Respiratory and Circulatory Effects of Saxitoxin in the Cerebrospinal Fluid

Abstract

I In cats anaesthetized with pentobarbitone, saxitoxin and, on a few occasions, tetrodotoxin were injected into a lateral cerebral ventricle or into the subarachnoid space of the lower brain stem. Observations were made on frequency and tidal volume of breathing, on CO2 responsiveness and on electrical responsiveness of the respiratory centre. Effects on the blood pressure were observed simultaneously. 2 A single large dose of toxin, e.g., 250 ng, produced within minutes apneustic breathing and a rise in blood pressure which were converted rapidly to respiratory failure and hypotension. In contrast, repeated small doses, e.g., 25 ng, yielded only progressive slowing of the respiration together with circulatory hypotension. Bulbar depression was produced as effectively by subarachnoid injection as by intraventricular injection of the toxins. Onset of action was detectable within seconds. 3 Slowing of the respiration occurred independently of change in tidal volume and whether or not the vagus nerves were cut. The reduction in breathing frequency is attributed to direct toxin-induced depression of the central respiratory oscillator. 4 Steady-state measurements of tidal volume at controlled levels of alveolar CO2 pressure in intermediate stages of respiratory depression showed that the toxins produced an increase in CO2 stimulation threshold as well as a reduction in gain of CO2 responsiveness, whether or not the vagus nerves were cut. Carotid arterial chemoreceptor reactivity to 02 was demonstrable when central sensitivity to CO2 was depressed. These effects are attributed to a direct influence of the toxins upon the brainstem C02-tidal volume controller. SResponsiveness of the medullary inspiratory centre to electrical stimulation persisted after the failure of spontaneous breathing was caused by the toxins. Conversely, restitution of electrical responsiveness preceded the reappearance of spontaneous respiratory activity in the recovery phase of toxic depression. Circulatory effects paralleled the changes in respiratory behaviour. 6 On the basis of the relatively prompt and discrete alterations in the central respiratory and circulatory control mechanisms produced by saxitoxin and tetrodotoxin placed in the cerebrospinal fluid, it is concluded that the agents rapidly penetrated to deep target loci in the lower brain stem.

Bidirectional modulation of isoflurane potency by intrathecal tetrodotoxin and veratridine in rats

“…Three deaths occurred in the first series of studies of intrathecal tetrodotoxin alone (Table 1), and six deaths occurred in rats given the combination of tetrodotoxin and veratridine (Table 2), all occurring with infusion of the highest tetrodotoxin doses of 0.47 or 0.63 µM. These deaths appeared to result from central respiratory depression, probably due to rostral spread of tetrodotoxin to medullary respiratory centres and respiratory arrest (Borison and McCarthy, 1977). MAC2/MAC0 values indicated complete recovery 24 h after tetrodotoxin alone or in combination with veratridine in all other animals (Tables 1 and 2; Figures 2 and 3).…”

Central Respiratory and Circulatory Depression Caused by Intravascular Saxitoxin

“…We have demonstrated in previous work (Borison & McCarthy, 1977) that minute amounts of STX introduced directly into the CSF surrounding the brain stem produced the following sequence of events in the respiration: slowing, apneustic activity, loss of spontaneous function and finally a depression of responsiveness to electrical stimulation of the respiratory centre. If the premise were correct that the bloodbrain barrier is impermeable to STX, then these past findings would have little bearing on the mechanisms involved in the systemic effects of STX.…”

Human intoxication with paralytic shellfish toxins: Clinical parameters and toxin analysis in plasma and urine

“…This hypotensive effect also has been described by saxitoxin administration in guinea pigs (Chang et al, 1992), dogs (Kao et al, 1967;Henderson et al, 1973;Nagasawa et al, 1971;Catteral et al, 1979;Strichartz, 1984;Moczydlowski et al, 1986;Guo et al, 1987;Hall et al, 1990), cats (Borinson et al, 1977;Borinson et al, 1980;Andrinolo et al, 1999) and in human intoxications with PST (Long et al, 1990;Montebruno, 1993).…”