This Article Full Text Full Text (PDF) All Versions of this Article: 89/11/1014    most recent hh2301.100002v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lee, P. J. Articles by Fozzard, H. A. Search for Related Content PubMed PubMed Citation Articles by Lee, P. J. Articles by Fozzard, H. A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB LIDOCAINE Related Collections Cardiovascular Pharmacology Ion channels/membrane transport

(Circulation Research. 2001;89:1014.)
© 2001 American Heart Association, Inc.

Cellular Biology

Cardiac-Specific External Paths for Lidocaine, Defined by Isoform-Specific Residues, Accelerate Recovery From Use-Dependent Block

Peter J. Lee, Akihiko Sunami, Harry A. Fozzard

From the Section of Cardiology (P.J.L., H.A.F.), Department of Medicine and Department of Neurobiology, Pharmacology and Physiology (A.S., H.A.F.), University of Chicago, Chicago, Ill.

Correspondence to Peter J. Lee, MD, PhD, University of Chicago, 5841 S Maryland Ave, MC 6080, Chicago, IL 60637. E-mail plee{at}medicine.bsd.uchicago.edu

Local anesthetic antiarrhythmic drugs block voltage-gated Na⁺ channels from the cytoplasmic side. In addition, cardiac Na⁺ channels can be also blocked by the membrane-impermeant local anesthetic QX via external paths not present in skeletal muscle or brain channels. Introduction of cardiac isoform-specific residues into wild-type skeletal muscle or brain channels creates access paths for external QX block. These paths should affect the characteristics of use-dependent block by influencing drug on- and off-rates. We investigated the effects of these external paths on drug kinetics of lidocaine, a lipophilic drug of clinical relevance, by studying use-dependent block using a two-electrode voltage clamp in Xenopus oocytes. Recovery from use-dependent block was slowed when cardiac isoform-specific residues important for external QX access were mutated to skeletal muscle or brain isoform-specific residues. As the fraction of charged lidocaine was decreased by raising external pH, differences in recovery kinetics diminished, indicating that these mutations mostly influenced block by charged lidocaine molecules. Data were fit into a model in which bound drug distributes into charged and neutral forms based on its pK_a and external pH with separate dissociation paths and recovery-time constants. These isoform-specific mutations altered the recovery-time constants for the charged molecules with smaller effects on those for the neutral molecules. We conclude that the external egress paths created by isoform-specific residues influence the drug kinetics of lidocaine, and these residues define cardiac-specific external paths for local anesthetic drugs.

Key Words: voltage-gated Na⁺ channel • lidocaine • electrophysiology • antiarrhythmic drugs

This article has been cited by other articles:

				Y.-C. Yang, J.-Y. Hsieh, and C.-C. Kuo The external pore loop interacts with S6 and S3-S4 linker in domain 4 to assume an essential role in gating control and anticonvulsant action in the Na+ channel J. Gen. Physiol., August 1, 2009; 134(2): 95 - 113. [Abstract] [Full Text] [PDF]

				I. Bruhova, D. B. Tikhonov, and B. S. Zhorov Access and Binding of Local Anesthetics in the Closed Sodium Channel Mol. Pharmacol., October 1, 2008; 74(4): 1033 - 1045. [Abstract] [Full Text] [PDF]

				H. A. Fozzard Increased Sensitivity to Local Anesthetic Drugs: Bedside to Bench Circ. Res., August 15, 2008; 103(4): 325 - 327. [Full Text] [PDF]

				Y.-C. Yang and C.-C. Kuo An Inactivation Stabilizer of the Na+ Channel Acts as an Opportunistic Pore Blocker Modulated by External Na+ J. Gen. Physiol., April 25, 2005; 125(5): 465 - 481. [Abstract] [Full Text] [PDF]

				S. Y. Tsang, R. G. Tsushima, G. F. Tomaselli, R. A. Li, and P. H. Backx A Multifunctional Aromatic Residue in the External Pore Vestibule of Na+ Channels Contributes to the Local Anesthetic Receptor Mol. Pharmacol., February 1, 2005; 67(2): 424 - 434. [Abstract] [Full Text] [PDF]

				A. Sunami, A. Tracey, I. W Glaaser, G. M Lipkind, D. A Hanck, and H. A Fozzard Accessibility of mid-segment domain IV S6 residues of the voltage-gated Na+ channel to methanethiosulfonate reagents J. Physiol., December 1, 2004; 561(2): 403 - 413. [Abstract] [Full Text] [PDF]

				E. Ramos and M. E O'Leary State-dependent trapping of flecainide in the cardiac sodium channel J. Physiol., October 1, 2004; 560(1): 37 - 49. [Abstract] [Full Text] [PDF]

				K. Sasaki, N. Makita, A. Sunami, H. Sakurada, N. Shirai, H. Yokoi, A. Kimura, N. Tohse, M. Hiraoka, and A. Kitabatake Unexpected Mexiletine Responses of a Mutant Cardiac Na+ Channel Implicate the Selectivity Filter as a Structural Determinant of Antiarrhythmic Drug Access Mol. Pharmacol., August 1, 2004; 66(2): 330 - 336. [Abstract] [Full Text] [PDF]

				M. E. O'Leary, M. Digregorio, and M. Chahine Closing and Inactivation Potentiate the Cocaethylene Inhibition of Cardiac Sodium Channels by Distinct Mechanisms Mol. Pharmacol., December 1, 2003; 64(6): 1575 - 1585. [Abstract] [Full Text] [PDF]

				M E O'Leary and M Chahine Cocaine binds to a common site on open and inactivated human heart (Nav1.5) sodium channels J. Physiol., June 15, 2002; 541(3): 701 - 716. [Abstract] [Full Text] [PDF]