title: Effects of tetrodotoxin on the mammalian cardiovascular system.
abstract: The human genome encodes nine functional voltage-gated Na+ channels. Three of them, namely Na(v)1.5, Na(v)1.8, and Na(v)1.9, are resistant to nanomolar concentrations of tetrodotoxin (TTX; IC(50) > or = 1 microM). The other isoforms, which are predominantly expressed in the skeletal muscle and nervous system, are highly sensitive to TTX (IC(50) approximately 10 nM). During the last two decades, it has become evident that in addition to the major cardiac isoform Na(v)1.5, several of those TTX sensitive isoforms are expressed in the mammalian heart. Whereas immunohistochemical and electrophysiological methods demonstrated functional expression in various heart regions, the physiological importance of those isoforms for cardiac excitation in higher mammals is still debated. This review summarizes our knowledge on the systemic cardiovascular effects of TTX in animals and humans, with a special focus on cardiac excitation and performance at lower concentrations of this marine drug. Altogether, these data strongly suggest that TTX sensitive Na+ channels, detected more recently in various heart tissues, are not involved in excitation phenomena in the healthy adult heart of higher mammals.
authors.affiliation: Institute of Physiology II, Friedrich Schiller University, Kollegiengasse 9, 07743 Jena, Germany. thomas.zimmer@mti.uni-jena.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Zimmer
mesh_terms: D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects*; D006801:Humans; D026941:Sodium Channel Blockers / Q000633:toxicity*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D013779:Tetrodotoxin / Q000633:toxicity*
chemical_list: D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin
references.citation: Jpn Circ J. 1966 Feb;30(2):134-8
references.pmid: 5952001
references.citation: Cardiovasc Res. 2005 Jan 1;65(1):117-27
references.pmid: 15621039
references.citation: Singapore Med J. 2007 Sep;48(9):830-3
references.pmid: 17728964
references.citation: Singapore Med J. 2004 Feb;45(2):73-4
references.pmid: 14985845
references.citation: J Physiol. 2005 Sep 1;567(Pt 2):387-400
references.pmid: 15932895
references.citation: Biophys J. 1995 Sep;69(3):873-82
references.pmid: 8519987
references.citation: Circulation. 1996 Dec 15;94(12):3083-6
references.pmid: 8989112
references.citation: Chem Pharm Bull (Tokyo). 1964 Nov;12(11):1357-74
references.pmid: 5888644
references.citation: J Pharmacol Exp Ther. 1963 Apr;140:31-40
references.pmid: 13962288
references.citation: J Pharmacol Exp Ther. 1971 Jul;178(1):110-21
references.pmid: 5089708
references.citation: MMWR Morb Mortal Wkly Rep. 1996 May 17;45(19):389-91
references.pmid: 8609880
references.citation: Prog Biophys Mol Biol. 2008 Oct-Nov;98(2-3):309-18
references.pmid: 19351521
references.citation: Am J Emerg Med. 2003 Jan;21(1):51-4
references.pmid: 12563582
references.citation: Neuron. 2000 Apr;26(1):13-25
references.pmid: 10798388
references.citation: J Physiol. 2007 Jul 15;582(Pt 2):675-93
references.pmid: 17478540
references.citation: Cardiovasc Res. 2009 Feb 15;81(3):528-35
references.pmid: 18977767
references.citation: Am J Trop Med Hyg. 1997 Jan;56(1):30-2
references.pmid: 9063357
references.citation: Pharmacol Rev. 2005 Dec;57(4):397-409
references.pmid: 16382098
references.citation: J Emerg Med. 2010 Nov;39(5):612-7
references.pmid: 19201132
references.citation: J Toxicol Clin Toxicol. 1986-1987;24(6):485-502
references.pmid: 3573123
references.citation: Acad Emerg Med. 1996 Dec;3(12):1106-12
references.pmid: 8959164
references.citation: Br J Pharmacol. 2008 Mar;153(6):1133-42
references.pmid: 18071303
references.citation: Pflugers Arch Gesamte Physiol Menschen Tiere. 1967;295(3):213-26
references.pmid: 5241427
references.citation: Annu Rev Physiol. 2001;63:871-94
references.pmid: 11181979
references.citation: J Cardiovasc Electrophysiol. 2001 Feb;12(2):218-25
references.pmid: 11232622
references.citation: J Physiol. 2004 Sep 15;559(Pt 3):835-48
references.pmid: 15254155
references.citation: Med J Aust. 2002 Dec  2-16;177(11-12):650-3
references.pmid: 12463990
references.citation: J Accid Emerg Med. 1995 Sep;12(3):214-5
references.pmid: 8581253
references.citation: Prog Biophys Mol Biol. 2008 Oct-Nov;98(2-3):171-8
references.pmid: 19027778
references.citation: J Mol Cell Cardiol. 2010 Jan;48(1):172-80
