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Blockade of Cardiac Sodium Channels by Amitriptyline and Diphenylhydantoin: Evidence for Two Use-Dependent Binding Sites
Cardiac toxicity is a frequent manifestation in amitriptyline overdose and is felt to be due, in part, to sodium channel blockade by the drug. Another agent with sodium channel blocking properties, diphenylhydantoin, has been used clinically to reverse cardiac conduction abnormalities induced by ami...
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| Published in: | Circulation research 1991-09, Vol.69 (3), p.677-696 |
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| container_title | Circulation research |
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| creator | Barber, Michael J Starmer, C Frank Grant, Augustus O |
| description | Cardiac toxicity is a frequent manifestation in amitriptyline overdose and is felt to be due, in part, to sodium channel blockade by the drug. Another agent with sodium channel blocking properties, diphenylhydantoin, has been used clinically to reverse cardiac conduction abnormalities induced by amitriptyline. This reversal of toxicity is believed to occur secondary to competition for the sodium channel binding site. We evaluated individually and in combination the effects of amitriptyline (0.4 μM) and diphenylhydantoin (10–80 μM) on the sodium current in isolated rabbit atrial and ventricular myocytes at 17°C. Using the whole-cell variant of the patch-clamp technique, we found that both amitriptyline and diphenylhydantoin reduced the sodium current in a use-dependent fashion. The time constant of recovery (τr) from block by amitriptyline at −130 mV was very slow (13.6±3.2 seconds), whereas τr during diphenylhydantoin exposure was fast (0.71±0.21 seconds, p |
| doi_str_mv | 10.1161/01.res.69.3.677 |
| format | article |
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Another agent with sodium channel blocking properties, diphenylhydantoin, has been used clinically to reverse cardiac conduction abnormalities induced by amitriptyline. This reversal of toxicity is believed to occur secondary to competition for the sodium channel binding site. We evaluated individually and in combination the effects of amitriptyline (0.4 μM) and diphenylhydantoin (10–80 μM) on the sodium current in isolated rabbit atrial and ventricular myocytes at 17°C. Using the whole-cell variant of the patch-clamp technique, we found that both amitriptyline and diphenylhydantoin reduced the sodium current in a use-dependent fashion. The time constant of recovery (τr) from block by amitriptyline at −130 mV was very slow (13.6±3.2 seconds), whereas τr during diphenylhydantoin exposure was fast (0.71±0.21 seconds, p<0.0001 compared with amitriptyline). During exposure of cells to a mixture of the two drugs, τr was found to be 6.6±1.8 seconds, but no evidence of direct competition between amitriptyline and diphenylhydantoin was seen. Attempts to fit the recovery data of the mixture to two exponentials resulted in no significant improvement in the fit when compared with that using a single exponential. Use of the sodium channel blocking agent lidocaine (similar kinetics to diphenylhydantoin) in competition with amitriptyline resulted in findings consistent with direct competition of these two drugs for a single binding site. These observations prompted us to evaluate the possibility that diphenylhydantoin was not acting at (and therefore not competing for) the same channel binding site as amitriptyline. Experiments altering pHi and pH. revealed dramatic differences between amitriptyline and diphenylhydantoin. When pHo. was increased from 7.4 to 8.0, τr was reduced approximately threefold (from 13.6±3.2 to 4.2±0.1 seconds, p<0.0001) during exposure to amitriptyline, but no effect was seen on τr after exposure to diphenylhydantoin. Conversely, when pHi was increased from 7.3 to 8.0, τr after amitriptyline was unaffected, but τr after diphenylhydantoin markedly increased (from 0.71±0.21 to 2.60±1.30 seconds, p<0.001). Additionally, diphenylhydantoin block demonstrated profound voltage dependence across the range of −130 to −90 mV, whereas amitriptyline block appeared less voltage sensitive. Single-channel studies using patch-clamp techniques in isolated ventricular myocytes supported these data. Superfusion of cells with diphenylhydantoin did not change mean channel open time but increased the probability of failure of the channel to open. When diphenylhydantoin was placed in the micropipette, no effect on sodium channel kinetics could be demonstrated. Our experiments show that amitriptyline blocks sodium channels via a drug-receptor complex site sensitive to changes in pHo, whereas diphenylhydantoin blocks from a pHo-insensitive