712 6. ARSENICALS 



potentials, one must assume that arsenite acts either directly on the contrac- 

 tile systems or on some aspect of excitation-contraction coupling.* There 

 is invariably some stimulation of the contractions at 2-5 min. The atria 

 usually stop in diastole, but some begin to shorten before this; all eventually 

 go into contracture, but more slowly than with iodoacetate, and the ulti- 

 mate tension reached is probably not as great. The effects observed on 

 glycerinated and actomyosin preparations of skeletal muscle, if they can 

 be extended to the heart, could explain some or all of the cardiac contractile 

 changes. And yet arsenite has been shown to cause accumulation of keto 

 acids and to deplete ATP in the heart; these actions must play a role in the 

 contractile depression, but apparently not through membrane changes. 

 Two questions come up in this work and are difficult to answer: why 

 does it require a relatively high arsenite concentration to depress mammalian 

 hearts, and why does it take so long for the depression to be manifest? 

 If arsenite penetrates readily into the heart cells, a concentration of 1-2 

 mM should almost completely block pyruvate oxidation, the operation of 

 the cycle, and a number of other metabolic pathways, if one can use the 

 data obtained on isolated enzyme systems. The heart is generally considered 

 to be a tissue energetically dependent on the cycle. The heart can utilize 

 fatty acids, but arsenite at this concentration should not only prevent 

 the entry of acetyl-CoA into the cycle (by blocking at the a-ketoglutarate 

 step) but also inhibit oxidation via the helix. The delay in effect cannot be 

 adequately explained on the basis of the time required to deplete ATP 

 stores, since low uncoupling concentrations of 2,4-dinitrophenol (around 

 0.01 mM) produce contractile failure in a much shorter time than arsenite. 

 Is it possible that the lipoate or other vicinal SH groups in the intact cell 

 may be relatively inaccessible to arsenite, as in some electron transport 

 systems (page 661)? Thus higher concentrations of arsenite and longer 

 periods of action would be required for depression, compared to systems 

 isolated from the cell. 



EFFECTS OBSERVED IN THE WHOLE ANIMAL 



We shall be concerned in this section primarily with the toxic effects 

 of the arsenicals in animals and with the dependence of these effects on the 

 metabolic disturbances produced in the tissues. The toxicology of arsenite 

 and the simpler arsenoxides will be emphasized inasmuch as it is with the 

 metabolic actions of these that we are best acquainted. The organic penta- 



* One can also assume that ATP is compartmentalized and the ATP used in mem- 

 brane events is from a different source than that used in contraction, pyruvate oxid- 

 ation being essential for the generation of ATP in the latter case, but actually what 

 little evidence is available is against this. 



