Effects of tetrodotoxin on the mammalian cardiovascular system.
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.
Zimmer
Thomas
T
Institute of Physiology II, Friedrich Schiller University, Kollegiengasse 9, 07743 Jena, Germany. thomas.zimmer@mti.uni-jena.de
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*
D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin
Jpn Circ J. 1966 Feb;30(2):134-8
5952001
Cardiovasc Res. 2005 Jan 1;65(1):117-27
15621039
Singapore Med J. 2007 Sep;48(9):830-3
17728964
Singapore Med J. 2004 Feb;45(2):73-4
14985845
J Physiol. 2005 Sep 1;567(Pt 2):387-400
15932895
Biophys J. 1995 Sep;69(3):873-82
8519987
Circulation. 1996 Dec 15;94(12):3083-6
8989112
Chem Pharm Bull (Tokyo). 1964 Nov;12(11):1357-74
5888644
J Pharmacol Exp Ther. 1963 Apr;140:31-40
13962288
J Pharmacol Exp Ther. 1971 Jul;178(1):110-21
5089708
MMWR Morb Mortal Wkly Rep. 1996 May 17;45(19):389-91
8609880
Prog Biophys Mol Biol. 2008 Oct-Nov;98(2-3):309-18
19351521
Am J Emerg Med. 2003 Jan;21(1):51-4
12563582
Neuron. 2000 Apr;26(1):13-25
10798388
J Physiol. 2007 Jul 15;582(Pt 2):675-93
17478540
Cardiovasc Res. 2009 Feb 15;81(3):528-35
18977767
Am J Trop Med Hyg. 1997 Jan;56(1):30-2
9063357
Pharmacol Rev. 2005 Dec;57(4):397-409
16382098
J Emerg Med. 2010 Nov;39(5):612-7
19201132
J Toxicol Clin Toxicol. 1986-1987;24(6):485-502
3573123
Acad Emerg Med. 1996 Dec;3(12):1106-12
8959164
Br J Pharmacol. 2008 Mar;153(6):1133-42
18071303
Pflugers Arch Gesamte Physiol Menschen Tiere. 1967;295(3):213-26
5241427
Annu Rev Physiol. 2001;63:871-94
11181979
J Cardiovasc Electrophysiol. 2001 Feb;12(2):218-25
11232622
J Physiol. 2004 Sep 15;559(Pt 3):835-48
15254155
Med J Aust. 2002 Dec  2-16;177(11-12):650-3
12463990
J Accid Emerg Med. 1995 Sep;12(3):214-5
8581253
Prog Biophys Mol Biol. 2008 Oct-Nov;98(2-3):171-8
19027778
J Mol Cell Cardiol. 2010 Jan;48(1):172-80
19665465
Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):554-8
1309946
J Physiol. 2005 May 1;564(Pt 3):683-96
15746173
J Clin Invest. 1989 Jul;84(1):331-6
2544627
Ann Emerg Med. 1986 Sep;15(9):1094-8
3740600
J Accid Emerg Med. 1998 Sep;15(5):334-6
9785165
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):4073-8
11891345
Nature. 1976 Sep 23;263(5575):344-5
958493
J Pathol Bacteriol. 1966 Oct;92(2):471-6
5964380
Neurology. 1989 May;39(5):743-5
2710368
J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Feb 17;832(1):75-80
16439187
Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6210-5
11972032
Am J Physiol. 1979 Apr;236(4):H561-7
434221
J Pharmacol Exp Ther. 1958 Feb;122(2):247-54
13514613
Circ Res. 1968 Oct;23(4):553-65
5677946
Biochem Biophys Res Commun. 2007 Mar 30;355(1):28-33
17286959
Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3507-12
12631690
Adv Food Nutr Res. 2007;52:141-236
17425946
Naunyn Schmiedebergs Arch Pharmacol. 1975;289(1):1-28
1186915
Singapore Med J. 1983 Jun;24(3):168-71
6635683
Circulation. 2001 Mar 6;103(9):1303-10
11238277
Toxicon. 1969 Dec;7(4):287-302
5368467
Toxicon. 2004 Oct;44(5):549-53
15450930
Circ Res. 2006 Mar 17;98(5):667-74
16484618
Mar Drugs. 2008 May 28;6(2):220-42
18728726
Naunyn Schmiedebergs Arch Pharmacol. 1986 Feb;332(2):184-95
2422563
Eur J Pharmacol. 1980 Jul 25;65(2-3):293-6
7398792
Ann N Y Acad Sci. 1960 Nov 17;90:820-36
13727055
J Mol Cell Cardiol. 2007 Mar;42(3):469-77
17289073
Prog Biophys Mol Biol. 2008 Oct-Nov;98(2-3):120-36
19027780
Circulation. 2006 Sep 26;114(13):1360-71
16966585
Prog Biophys Mol Biol. 2008 Jan-Apr;96(1-3):452-64
17850852
Europace. 2007 Aug;9(8):571-7
17579244
Hum Exp Toxicol. 1995 May;14(5):446-50
7612308
Brain Res. 1990 Oct 1;528(2):259-68
2271927
Int J Biol Sci. 2009;5(2):201-4
19240810
Pharmacol Rev. 1966 Jun;18(2):997-1049
5328391
Cardiovasc Hematol Agents Med Chem. 2008 Oct;6(4):348-59
18855648
Proc Natl Acad Sci U S A. 1989 Oct;86(20):8170-4
2554302
Circ Res. 1968 Oct;23(4):501-6
4300393
Anesth Analg. 1995 Apr;80(4):857
7893064
Southeast Asian J Trop Med Public Health. 2008 Mar;39(2):303-6
18564717
J Physiol. 1997 Feb 1;498 ( Pt 3):641-8
9051576
J Mol Cell Cardiol. 1975 Sep;7(9):655-62
1185792
Lancet. 1994 Feb 26;343(8896):538-9
7906776
Anal Chem. 2008 Jul 15;80(14):5622-9
18558725
J Physiol. 1996 Apr 1;492 ( Pt 1):21-30
8730579
Circulation. 2004 Mar 23;109(11):1421-7
15007009
Anesthesiology. 1990 Dec;73(6):1158-68
2174210
Am J Trop Med Hyg. 2005 Nov;73(5):985-90
16282316
J Pathol. 1970 Feb;100(2):121-6
5420754