The human genome encodes nine functional voltage-gated Na+
channels. Three of them, namely Nav
1.8, and Nav
1.9, are resistant to nanomolar concentrations of tetrodotoxin (TTX; IC50
≥ 1 μM). The other isoforms, which are predominantly expressed in the skeletal muscle and nervous system, are highly sensitive to TTX (IC50
~ 10 nM). During the last two decades, it has become evident that in addition to the major cardiac isoform Nav
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.