site that is susceptible to changes in pHi. The decrease in amitriptyline-induced τr by diphenylhydantoin may result from allosteric modulation and suggests the presence of a separate (intracellular) binding site for diphenylhydantoin action. (Circulation Research 1991;69:677–696)</description><identifier>ISSN: 0009-7330</identifier><identifier>EISSN: 1524-4571</identifier><identifier>DOI: 10.1161/01.res.69.3.677</identifier><identifier>PMID: 1651817</identifier><identifier>CODEN: CIRUAL</identifier><language>eng</language><publisher>Hagerstown, MD: American Heart Association, Inc</publisher><subject>amitriptyline ; Amitriptyline - metabolism ; Amitriptyline - pharmacology ; Animals ; Binding Sites ; Binding, Competitive ; Biological and medical sciences ; cardiac muscle ; channels ; diphenylhydantoin ; Drug toxicity and drugs side effects treatment ; Heart - drug effects ; In Vitro Techniques ; inactivation ; Lidocaine - metabolism ; Lidocaine - pharmacology ; Medical sciences ; Myocardium - cytology ; Myocardium - metabolism ; Pharmacology. Drug treatments ; Phenytoin - metabolism ; Phenytoin - pharmacology ; Rabbits ; sodium ; Sodium - metabolism ; Sodium - physiology ; Sodium Channels - drug effects ; Sodium Channels - metabolism ; Toxicity: cardiovascular system</subject><ispartof>Circulation research, 1991-09, Vol.69 (3), p.677-696</ispartof><rights>1991 American Heart Association, Inc.</rights><rights>1992 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5013-d827d30ecfc7523a4ffa95c3971b2ad9778b8fee6da5d47b53b6c1a4c8078f4e3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4993143$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1651817$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Barber, Michael J</creatorcontrib><creatorcontrib>Starmer, C Frank</creatorcontrib><creatorcontrib>Grant, Augustus O</creatorcontrib><title>Blockade of Cardiac Sodium Channels by Amitriptyline and Diphenylhydantoin: Evidence for Two Use-Dependent Binding Sites</title><title>Circulation research</title><addtitle>Circ Res</addtitle><description>Cardiac toxicity is a frequent manifestation in amitriptyline overdose and is felt to be due, in part, to sodium channel blockade by the drug. Another agent with sodium channel blocking properties, diphenylhydantoin, has been used clinically to reverse cardiac conduction abnormalities induced by amitriptyline. This reversal of toxicity is believed to occur secondary to competition for the sodium channel binding site. We evaluated individually and in combination the effects of amitriptyline (0.4 μM) and diphenylhydantoin (10–80 μM) on the sodium current in isolated rabbit atrial and ventricular myocytes at 17°C. Using the whole-cell variant of the patch-clamp technique, we found that both amitriptyline and diphenylhydantoin reduced the sodium current in a use-dependent fashion. The time constant of recovery (τr) from block by amitriptyline at −130 mV was very slow (13.6±3.2 seconds), whereas τr during diphenylhydantoin exposure was fast (0.71±0.21 seconds, p<0.0001 compared with amitriptyline). During exposure of cells to a mixture of the two drugs, τr was found to be 6.6±1.8 seconds, but no evidence of direct competition between amitriptyline and diphenylhydantoin was seen. Attempts to fit the recovery data of the mixture to two exponentials resulted in no significant improvement in the fit when compared with that using a single exponential. Use of the sodium channel blocking agent lidocaine (similar kinetics to diphenylhydantoin) in competition with amitriptyline resulted in findings consistent with direct competition of these two drugs for a single binding site. These observations prompted us to evaluate the possibility that diphenylhydantoin was not acting at (and therefore not competing for) the same channel binding site as amitriptyline. Experiments altering pHi and pH. revealed dramatic differences between amitriptyline and diphenylhydantoin. When pHo. was increased from 7.4 to 8.0, τr was reduced approximately threefold (from 13.6±3.2 to 4.2±0.1 seconds, p<0.0001) during exposure to amitriptyline, but no effect was seen on τr after exposure to diphenylhydantoin. Conversely, when pHi was increased from 7.3 to 8.0, τr after amitriptyline was unaffected, but τr after diphenylhydantoin markedly increased (from 0.71±0.21 to 2.60±1.30 seconds, p<0.001). Additionally, diphenylhydantoin block demonstrated profound voltage dependence across the range of −130 to −90 mV, whereas amitriptyline block appeared less voltage sensitive. Single-channel studies using patch-clamp techniques in isolated ventricular myocytes supported these data. Superfusion of cells with diphenylhydantoin did not change mean channel open time but increased the probability of failure of the channel to