EFFECTS ON THE HEART 213 



brane potentials (Webb and Hollander, 1959), concentrations of 0.2-0.4 mM 

 were found to be ineffective within the time required for accurate determi- 

 nation of changes in the electrical properties and the concentration of 1 mM 

 generally used undoubtedly inhibits the oxidation of pyruvate and fatty 

 acids through the cycle. The respiration of intact preparations is consequent- 

 ly only slightly or moderately reduced by lower concentrations of iodoace- 

 tate (0.2-0.5 mM), as shown in the perfused frog heart (Weicker, 1934), 

 the heart-lung (Riihl, 1934; Burns and Cruickshank, 1937), and the cat 

 papillary muscle (Lee, 1954). The respiration of ventricle slices (Webb et al., 

 1949) and human atrial appendages (Burdette, 1951) is more sensitive, 

 concentrations of 1-2 mM inhibiting well, but here a good part of the effect 

 must be due to depression of the cycle. 



The formation of lactate in the heart is reduced, as in skeletal muscle. 

 Early work showed that lactate can generally be utilized by the function- 

 ing heart (Evans et al., 1933) and if lactate is exogenously available, as in 

 the heart-lung, its uptake may actually increase (Riihl, 1934; Gottdenker 

 and Rothberger, 1936). The effects of iodoacetate on the uptake and oxida- 

 tion of lactate and pyruvate by duckling ventricle slices are shown in Fig. 

 1-9 and have been discussed (page 94) (Miller and Olson, 1954). 



The levels of creatine-P and ATP in the heart fall as a result of the action of 

 iodoacetate, but a lack of parallelism between depletion of these phosphates 

 and functional failure has generally been noted (Clark et al., 1932; Clark 

 and Eggleton, 1936). When the frog heart stops beating, whether from iodo- 

 acetate alone or with anoxia in addition, the levels are not markedly re- 

 duced, but during the development of rigor they fall rather rapidly. Rabbit 

 atria behave similarly according to the data presented on the phosphagen 

 index by Chang (1937), in that at the time of contractile failure the high- 

 energy phosphate has not fallen below 50% of the normal value. The mam- 

 malian heart poisoned with iodoacetate utilizes lipid for synthesis of ATP 

 and creatine-P aerobically, and this prolongs the period of activity (Burns 

 and Cruickshank, 1937). There is also a rise in the hexose-P's, as in skeletal 

 muscle (Weicker, 1934). The metabolic response of the heart to iodoacetate 

 is thus very much like that of skeletal muscle, except for the greater ability 

 of the heart to subsist aerobically by fatty acid oxidation. 



(D) Antagonism of iodoacetate depression by substrates. The best method 

 for demonstrating the degree of selectivity of the action of iodoacetate on 

 the heart is to determine the amount of protection or recovery produced by 

 certain substrates. Edwards and Sanger (1933) found that the changes in 

 the refractory period and contractility of turtle atria brought about by 

 0.32 mM iodoacetate can be partially prevented or reversed by lactate. 

 Parnas et al. (1935) studied the role of P-gly cerate in the frog heart and 

 found that it prevents the systolic arrest produced by 0.4 mM iodoacetate, 

 the heart beating strongly and regularly for at least half an hour longer 



