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Article: Local anesthetic anchoring to cardiac sodium channels: Implications into tissue-selective drug targeting

TitleLocal anesthetic anchoring to cardiac sodium channels: Implications into tissue-selective drug targeting
Authors
KeywordsChemicals And Cas Registry Numbers
Issue Date1999
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://circres.ahajournals.org
Citation
Circulation Research, 1999, v. 85 n. 1, p. 88-98 How to Cite?
AbstractLocal anesthetics inhibit Na + channels in a variety of tissues, leading to potentially serious side effects when used clinically. We have created a series of novel local anesthetics by connecting benzocaine (BZ) to the sulfhydryl-reactive group methanethiosulfonate (MTS) via variable-length polyethylether linkers (L) (MTS-LX-BZ [X represents 0, 3, 6, or 9]). The application of MTS-LX-BZ agents modified native rat cardiac as well as heterologously expressed human heart (hH1) and rat skeletal muscle (rSkM1) Na + channels in a manner resembling that of free BZ. Like BZ, the effects of MTS-LX-BZ on rSkM1 channels were completely reversible. In contrast, MTS-LX- BZ modification of heart and mutant rSkM1 channels, containing a pore cysteine at the equivalent location as cardiac Na + channels (ie, Y401C), persisted after drug washout unless treated with DTT, which suggests anchoring to the pore via a disulfide bond. Anchored MTS-LX-BZ competitively reduced the affinity of cardiac Na + channels for lidocaine but had minimal effects on mutant channels with disrupted local anesthetic modification properties. These results establish that anchored MTS-LX-BZ compounds interact with the local anesthetic binding site (LABS). Variation in the linker length altered the potency of channel modification by the anchored drugs, thus providing information on the spatial relationship between the anchoring site and the LABS. Our observations demonstrate that local anesthetics can he anchored to the extracellular pore cysteine in cardiac Na + channels and dynamically interact with the intracellular LABS. These results suggest that nonselective agents, such as local anesthetics, might be made more selective by linking these agents to target-specific anchors.
Persistent Identifierhttp://hdl.handle.net/10722/91564
ISSN
2015 Impact Factor: 11.551
2015 SCImago Journal Rankings: 5.755
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLi, RAen_HK
dc.contributor.authorTsushima, RGen_HK
dc.contributor.authorHimmeldirk, Ken_HK
dc.contributor.authorDime, DSen_HK
dc.contributor.authorBackx, PHen_HK
dc.date.accessioned2010-09-17T10:21:26Z-
dc.date.available2010-09-17T10:21:26Z-
dc.date.issued1999en_HK
dc.identifier.citationCirculation Research, 1999, v. 85 n. 1, p. 88-98en_HK
dc.identifier.issn0009-7330en_HK
dc.identifier.urihttp://hdl.handle.net/10722/91564-
dc.description.abstractLocal anesthetics inhibit Na + channels in a variety of tissues, leading to potentially serious side effects when used clinically. We have created a series of novel local anesthetics by connecting benzocaine (BZ) to the sulfhydryl-reactive group methanethiosulfonate (MTS) via variable-length polyethylether linkers (L) (MTS-LX-BZ [X represents 0, 3, 6, or 9]). The application of MTS-LX-BZ agents modified native rat cardiac as well as heterologously expressed human heart (hH1) and rat skeletal muscle (rSkM1) Na + channels in a manner resembling that of free BZ. Like BZ, the effects of MTS-LX-BZ on rSkM1 channels were completely reversible. In contrast, MTS-LX- BZ modification of heart and mutant rSkM1 channels, containing a pore cysteine at the equivalent location as cardiac Na + channels (ie, Y401C), persisted after drug washout unless treated with DTT, which suggests anchoring to the pore via a disulfide bond. Anchored MTS-LX-BZ competitively reduced the affinity of cardiac Na + channels for lidocaine but had minimal effects on mutant channels with disrupted local anesthetic modification properties. These results establish that anchored MTS-LX-BZ compounds interact with the local anesthetic binding site (LABS). Variation in the linker length altered the potency of channel modification by the anchored drugs, thus providing information on the spatial relationship between the anchoring site and the LABS. Our observations demonstrate that local anesthetics can he anchored to the extracellular pore cysteine in cardiac Na + channels and dynamically interact with the intracellular LABS. These results suggest that nonselective agents, such as local anesthetics, might be made more selective by linking these agents to target-specific anchors.en_HK
dc.languageengen_HK
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://circres.ahajournals.orgen_HK
dc.relation.ispartofCirculation Researchen_HK
dc.subjectChemicals And Cas Registry Numbersen_HK
dc.subject.meshAnesthetics, Local - metabolism - pharmacologyen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshBenzocaine - pharmacologyen_HK
dc.subject.meshBinding Sites - drug effectsen_HK
dc.subject.meshDrug Combinationsen_HK
dc.subject.meshFemaleen_HK
dc.subject.meshHumansen_HK
dc.subject.meshLidocaine - pharmacologyen_HK
dc.subject.meshMaleen_HK
dc.subject.meshMesylates - pharmacologyen_HK
dc.subject.meshMyocardium - metabolismen_HK
dc.subject.meshOocytesen_HK
dc.subject.meshPatch-Clamp Techniquesen_HK
dc.subject.meshRatsen_HK
dc.subject.meshRats, Sprague-Dawleyen_HK
dc.subject.meshSodium Channels - drug effects - metabolism - physiologyen_HK
dc.subject.meshXenopus laevisen_HK
dc.titleLocal anesthetic anchoring to cardiac sodium channels: Implications into tissue-selective drug targetingen_HK
dc.typeArticleen_HK
dc.identifier.emailLi, RA:ronaldli@hkucc.hku.hken_HK
dc.identifier.authorityLi, RA=rp01352en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.pmid10400914-
dc.identifier.scopuseid_2-s2.0-0033538613en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0033538613&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume85en_HK
dc.identifier.issue1en_HK
dc.identifier.spage88en_HK
dc.identifier.epage98en_HK
dc.identifier.isiWOS:000081424900012-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLi, RA=7404724466en_HK
dc.identifier.scopusauthoridTsushima, RG=7006183117en_HK
dc.identifier.scopusauthoridHimmeldirk, K=7801500144en_HK
dc.identifier.scopusauthoridDime, DS=55296430600en_HK
dc.identifier.scopusauthoridBackx, PH=7006796226en_HK

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