214 1. lODOACETATE AND lODOACETAMIDE 



than without the P-glycerate. The fact that the heart stops eventually may 

 indicate that the penetration of the P-glycerate may limit its action, or 

 that iodoacetate is acting elsewhere; indeed, that P-glycerate penetrates at 

 all is rather surprising. Pyruvate and lactate increase the contractile ampli- 

 tude of frog ventricle treated with 1 mM bromoacetate, but Grimlund (1936) 

 found no reversal with succinate, fumarate, or P-glycerate. Clark et al. (1937) 

 tested a variety of substrates on the frog heart poisoned with 0.18 mM iodo- 

 acetate, and observed marked recovery with pyruvate, lactate, methyl- 

 glyoxal, various fatty acids, and certain amino acids, while glucose, suc- 

 cinate, and malate were without effect. These results provide additional 

 evidence that the poisoned heart is able to utilize fatty acids and amino 

 acids. Chang (1938 b) extended these observations to the mammalian heart, 

 finding that rabbit atria depressed by 0.18 mM iodoacetate can be stimulat- 

 ed with pyruvate, lactate, P-glycerate, and propionate, but not by glucose, 

 succinate, fumarate, or malate. In contrast to the frog heart, he found no 

 restoration with amino acids. Masuoka et al. (1952) reported that rat ven- 

 tricle strips incubated 30 min with 0.2 mM iodoacetate can be restored to 

 near-normal activity by pyruvate but not by glucose, indicating that this 

 concentration is effective in producing a selective block. Identical results 

 were obtained by Covin and Berman (1956). 



Other studies have shown that the situation is by no means simple and 

 that the effects of substrates on iodoacetate-poisoned cardiac tissue depend 

 on the concentration of inhibitor, the duration of exposure, the pH, and 

 other factors. Pyruvate has only limited ability to counteract iodoacetate on 

 rabbit atria; marked depression with 1 mM iodoacetate cannot be reversed 

 at all whereas with 0.2 mM iodoacetate partial restoration can be achieved 

 only if the pyruvate is added early before severe depression occurs (Webb, 

 1950 a). Acetate does not counteract the inhibition by iodoacetate in rabbit 

 atria if it is added later, but may protect slightly if present from the be- 

 ginning. Yet frog hearts severely poisoned with 54 mM iodoacetate revive 

 gradually when acetate is added, although lactate is more effective (Druck- 

 rey and Loch, 1943). Succinate and fumarate do not protect rabbit atria 

 from iodoacetate at pH 7.4, but provide some protection, at least against 

 the reduction in rate, at pH 6.2, indicating that failure to penetrate may 

 explain the ineffectiveness of certain substrates (Wilson et al, 1953). 



Iodoacetate depresses the contractile amplitude of rabbit atria much 

 more than the rate, and the antagonism exerted by pyruvate and acetate 

 is more evident on the rate than the contractility (Webb, 1950 a; Wilson et 

 al., 1953). This may well be correlated with the effect of pyruvate on sub- 

 strate-depleted atria, the rate being restored better than the mechanical 

 function (Webb, 1950 a). Possibly the pacemaker cells possess a different 

 pattern of metabolism from that of the bulk of the atrial cells, as suggested 

 by Wilson et al. (1953). However, other possibilities present themselves: 



