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.

Keywords: Na+ channel; TTX poisoning; TTX sensitivity; cardiac conduction.

Figure 1

TTX concentrations in blood or serum samples of intoxicated patients. The degree of intoxication was either reported by the authors or assessed according to documented symptoms (for individual data points see Table 4 and the respective references). The lowest and highest concentration reported in [62] was assigned to the first and fourth stage, respectively. Patients 4, 2, 3, and 1, previously reported in [76,81] were assigned to the first, second, third, and fourth stage, respectively. A value of 80 nM was assumed for a severely intoxicated patient whose serum and blood levels were about 83 and 77 nM, respectively [65,66].