Tetrodotoxin infusion: nonventilatory effects and role in toxicity models

To determine the cardiovascular, autonomic, and neuromuscular effects of an IV infusion of tetrodotoxin (TTX) when ventilation is supported.

TTX was infused in 18 anesthetized beagles during conventional mechanical ventilation. TTX infusion continued at a rate of 9.3 micrograms/kg/hr until apnea occurred with 1 minute of ventilator disconnection. Measurements included intravascular pressures, heart rate (HR), cardiac output, blood gases, displacements of the rib cage and abdomen, O2 delivery, and responses to train-of-four and tetanic peripheral nerve stimulation. Results are expressed as mean +/- SD.

During TTX infusion, all the dogs had discoordinate movements of the rib cage, abdomen, and limbs. Vomiting, urination, defecation, and increased salivation occurred. Nicotinic and muscarinic effects, neuromuscular blockade, and cardiovascular depression were produced by TTX. Apnea occurred in 72.0 +/- 17.0 minutes when a total of 119.0 +/- 17.4 micrograms of TTX was infused. At apnea, decreases in arterial pressure, cardiac index, HR, O2 delivery, and systemic vascular resistance occurred, while pulmonary artery pressure and pulmonary vascular resistance increased. Loss of response to tetanic stimulation was closely correlated with the dose of TTX that produced apnea.

The clinical symptoms and signs of TTX poisoning are similar to those of anticholinesterase poisons, and TTX dosing as described by this model may serve as a surrogate for organophosphorus poisoning. The model may be useful to determine optimum therapies for TTX poisoning and, since TTX prevents sodium influx into cells, to investigate enhanced survival in animals suffering from ischemia.