Tocainide blocked the Na current ( I Na) in ventricular myocytes in either a tonic or a phasic block manner, having a higher affinity for the inactivated state ( Kd i = 18 μM) than for the rested state ( Kd rest = 606 μM). The degree of phasic block was enhanced and the onset of phasic block was fas...
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| Published in: | General pharmacology 1999-05, Vol.32 (5), p.541-550 |
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| Main Authors: | , , , , , , , , , , , , , |
| Format: | Article |
| Language: | English |
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| container_end_page | 550 |
| container_issue | 5 |
| container_start_page | 541 |
| container_title | General pharmacology |
| container_volume | 32 |
| creator | Tanaka, Yasunori Hisatome, Ichiro Sasaki, Norihito Ahmmed, Gias U Yatsuhashi, Toru Yamanouchi, Yumi Uchida, Kazuhiko Hamada, Toshihiro Taniguchi, Shin-ichi Ogino, Kazuhide Igawa, Osamu Yoshida, Akio Shigemasa, Chiaki Sato, Ryoichi |
| description | Tocainide blocked the Na current (
I
Na) in ventricular myocytes in either a tonic or a phasic block manner, having a higher affinity for the inactivated state (
Kd
i = 18 μM) than for the rested state (
Kd
rest = 606 μM). The degree of phasic block was enhanced and the onset of phasic block was faster with an increase in pulse duration as well as at less-negative holding potential (HP). The recovery-time constant from the phasic block of
I
Na induced by tocainide was independent of either the HP or the removal of fast inactivation. After removal of fast inactivation, tocainide showed the pulse-duration dependency of phasic block but not the voltage dependency. These results suggest that tocainide could bind to the inactivated-state receptor through the hydrophilic pathway and leave the receptor through the hydrophobic pathway, producing the tonic and phasic block of
I
Na. |
| doi_str_mv | 10.1016/S0306-3623(98)00228-6 |
| format | article |
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I
Na) in ventricular myocytes in either a tonic or a phasic block manner, having a higher affinity for the inactivated state (
Kd
i = 18 μM) than for the rested state (
Kd
rest = 606 μM). The degree of phasic block was enhanced and the onset of phasic block was faster with an increase in pulse duration as well as at less-negative holding potential (HP). The recovery-time constant from the phasic block of
I
Na induced by tocainide was independent of either the HP or the removal of fast inactivation. After removal of fast inactivation, tocainide showed the pulse-duration dependency of phasic block but not the voltage dependency. These results suggest that tocainide could bind to the inactivated-state receptor through the hydrophilic pathway and leave the receptor through the hydrophobic pathway, producing the tonic and phasic block of
I
Na.</description><identifier>ISSN: 0306-3623</identifier><identifier>EISSN: 1879-0011</identifier><identifier>DOI: 10.1016/S0306-3623(98)00228-6</identifier><identifier>PMID: 10382855</identifier><language>eng</language><publisher>England: Elsevier Inc</publisher><subject>Animals ; Anti-Arrhythmia Agents - pharmacology ; Electrophysiology ; Fast inactivation process ; Guinea Pigs ; Heart - drug effects ; Heart - physiology ; Heart Ventricles - cytology ; Hydrophobic pathway ; In Vitro Techniques ; Modulated receptor hypothesis ; Na channels ; Sodium Channel Blockers ; Sodium Channels - physiology ; Tocainide ; Tocainide - pharmacology ; Ventricular myocytes</subject><ispartof>General pharmacology, 1999-05, Vol.32 (5), p.541-550</ispartof><rights>1999 Elsevier Science Inc.