EFFECTS OF MALOXATE IN THE WHOLE ANIMAL 217 



The response of the heart to neurohormones is not altered by malonate. 

 The positive chronotropic effect of epinephrine on the frog heart is not 

 changed by 0.1 roM malonate (Nickerson and Nomaguchi, 1950), which is 

 not surprising considering the concentration. A brief report by Ellis and 

 Anderson (1951 a) stated that malonate does not affect the stimulation by 

 epinephrine except after prolonged treatment when the frog heart is de- 

 pressed. The malonate concentration was not given. It would seem likely 

 that any severe metabolic disturbance producing marked cardiac depression 

 would prevent, or at least reduce, any type of stimulation, since the ad- 

 ditional functional activity would demand more energy, so that an an- 

 tagonism of epinephrine by malonate is not of much significance unless it 

 occurs when the heart is not too much depressed. Malonate has no demon- 

 strable effect on the response of the heart to acetylcholine, with respect to 

 reduction of either rate or contractility (Webb, 1950 b), whereas fluoroace- 

 tate alters the response markedly, indicating again that the cycle is of im- 

 portance in these myocardial functions but that malonate does not reach 

 sufficiently high intracellular concentrations. 



EFFECTS OF MALONATE IN THE WHOLE ANIMAL 



A summary of the miscellaneous results relating to toxic and lethal ef- 

 fects of malonate is given in Table 1-28. One may conclude that in mammals 

 injected doses of 1.5 2.5 g/kg (10 17 millimoles/kg) of sodium malonate are 

 generally lethal. Such doses, especially when given intravenously, probably 

 produce plasma levels in excess of 10 inM malonate at peak concentra- 

 tions. A dose of 12 millimoles/kg subcutaneously in rats leads to a plasma 

 concentration of 4.5 mill at 30 min, and another similar dose raises the 

 plasma level to around 8 mM (Busch and Potter, 1952 a). Intravenous 

 injection would give higher peak levels. When compared in the same ex- 

 periments, the acid is more toxic than the sodium salt. It is difficult to 

 know if this is due to a nonspecific acid effect or to better penetration into 

 the tissues. It would appear that malonate is more toxic to mice at 38° than 

 at 30° environmental temperature (Gruber et al., 1949). 



The sequence of symptoms resulting from the injection of malonate into 

 rats and mice was described by Gruber et al. (1949) as: champing, air hunger, 

 maintenance of the head in a dorsally flexed position, and clonic convulsions. 

 Busch and Potter (1952 a) found dyspnea and convulsions in rats follow- 

 ing injection of toxic doses. The cause of death has been attributed to var- 

 ious actions. Forssman (1941) and Forsmann and Lindsten (1946) believed 

 that death is due to cardiac failure (the cardiovascular effects observed were 

 discussed in the previous section). Handler (1945) also favored a cardiac 

 mechanism for death and found the succinate oxidase to be inhibited 50- 

 75% in homogenates prepared from poisoned animals. He also noted that 



