214 1. MALONATE 



for hours in 50 mikf malonate. The temporary depression brought about 

 by malonate is not counteracted by fumarate added either before, with, or 

 after the malonate. In fact, fumarate, along with pyruvate, acetate, suc- 

 cinate, and malate, has an action very similar to that of malonate on the 

 atria. It is not known if this inhibition and recovery are related to the 

 somewhat slower but similar time course of ventricular respiration under 

 the influence of malonate (page 181) (Webb et al, 1949). The depression is 

 not due to chelation of Ca++ or Mg++ since reduction in the concentrations 

 of these ions produces a different response. Gardner and Farah (1954) con- 

 firmed the resistance of rabbit atria to malonate, finding that 10-20 milf 

 has no significant effects on contractility, spontaneous rate, excitability 

 threshold, refractory period, and conduction rate. 



The effects of malonate were investigated more thoroughly on rat atria 

 (Webb and Hollander, 1959). The contractility is depressed 21% imme- 

 diately but slow recovery occurs: the inhibition is 13% during 5-25 min, 

 9% during 25-45 min, and 5% during 45-60 min. The malonate concen- 

 tration used was 15 mM. The addition of 15 mM NaCl produces a rapid 

 contractile depression about half as great as from malonate, so that at least 

 part of the initial malonate effect is attributable to the Na+ ion. A slight 

 initial rise in the magnitude of the action potential is observed with both 

 malonate and NaCl, but in the case of malonate this is soon replaced by a 

 small depression. There is also some shortening of the action potential and 

 a decrease in its area after the first 5 min, which could be responsible for 

 the fall in tension. In summary, the addition of 15 ml/ malonate produces 

 a rapid initial effect attributable mainly to the Na+ and this is progressively 

 replaced by changes due to the malonate, these latter changes being mod- 

 erate depressions of the action potential and contractility. The importance 

 of the cycle in the atrial function is indicated by the marked changes brought 

 about by fluoroacetate, and thus the resistance to malonate is probably due 

 to a low intracellular concentration of malonate. Greater effects on the con- 

 tractility of rat atrium were observed by Venturi and Schoepke (1960), 

 5 mM depressing 22%, 10 mM 44%, and 20 mM 90%. It was stated that 

 NaCl at these concentrations does not alter the contractility. Furthermore, 

 succinate is as inhibitory as malonate. The greater depression observed here 

 compared to my work is difficult to explain. Venturi and Schoepke used 

 Locke solution at pH 7 whereas I used Krebs-Ringer-bicarbonate medium 

 at pH 7.4. Part of the larger inhibition seen by Venturi and Schoepke thus 

 might be due to the lower pH. In any event, these effects seem to be un- 

 related to the inhibition of succinate oxidase and again must be attributed 

 to some action directly on the membrane. Venturi and Schoepke found that 

 increasing Ca++ concentration can completely overcome the depressant ac- 

 tions of malonate, succinate, and the other organic anions used, leading 

 them to suggest that the negative inotropic action is due to the chelation 