</rights><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c309t-3c974ea0bb0db75244a2ac0e0a4902ea14fe2d7c9a029ee875fd04dcb618620e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10382855$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tanaka, Yasunori</creatorcontrib><creatorcontrib>Hisatome, Ichiro</creatorcontrib><creatorcontrib>Sasaki, Norihito</creatorcontrib><creatorcontrib>Ahmmed, Gias U</creatorcontrib><creatorcontrib>Yatsuhashi, Toru</creatorcontrib><creatorcontrib>Yamanouchi, Yumi</creatorcontrib><creatorcontrib>Uchida, Kazuhiko</creatorcontrib><creatorcontrib>Hamada, Toshihiro</creatorcontrib><creatorcontrib>Taniguchi, Shin-ichi</creatorcontrib><creatorcontrib>Ogino, Kazuhide</creatorcontrib><creatorcontrib>Igawa, Osamu</creatorcontrib><creatorcontrib>Yoshida, Akio</creatorcontrib><creatorcontrib>Shigemasa, Chiaki</creatorcontrib><creatorcontrib>Sato, Ryoichi</creatorcontrib><title>Mechanism of inhibition of the Na current by tocainide in guinea-pig isolated ventricular cells</title><title>General pharmacology</title><addtitle>Gen Pharmacol</addtitle><description>Tocainide blocked the Na current (
I
Na) in ventricular myocytes in either a tonic or a phasic block manner, having a higher affinity for the inactivated state (
Kd
i = 18 μM) than for the rested state (
Kd
rest = 606 μM). The degree of phasic block was enhanced and the onset of phasic block was faster with an increase in pulse duration as well as at less-negative holding potential (HP). The recovery-time constant from the phasic block of
I
Na induced by tocainide was independent of either the HP or the removal of fast inactivation. After removal of fast inactivation, tocainide showed the pulse-duration dependency of phasic block but not the voltage dependency. These results suggest that tocainide could bind to the inactivated-state receptor through the hydrophilic pathway and leave the receptor through the hydrophobic pathway, producing the tonic and phasic block of
I
Na.</description><subject>Animals</subject><subject>Anti-Arrhythmia Agents - pharmacology</subject><subject>Electrophysiology</subject><subject>Fast inactivation process</subject><subject>Guinea Pigs</subject><subject>Heart - drug effects</subject><subject>Heart - physiology</subject><subject>Heart Ventricles - cytology</subject><subject>Hydrophobic pathway</subject><subject>In Vitro Techniques</subject><subject>Modulated receptor hypothesis</subject><subject>Na channels</subject><subject>Sodium Channel Blockers</subject><subject>Sodium Channels - physiology</subject><subject>Tocainide</subject><subject>Tocainide - pharmacology</subject><subject>Ventricular myocytes</subject><issn>0306-3623</issn><issn>1879-0011</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><recordid>eNqFkMlKBDEQhoMoOi6PoOQkemitpLfkJCJu4HJQzyGdVM-U9HSPSbfg29szI-LNU1Hw_bV8jB0KOBMgivMXSKFI0kKmJ1qdAkipkmKDTYQqdQIgxCab_CI7bDfGdxipXMpttiMgVVLl-YSZR3Qz21Kc867m1M6oop66dtn1M-RPlrshBGx7Xn3xvnOWWvI4knw6UIs2WdCUU-wa26PnnyMYyA2NDdxh08R9tlXbJuLBT91jbzfXr1d3ycPz7f3V5UPiUtB9kjpdZmihqsBXZS6zzErrAMFmGiRakdUofem0BakRVZnXHjLvqkKoQgKme-x4PXcRuo8BY2_mFJcX2Ba7IZpCq6yUMhvBfA260MUYsDaLQHMbvowAszRrVmbNUpvRyqzMmmLMHf0sGKo5-j-ptcoRuFgDOL75SRhMdIStQ08BXW98R_-s-AbqIok1</recordid><startdate>19990501</startdate><enddate>19990501</enddate><creator>Tanaka, Yasunori</creator><creator>Hisatome, Ichiro</creator><creator>Sasaki, Norihito</creator><creator>Ahmmed, Gias U</creator><creator>Yatsuhashi, Toru</creator><creator>Yamanouchi, Yumi</creator><creator>Uchida, Kazuhiko</creator><creator>Hamada, Toshihiro</creator><creator>Taniguchi, Shin-ichi</creator><creator>Ogino, Kazuhide</creator><creator>Igawa, Osamu</creator><creator>Yoshida, Akio</creator><creator>Shigemasa, Chiaki</creator><creator>Sato, Ryoichi</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>19990501</creationdate><title>Mechanism of inhibition of the Na current by tocainide in guinea-pig isolated ventricular cells</title><author>Tanaka, Yasunori ; Hisatome, Ichiro ; Sasaki, Norihito ; Ahmmed, Gias U ; Yatsuhashi, Toru ; Yamanouchi, Yumi ; Uchida, Kazuhiko ; Hamada, Toshihiro ; Taniguchi, Shin-ichi ; Ogino, Kazuhide ; Igawa, Osamu ; Yoshida, Akio ; Shigemasa, Chiaki ; Sato, Ryoichi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c309t-3c974ea0bb0db75244a2ac0e0a4902ea14fe2d7c9a029ee875fd04dcb618620e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Animals</topic><topic>Anti-Arrhythmia