208 1. MALONATE 



more readily by a number of substances; malonate at 10 mM inhibits up- 

 take 16% and transport 70% (Herz et al., 1961). 



Everted segments of the rat duodenum transport iron from the mucosal 

 to the serosal surface against concentration gradients and this process is 

 dependent on oxidative phosphorylations (Dowdle et al., 1960). Malonate 

 at 50 mM reduces the inside/outside ratio of Fe++ from 4.0 to 0.6. Ca++ is 

 also transported actively and malonate at 20 mM reduces the inside/outside 

 ratio of Ca*^ from 5.0 to 2.5 (Schachter and Rosen, 1959). Ca++ is also ac- 

 cumulated by the intestinal cells, the tissue/medium ratio being 5.8, which 

 is decreased by 20 mM malonate to 3.4 (Schachter et al., 1960). The question 

 of the chelation of Ca++ and Fe+++ by the malonate arises, since the high 

 malonate concentrations would certainly reduce the free ions appreciably. 

 This must play some role but in the case of Ca++ cannot explain the reduc- 

 tion in the transport, inasmuch as the inside/outside ratio is increased as 

 the Ca++ concentration is lowered. 



Gastric Acid Secretion 



The secretion of hydrochloric acid by the parietal cells is dependent on 

 oxidations and the formation of ATP, since it is strongly inhibited by cya- 

 nide, antimycin, and 2.4-dinitrophenol. However, the secretion in isolated 

 rat stomachs is not affected by 10 mM malonate (Patterson and Stetten, 

 1949). Injection of malonate in mice subcutaneously inhibits the accumu- 

 lation of p-aminohippurate in the kidney but does not inhibit acid secretion: 

 4.8 millimoles of malonate reduces the kidney/medium p-aminohippurate 

 ratio from 6.1 to 2.9 but inhibits the secretion of hydrochloric acid only 

 6% (Davenport and Chavre, 1956). This is near the fatal dose of malonate 

 and many of the mice did not live long enough to perform the test. Inas- 

 much as succinate oxidase activity is high in the stomach and is readily 

 inhibited by malonate, and since fluoroacetate inhibits acid secretion, the 

 most likely explanation for the lack of a malonate effect is a failure to 

 penetrate into the parietal cells sufficiently. Some evidence for the partici- 

 pation of succinate oxidase in acid secretion was obtained by Vitale et al. 

 (1956), who showed that stimulation of guinea pig or human gastric mucosa 

 with histamine leads to significant increases in the succinate oxidase activity, 

 although histamine has no such effect in liver or duodenum. Furthermore, 

 succinate oxidase is concentrated in those regions of the stomach where 

 the parietal cells are abundant. 



Active Transport of Ions in Various Cells and Tissues 



The effects of malonate on nerve and muscle, to be discussed in the fol- 

 lowing sections, depend in part on the modification of the active transport 

 of ions in these tissues. Malonate depresses many types of active transport. 



