Influence of nerve‐ending activity and of drugs on the rate of paralysis of rat diaphragm preparation by Cl. botulinum type A toxin

Since the studies of Guyton & MacDonald (1947), Ambache (1948, 1949, 1951) and Burgen, Dickens & Zatman (1949) on the action of botulinum toxin it is generally agreed that the paralysis is caused by failure of release of the neurohumoral transmitter at the effector site (see also Brooks, 1954, 1956; Ambache & Lessin, 1955). So far, however, it has proved difficult to modify the course of the neuromuscular paralysis caused by the toxin. Guyton & MacDonald (1947), using intact animals, and Burgen et al. (1949), using the isolated rat diaphragm preparation, were unable to modify by drugs either the rate at which paralysis took place or the rate of recovery of the paralysed muscles. The only observations showing some modification of the rate of intoxication are those of Bronfenbrenner & Weiss (1924), who showed that the survival times of guineapigs given lethal doses of toxin could be considerably prolonged by anaesthesia. This suggested that inactivity delayed the onset of paralysis, as was borne out also by the following observations made by May & Whaler (1958) during experiments on the intestinal absorption of toxin. It was noticed that in intoxicated rabbits respiratory distress and inability to hold up the head often preceded paralysis of the limb muscles. Since the groups of muscles thus involved are in a state of continuous activity it seemed likely that the degree of activity might be important in determining the rate of onset of paralysis. This has now been confirmed on rat phrenic nerve-diaphragm preparations. Moreover, it has also been possible to alter appreciably the rate of onset of neuromuscular paralysis by means of drugs known to modify acetylcholine metabolism and function.