references.pmid: 19665465
references.citation: Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):554-8
references.pmid: 1309946
references.citation: J Physiol. 2005 May 1;564(Pt 3):683-96
references.pmid: 15746173
references.citation: J Clin Invest. 1989 Jul;84(1):331-6
references.pmid: 2544627
references.citation: Ann Emerg Med. 1986 Sep;15(9):1094-8
references.pmid: 3740600
references.citation: J Accid Emerg Med. 1998 Sep;15(5):334-6
references.pmid: 9785165
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):4073-8
references.pmid: 11891345
references.citation: Nature. 1976 Sep 23;263(5575):344-5
references.pmid: 958493
references.citation: J Pathol Bacteriol. 1966 Oct;92(2):471-6
references.pmid: 5964380
references.citation: Neurology. 1989 May;39(5):743-5
references.pmid: 2710368
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Feb 17;832(1):75-80
references.pmid: 16439187
references.citation: Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6210-5
references.pmid: 11972032
references.citation: Am J Physiol. 1979 Apr;236(4):H561-7
references.pmid: 434221
references.citation: J Pharmacol Exp Ther. 1958 Feb;122(2):247-54
references.pmid: 13514613
references.citation: Circ Res. 1968 Oct;23(4):553-65
references.pmid: 5677946
references.citation: Biochem Biophys Res Commun. 2007 Mar 30;355(1):28-33
references.pmid: 17286959
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3507-12
references.pmid: 12631690
references.citation: Adv Food Nutr Res. 2007;52:141-236
references.pmid: 17425946
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 1975;289(1):1-28
references.pmid: 1186915
references.citation: Singapore Med J. 1983 Jun;24(3):168-71
references.pmid: 6635683
references.citation: Circulation. 2001 Mar 6;103(9):1303-10
references.pmid: 11238277
references.citation: Toxicon. 1969 Dec;7(4):287-302
references.pmid: 5368467
references.citation: Toxicon. 2004 Oct;44(5):549-53
references.pmid: 15450930
references.citation: Circ Res. 2006 Mar 17;98(5):667-74
references.pmid: 16484618
references.citation: Mar Drugs. 2008 May 28;6(2):220-42
references.pmid: 18728726
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 1986 Feb;332(2):184-95
references.pmid: 2422563
references.citation: Eur J Pharmacol. 1980 Jul 25;65(2-3):293-6
references.pmid: 7398792
references.citation: Ann N Y Acad Sci. 1960 Nov 17;90:820-36
references.pmid: 13727055
references.citation: J Mol Cell Cardiol. 2007 Mar;42(3):469-77
references.pmid: 17289073
references.citation: Prog Biophys Mol Biol. 2008 Oct-Nov;98(2-3):120-36
references.pmid: 19027780
references.citation: Circulation. 2006 Sep 26;114(13):1360-71
references.pmid: 16966585
references.citation: Prog Biophys Mol Biol. 2008 Jan-Apr;96(1-3):452-64
references.pmid: 17850852
references.citation: Europace. 2007 Aug;9(8):571-7
references.pmid: 17579244
references.citation: Hum Exp Toxicol. 1995 May;14(5):446-50
references.pmid: 7612308
references.citation: Brain Res. 1990 Oct 1;528(2):259-68
references.pmid: 2271927
references.citation: Int J Biol Sci. 2009;5(2):201-4
references.pmid: 19240810
references.citation: Pharmacol Rev. 1966 Jun;18(2):997-1049
references.pmid: 5328391
references.citation: Cardiovasc Hematol Agents Med Chem. 2008 Oct;6(4):348-59
references.pmid: 18855648
references.citation: Proc Natl Acad Sci U S A. 1989 Oct;86(20):8170-4
references.pmid: 2554302
references.citation: Circ Res. 1968 Oct;23(4):501-6
references.pmid: 4300393
references.citation: Anesth Analg. 1995 Apr;80(4):857
references.pmid: 7893064
references.citation: Southeast Asian J Trop Med Public Health. 2008 Mar;39(2):303-6
references.pmid: 18564717
references.citation: J Physiol. 1997 Feb 1;498 ( Pt 3):641-8
references.pmid: 9051576
references.citation: J Mol Cell Cardiol. 1975 Sep;7(9):655-62
references.pmid: 1185792
references.citation: Lancet. 1994 Feb 26;343(8896):538-9
references.pmid: 7906776
references.citation: Anal Chem. 2008 Jul 15;80(14):5622-9
references.pmid: 18558725
references.citation: J Physiol. 1996 Apr 1;492 ( Pt 1):21-30
references.pmid: 8730579
references.citation: Circulation. 2004 Mar 23;109(11):1421-7
references.pmid: 15007009
references.citation: Anesthesiology. 1990 Dec;73(6):1158-68
references.pmid: 2174210
references.citation: Am J Trop Med Hyg. 2005 Nov;73(5):985-90
references.pmid: 16282316
references.citation: J Pathol. 1970 Feb;100(2):121-6
references.pmid: 5420754