878 16. SPECIFICITY or inhibition 



gressively depressant action on the atria: after 16 min pyruvate can stim- 

 ulate both rate and amplitude somewhat, after 25 min only the rate, 

 and later pyruvate is completely inactive. On the other hand, studies with 

 rat ventricle strips have indicated reasonably selective glycolytic block 

 with 0.2 mM iodoacetate (Masuoka et al., 1952; Covin and Berman, 1956). 

 This concentration did not interfere with the positive inotropic action of 

 pyruvate on hypodynamic preparations. If differences in the selectivity 

 of iodoacetate are observed on different cardiac tissues, it is likely that 

 much greater variability would be found in testing a variety of tissues from 

 different species, and this emphasizes the danger of applying results on one 

 tissue to another. 



Sometimes a greater faith than is justified is applied to the specificity 

 of certain inhibitors because of categorical statements made in the litera- 

 ture. Thus, Krebs has stated: "If the concentration of malonate is below 

 0.01 M, succinic dehydrogenase is the only muscle enzyme affected by this 

 inhibitor; this high specificity makes malonate a most valuable tool." 

 This statement is, in general, true as far as we know and malonate, when 

 used properly, is indeed a very useful inhibitor. However, Das (1937) 

 has reported 50% inhibition of lactic dehydrogenase from pigeon breast 

 muscle, and a number of other enzymes from other tissues have been found 

 to be inhibited appreciably by 10 uiM or less malonate: oxalacetate decar- 

 boxylase from pigeon liver (100% by 10 mM), malic enzyme from cattle 

 lens (55% by 8.3 mM), «-ketoglutarate oxidase from pea seedlings (15% 

 by 1 mM), and others, some of which have not been tested in muscle pre- 

 parations. Also it must be admitted that many muscle enzymes have never 

 been studied with respect to malonate inhibition so that we simply do 

 not have a complete spectrum of action. One must also consider the pos- 

 sibility of nonenzymic actions by such inhibitors when intact tissues are 

 used. Thus, the above statement may be true for many types of preparation 

 and was undoubtedly made with these reservations in mind, and yet some 

 investigators will interpret it too rigorously and possibly be led astray with 

 a false sense of security. Certainly in our laboratory we have obtained re- 

 sults with 1 mM to 10 mM malonate that cannot be readily interpreted 

 in terms of an inhibition of succinic dehydrogenase. The positive inotropic 

 action of malonate on the rat ventricle is apparently unrelated to any 

 action on this enzyme or the tricarboxylic acid cycle (Covin and Berman, 

 1956) and evidence for a stimulatory action on the glycolytic pathway in 

 brain slices (Heald, 1953) and ventricle slices (Webb et al., 1949 b) has 

 been reported. There is a great need for more emphasis on the important 

 problem of inhibitor specificity and for more energetic attempts to evaluate 

 the specificity in the particular systems being studied. 



