The Failure of Respiration in Death by Tetrodotoxin Poisoning

Abstract

After intravenous injection of tetrodotoxin in a dose which led to respiratory failure in the rat, the phrenic nerve continued to convey massive bursts of nerve impulses from the medullary centre for some time after cessation of respiratory movement, contraction of diaphragm and diaphragmatic muscle action potentials. In artificially ventilated intact rats the contractile response of a hemidiaphragm to indirect and direct stimulation diminished and disappeared together when tetrodotoxin was injected intravenously. In curarized rats, the response to direct stimulation disappeared when tetrodotoxin was given. In artificially ventilated rats which had one phrenic nerve cut 2 months previously, the contractile response of the denervated hemidiaphragm to direct stimulation and that of the intact opposite hemidiaphragm to indirect stimulation both diminished and stopped after the administration of tetrodotoxin. Action potentials were elicited from the biceps brachii muscle and its motor nerve following stimulation of the motor cortex; after injection of tetrodotoxin, both nerve and muscle action potentials diminished and disappeared together. It appears from the evidence presented that the failure of respiration in tetrodotoxin poisoning is due to paralysis of the respiratory muscles which were apparently more susceptible to the action of tetrodotoxin than the respiratory and other motor nerves or the non‐respiratory striated muscles.

Two toxins from a poisonous sample of mussels Mytilus edulis

“…These effects produced by the major and minor toxins are indistinguishable from those seen when saxitoxin is infused slowly into anaesthetized cats or rabbits (Evans, 1965) and are also similar to those seen when tetrodotoxin is given to rats (Sakai, Sato & Uraguchi, 1961;Cheng, Ling & Wang, 1968).…”

“…The respiratory paralysis was found to be due to a direct action of the toxins on the respiratory muscles or nerve terminals; the medullary centres were not depressed after intravenous administration. In this respect also, the toxins resemble saxitoxin and tetrodotoxin (Sakai, Sato & Uraguchi, 1961;Evans, 1965;Cheng et al, 1968).…”

Parallel Evolution of Tetrodotoxin Resistance in Three Voltage-Gated Sodium Channel Genes in the Garter Snake Thamnophis sirtalis

“…Later motor symptoms are likely mediated by effects on Na v 1.6, which is found mainly at nodes of Ranvier, where it is involved in propagation of action potentials along axons ( Caldwell et al 2000 ). Human deaths from severe TTX poisoning are usually caused by respiratory failure, and evidence from laboratory mammals suggests that this effect derives from direct blockade of sodium channels in the diaphragm, which seems to be more sensitive to the toxin than most muscles ( Cheng et al 1968 ). However, squamates lack a diaphragm and instead power respiration with a variety of axial muscles ( Rosenberg 1973 ; Carrier 1989 ).…”

Tetrodotoxin

“…Although TTX primarily inhibits the transmission of nerve impulses, it also has a direct action on skeletal muscle. This blockade of neuromuscular transmission generally is believed to occur on motor nerve axons and on muscle fiber membranes, rather than at the motor end plates [3,60,63]. After administration, the time required to inhibit muscle fiber function is usually longer than that for nerve block, except in the case of diaphragmatic muscle involvement [3,63].…”