open. When diphenylhydantoin was placed in the micropipette, no effect on sodium channel kinetics could be demonstrated. Our experiments show that amitriptyline blocks sodium channels via a drug-receptor complex site sensitive to changes in pHo, whereas diphenylhydantoin blocks from a pHo-insensitive site that is susceptible to changes in pHi. The decrease in amitriptyline-induced τr by diphenylhydantoin may result from allosteric modulation and suggests the presence of a separate (intracellular) binding site for diphenylhydantoin action. (Circulation Research 1991;69:677–696)</description><subject>amitriptyline</subject><subject>Amitriptyline - metabolism</subject><subject>Amitriptyline - pharmacology</subject><subject>Animals</subject><subject>Binding Sites</subject><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>cardiac muscle</subject><subject>channels</subject><subject>diphenylhydantoin</subject><subject>Drug toxicity and drugs side effects treatment</subject><subject>Heart - drug effects</subject><subject>In Vitro Techniques</subject><subject>inactivation</subject><subject>Lidocaine - metabolism</subject><subject>Lidocaine - pharmacology</subject><subject>Medical sciences</subject><subject>Myocardium - cytology</subject><subject>Myocardium - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenytoin - metabolism</subject><subject>Phenytoin - pharmacology</subject><subject>Rabbits</subject><subject>sodium</subject><subject>Sodium - metabolism</subject><subject>Sodium - physiology</subject><subject>Sodium Channels - drug effects</subject><subject>Sodium Channels - metabolism</subject><subject>Toxicity: cardiovascular system</subject><issn>0009-7330</issn><issn>1524-4571</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1991</creationdate><recordtype>article</recordtype><recordid>eNpFkc1v1DAQxSMEKkvhzAnJB9RbUk-cxDG3drt8SJWQ2PZsOfaYmHqdYCcs-e8J2hUcRqOZ95t3eJNlb4EWAA1cUygipqIRBSsazp9lG6jLKq9qDs-zDaVU5Jwx-jJ7ldIPSqFipbjILqCpoQW-yX7f-kE_KYNksGSronFKk_1g3Hwg216FgD6RbiE3BzdFN06LdwGJCobcubHHsPh-MSpMgwsfyO6XMxg0EjtE8nAcyGPC_A5HDOt6IrcuGBe-k72bML3OXljlE74598vs8ePuYfs5v__66cv25j7XNQWWm7bkhlHUVvO6ZKqyVolaM8GhK5URnLddaxEbo2pT8a5mXaNBVbqlvLUVssvs6uQ7xuHnjGmSB5c0eq8CDnOS0JSlqBu6gtcnUMchpYhWjtEdVFwkUPk3a0lBftvtZSMkk2vW68W7s_XcHdD850_hrvr7s66SVt5GFbRL_7BKCLb-Y8WqE3Yc_IQxPfn5iFH2qPzUy_WFlFEocxACqFinfC1g7A-jp5gN</recordid><startdate>199109</startdate><enddate>199109</enddate><creator>Barber, Michael J</creator><creator>Starmer, C Frank</creator><creator>Grant, Augustus O</creator><general>American Heart Association, Inc</general><general>Lippincott</general><scope>IQODW</scope><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>8FD</scope><scope>FR3</scope><scope>M7Z</scope><scope>P64</scope></search><sort><creationdate>199109</creationdate><title>Blockade of Cardiac Sodium Channels by Amitriptyline and Diphenylhydantoin: Evidence for Two Use-Dependent Binding Sites</title><author>Barber, Michael J ; Starmer, C Frank ; Grant, Augustus O</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5013-d827d30ecfc7523a4ffa95c3971b2ad9778b8fee6da5d47b53b6c1a4c8078f4e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1991</creationdate><topic>amitriptyline</topic><topic>Amitriptyline - metabolism</topic><topic>Amitriptyline - pharmacology</topic><topic>Animals</topic><topic>Binding Sites</topic><topic>Binding, Competitive</topic><topic>Biological and medical sciences</topic><topic>cardiac muscle</topic><topic>channels</topic><topic>diphenylhydantoin</topic><topic>Drug toxicity and drugs side effects treatment</topic><topic>Heart - drug effects</topic><topic>In Vitro Techniques</topic><topic>inactivation</topic><topic>Lidocaine - metabolism</topic><topic>Lidocaine - pharmacology</topic><topic>Medical sciences</topic><topic>Myocardium - cytology</topic><topic>Myocardium - metabolism</topic><topic>Pharmacology. Drug treatments</topic><topic>Phenytoin - metabolism</topic><topic>Phenytoin - pharmacology</topic><topic>Rabbits</topic><topic>sodium</topic><topic>Sodium - metabolism</topic><topic>Sodium - physiology</topic><topic>Sodium Channels - drug effects</topic><topic>Sodium Channels - metabolism</topic><topic>Toxicity: cardiovascular system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Barber, Michael J</creatorcontrib><creatorcontrib>Starmer, C Frank</creatorcontrib><creatorcontrib>Grant, Augustus O</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biochemistry Abstracts 1</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Circulation research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Barber, Michael J</au><au>Starmer, C Frank</au><au>Grant, Augustus O</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Blockade of Cardiac Sodium Channels by Amitriptyline and Diphenylhydantoin: Evidence for Two