EFFECTS OBSERVED IN THE WHOLE ANIMAL 247 



(5) Sudden violent tonic convulsions of the whole body occur, lasting 

 about 10 sec, leaving the animal in a state of rigor (opisthotonus, upper 

 extremities flexed and lower extremities extended), and respiration ceases 

 with a few gasping movements. 



The heart continues beating and probably would have continued much 

 longer if asphyxia had not been induced by respiratory failure. Animals 

 receiving around 70-90 mg/kg survive longer, show many of the above 

 effects, but exhibit a somewhat different terminal picture. Clonic convul- 

 sions, often of a rolling type, occur in repeated attacks over a long period 

 of time rather than a sudden tonic phase, and do not cause death. The 

 respiratory rate progressively slows and death occurs without terminal con- 

 vulsions, rigor not appearing until 15 min after death. Finally, animals 

 receiving 30-50 mg/kg, in which survival is over 24 hr, show maximal 

 hypoactivity at 4 hr and no signs of convulsions. It was believed that the 

 earliest effects of iodoacetate are on the central nervous system and only 

 later are the muscles or circulation adversely affected. Neuss (1931) found 

 very similar reactions in mice and rabbits to intravenous injections of bro- 

 moacetate, death occurring from respiratory failure following convulsions. 

 However, in anesthetized rabbits in which small amounts of bromoacetate 

 are injected over a period of time, circulatory collapse can occur and this is 

 the cause of death. It is probable that anesthesia protects the central ner- 

 vous system by reducing its activity, thus helping to maintain levels of 

 creatine-P and ATP, and also counteracts hyperactivity and convulsions. 

 Indeed, Neuss found urethane to raise the lethal dose of bromoacetate, as 

 did Haarmann (1932). Intravenous bromoacetate (2-8 mg/kg) produces 

 varying degrees of ataxia in dogs; at the higher doses the ataxia is prolonged 

 to several days (Andersen et al., 1955). As the dosage is increased to 16- 

 24 mg/kg, early periods of apathy are superimposed on the ataxia, with a 

 greater tendency to muscular rigidity. The mechanism by which iodoacetate 

 produces the central nervous system effects is obscure. Possibly the con- 

 vulsions are due to a fall in the membrane potentials in certain areas which 

 discharge spontaneously, or even to the depression of certain inhibitory 

 areas. Convulsive phases are often observed in poisoning with other meta- 

 bolic depressants (e.g. cyanide), or in asphyxia or hypoglycemia. There is 

 no evidence that the central effects are related to changes in the blood 

 chemistry. 



Hyperglycemia and Other Changes in the Blood 



Predictions of the response of blood glucose levels to iodoacetate are dif- 

 ficult because there are not only the more or less direct effects on tissue 

 metabolism, but perhaps many secondary factors. The experimental results 

 have been by no means uniform. A rise in the blood glucose in rabbits inject- 

 ed with 40-50 mg/kg bromoacetate was described by Neuss (1931) (see ac- 