Agents - pharmacology</topic><topic>Electrophysiology</topic><topic>Fast inactivation process</topic><topic>Guinea Pigs</topic><topic>Heart - drug effects</topic><topic>Heart - physiology</topic><topic>Heart Ventricles - cytology</topic><topic>Hydrophobic pathway</topic><topic>In Vitro Techniques</topic><topic>Modulated receptor hypothesis</topic><topic>Na channels</topic><topic>Sodium Channel Blockers</topic><topic>Sodium Channels - physiology</topic><topic>Tocainide</topic><topic>Tocainide - pharmacology</topic><topic>Ventricular myocytes</topic><toplevel>online_resources</toplevel><creatorcontrib>Tanaka, Yasunori</creatorcontrib><creatorcontrib>Hisatome, Ichiro</creatorcontrib><creatorcontrib>Sasaki, Norihito</creatorcontrib><creatorcontrib>Ahmmed, Gias U</creatorcontrib><creatorcontrib>Yatsuhashi, Toru</creatorcontrib><creatorcontrib>Yamanouchi, Yumi</creatorcontrib><creatorcontrib>Uchida, Kazuhiko</creatorcontrib><creatorcontrib>Hamada, Toshihiro</creatorcontrib><creatorcontrib>Taniguchi, Shin-ichi</creatorcontrib><creatorcontrib>Ogino, Kazuhide</creatorcontrib><creatorcontrib>Igawa, Osamu</creatorcontrib><creatorcontrib>Yoshida, Akio</creatorcontrib><creatorcontrib>Shigemasa, Chiaki</creatorcontrib><creatorcontrib>Sato, Ryoichi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>General pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tanaka, Yasunori</au><au>Hisatome, Ichiro</au><au>Sasaki, Norihito</au><au>Ahmmed, Gias U</au><au>Yatsuhashi, Toru</au><au>Yamanouchi, Yumi</au><au>Uchida, Kazuhiko</au><au>Hamada, Toshihiro</au><au>Taniguchi, Shin-ichi</au><au>Ogino, Kazuhide</au><au>Igawa, Osamu</au><au>Yoshida, Akio</au><au>Shigemasa, Chiaki</au><au>Sato, Ryoichi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanism of inhibition of the Na current by tocainide in guinea-pig isolated ventricular cells</atitle><jtitle>General pharmacology</jtitle><addtitle>Gen Pharmacol</addtitle><date>1999-05-01</date><risdate>1999</risdate><volume>32</volume><issue>5</issue><spage>541</spage><epage>550</epage><pages>541-550</pages><issn>0306-3623</issn><eissn>1879-0011</eissn><abstract>Tocainide blocked the Na current (
I
Na) in ventricular myocytes in either a tonic or a phasic block manner, having a higher affinity for the inactivated state (
Kd
i = 18 μM) than for the rested state (
Kd
rest = 606 μM). The degree of phasic block was enhanced and the onset of phasic block was faster with an increase in pulse duration as well as at less-negative holding potential (HP). The recovery-time constant from the phasic block of
I
Na induced by tocainide was independent of either the HP or the removal of fast inactivation. After removal of fast inactivation, tocainide showed the pulse-duration dependency of phasic block but not the voltage dependency. These results suggest that tocainide could bind to the inactivated-state receptor through the hydrophilic pathway and leave the receptor through the hydrophobic pathway, producing the tonic and phasic block of
I
Na.</abstract><cop>England</cop><pub>Elsevier Inc</pub><pmid>10382855</pmid><doi>10.1016/S0306-3623(98)00228-6</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0306-3623 |
| ispartof | General pharmacology, 1999-05, Vol.32 (5), p.541-550 |
| issn | 0306-3623 1879-0011 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_69847224 |
| source | Elsevier |
| subjects | Animals Anti-Arrhythmia Agents - pharmacology Electrophysiology Fast inactivation process Guinea Pigs Heart - drug effects Heart - physiology Heart Ventricles - cytology Hydrophobic pathway In Vitro Techniques Modulated receptor hypothesis Na channels Sodium Channel Blockers Sodium Channels - physiology Tocainide Tocainide - pharmacology Ventricular myocytes |
| title | Mechanism of inhibition of the Na current by tocainide in guinea-pig isolated ventricular cells |
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