708 6. ARSENICALS 



that relatively little ATP is required for the ion pumps in relatively inactive 

 nerve, and respiration must be depressed to a fairly low level before it 

 would fail to provide sufficient ATP. The second is that the ion distributions 

 involved in the membrane potentials are ultimately but not immediately 

 dependent on oxidatiye metabolism, failure in conduction occurring only 

 when sufficient K+ has been lost from the cells, this requiring a long time 

 because very small amounts of K+ leave the cell during each impulse. 

 Jenerick (1957) similarly found a very slow action of 5 mM arsenite on 

 sciatic nerve, conduction block occurring when the resting potential has 

 fallen 30-40%, excitability being reduced after the action potentials are 

 lowered 10-20%. The intraaxonal injection of 5.6 X 10-^ ml 27 mM 

 arsenite into giant axons of the squid (this corresponds to 1.5 X 10"® 

 millimole/mm) has no effect on the action potential (Brady et al., 1958). 

 This can be calculated to give an internal concentration of about 3 mM, 

 which should be quite adequate to block oxidative metabolism. 



Skeletal Muscle 



We have seen that paralysis in frogs given arsenite is not primarily 

 muscular (Ringer and Murrell, 1878). However, it was noted that rigor 

 mortis occurs earlier in poisoned animals, so the authors concluded that 

 the muscles are affected. Further evidence that muscle can be altered 

 in vivo was obtained in an experiment in which muscle excitability was lost 

 within 13 hr in a poisoned limb but only after 34 hr in a ligatured limb. 

 Heffter (1893) reported a moderate rise in muscle lactate after death 

 from arsenite but did not observe rigor, while Nonnenbruch et al. (1936) 

 found decreases in muscle hexose-P, ADP, and phosphorylative ability 

 in arsenite-poisoned rabbits. Stimulated isolated frog muscle in 40 raM 

 arsenite shows a steady increase in tone until full contracture develops 

 (termed a Lundsgaard effect) and the muscle is inexcitable* (Gernay and 

 Lecomte, 1948). It was assumed that the block of pyruvate oxidation was 

 responsible for the contracture, but no evidence was presented. Neoarsphen- 

 amine causes contracture of frog muscle and thiamine prevents this (Pick 

 and Holland, 1951), but it is doubtful if this antagonism is in any way 

 related to the keto acid oxidases. The contracture produced by oxophenar- 

 sine is of the slowly developing type (Kuschinsky and Liillmann, 1954), 

 and in the rat diaphragm there is no change in the magnitudes of the resting 

 or action potentials while the muscle passes into contracture, although 

 depolarization occurs when contracture is complete (Muscholl, 1958). 

 Thus contracture appears to be a common effect of the arsenicals, occurring 



* The potassium salt of arsenite was used here for some obscure reason and, since 

 this ion can induce contracture, one does not know how much of the effect was due 

 to the arsenite. However, oxophenarsine at 12.6 mM produced a similar effect. 



