212 1. lODOACETATE AND lODOACETAMIDE 



but stops within 7 min if the oxygen is withdrawn (Gaddie and Stewart, 

 1933). Variation of the Og tension from to 20 mm Hg produced a steady 

 increase in survival and the rate of beating, but the electrical events are 

 not as sensitive to oxygen lack (Clark and Kingisepp, 1935). The fall of 

 ATP in iodoacetate-treated frog hearts is twice as fast anerobically as 

 aerobically (Clark and Eggleton, 1936), and creatine-P is much more re- 

 duced in rabbit atria when anoxia is superimposed on iodoacetate poisoning 

 (Chang, 1938 a). Mammalian hearts are not able to function aerobically 

 when treated with iodoacetate for as long as amphibian hearts, but anoxia 

 still increases the rate of failure. Anoxia depresses the rate of rabbit atria 

 50% in 21.8 min but in the presence of 0.08 mill iodoacetate this is reduced 

 to 14.2 min; the time for 50% anoxic depression of contractility is likewise 

 reduced from 9.0 to 5.9 min by iodoacetate (Gardner and Farah, 1954). 

 Indeed, anoxia has often been utilized as a criterion for adequate action by 

 iodoacetate; if the preparation fails rapidly during anoxia (i.e., much faster 

 than an unpoisoned preparation), one can be certain that the EM pathway 

 is fairly well blocked and the function aerobically is being maintained by 

 other pathways and substrates. Cyanide also causes rapid failure of hearts 

 treated with iodoacetate (Wertheimer, 1931; Dale, 1937), and fluoroacetate 

 acts similarly (Lee, 1954), as would be expected. These results show that 

 at the proper concentrations of iodoacetate, the heart can derive energy 

 from nonglycolytic sources and that iodoacetate is not markedly inhibiting 

 these oxidative processes. 



(B) Ejfect of functional activity on response to iodoacetate. Most of the 

 preparations studied have been active and failure has been equated with 

 the cessation of this activity. Anoxic failure in the presence of iodoacetate 

 varies linearly with the stimulation frequency, i.e., the rate of energy utili- 

 zation (Clark, 1935). Quiescent papillary muscles incubated with 0.54 mM 

 iodoacetate for 90 min show normal contractions when stimulation is be- 

 gun, but they soon fail, the higher the rate of stimulation the more rapid 

 being the failure (Lee, 1954). This relation is seen particularly well in the 

 results of Gardner et al. (1954) on rabbit atria (Fig. 1-12-30). These results 

 are quite like those obtained on skeletal muscle. 



(C) Metabolic disturbances 'produced by iodoacetate. The problems of pro- 

 ducing a selective inhibition of the EM pathway in heart have been touched 

 on (page 1-877) and it is likely that one can achieve a reasonably specific 

 effect, at least over a certain time interval, if care is taken. It seems diffi- 

 cult, however, to obtain marked changes in cardiac function aerobically 

 with such a specific block, inasmuch as the myocardium usually gets along 

 very well without glycolysis, due presumably to the utilization of lipid, 

 which is indicated by the low R.Q. values (0.74-0.78) generally found in 

 poisoned preparations (Table 1-21) (Clark et al., 1937; Burns and Cruick- 

 shank, 1937). Thus in our work on the effects of iodoacetate on atrial mem- 