Use-Dependent Binding Sites</atitle><jtitle>Circulation research</jtitle><addtitle>Circ Res</addtitle><date>1991-09</date><risdate>1991</risdate><volume>69</volume><issue>3</issue><spage>677</spage><epage>696</epage><pages>677-696</pages><issn>0009-7330</issn><eissn>1524-4571</eissn><coden>CIRUAL</coden><abstract>Cardiac toxicity is a frequent manifestation in amitriptyline overdose and is felt to be due, in part, to sodium channel blockade by the drug. Another agent with sodium channel blocking properties, diphenylhydantoin, has been used clinically to reverse cardiac conduction abnormalities induced by amitriptyline. This reversal of toxicity is believed to occur secondary to competition for the sodium channel binding site. We evaluated individually and in combination the effects of amitriptyline (0.4 μM) and diphenylhydantoin (10–80 μM) on the sodium current in isolated rabbit atrial and ventricular myocytes at 17°C. Using the whole-cell variant of the patch-clamp technique, we found that both amitriptyline and diphenylhydantoin reduced the sodium current in a use-dependent fashion. The time constant of recovery (τr) from block by amitriptyline at −130 mV was very slow (13.6±3.2 seconds), whereas τr during diphenylhydantoin exposure was fast (0.71±0.21 seconds, p<0.0001 compared with amitriptyline). During exposure of cells to a mixture of the two drugs, τr was found to be 6.6±1.8 seconds, but no evidence of direct competition between amitriptyline and diphenylhydantoin was seen. Attempts to fit the recovery data of the mixture to two exponentials resulted in no significant improvement in the fit when compared with that using a single exponential. Use of the sodium channel blocking agent lidocaine (similar kinetics to diphenylhydantoin) in competition with amitriptyline resulted in findings consistent with direct competition of these two drugs for a single binding site. These observations prompted us to evaluate the possibility that diphenylhydantoin was not acting at (and therefore not competing for) the same channel binding site as amitriptyline. Experiments altering pHi and pH. revealed dramatic differences between amitriptyline and diphenylhydantoin. When pHo. was increased from 7.4 to 8.0, τr was reduced approximately threefold (from 13.6±3.2 to 4.2±0.1 seconds, p<0.0001) during exposure to amitriptyline, but no effect was seen on τr after exposure to diphenylhydantoin. Conversely, when pHi was increased from 7.3 to 8.0, τr after amitriptyline was unaffected, but τr after diphenylhydantoin markedly increased (from 0.71±0.21 to 2.60±1.30 seconds, p<0.001). Additionally, diphenylhydantoin block demonstrated profound voltage dependence across the range of −130 to −90 mV, whereas amitriptyline block appeared less voltage sensitive. Single-channel studies using patch-clamp techniques in isolated ventricular myocytes supported these data. Superfusion of cells with diphenylhydantoin did not change mean channel open time but increased the probability of failure of the channel to open. When diphenylhydantoin was placed in the micropipette, no effect on sodium channel kinetics could be demonstrated. Our experiments show that amitriptyline blocks sodium channels via a drug-receptor complex site sensitive to changes in pHo, whereas diphenylhydantoin blocks from a pHo-insensitive site that is susceptible to changes in pHi. The decrease in amitriptyline-induced τr by diphenylhydantoin may result from allosteric modulation and suggests the presence of a separate (intracellular) binding site for diphenylhydantoin action. (Circulation Research 1991;69:677–696)</abstract><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>1651817</pmid><doi>10.1161/01.res.69.3.677</doi><tpages>20</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Circulation research, 1991-09, Vol.69 (3), p.677-696 |
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| source | Freely Accessible Science Journals - check A-Z of ejournals |
| subjects | amitriptyline Amitriptyline - metabolism Amitriptyline - pharmacology Animals Binding Sites Binding, Competitive Biological and medical sciences cardiac muscle channels diphenylhydantoin Drug toxicity and drugs side effects treatment Heart - drug effects In Vitro Techniques inactivation Lidocaine - metabolism Lidocaine - pharmacology Medical sciences Myocardium - cytology Myocardium - metabolism Pharmacology. Drug treatments Phenytoin - metabolism Phenytoin - pharmacology Rabbits sodium Sodium - metabolism Sodium - physiology Sodium Channels - drug effects Sodium Channels - metabolism Toxicity: cardiovascular system |
| title | Blockade of Cardiac Sodium Channels by Amitriptyline and Diphenylhydantoin: Evidence for Two Use-Dependent Binding Sites |
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