EFFECTS OF MALONATE IN THE WHOLE ANIMAL 219 



the heart is dilated at death and that there is an accumulation of ascitic 

 and pleural fluid. Forssman and Lindsten, from their failure to obtain appre- 

 ciable direct action on the isolated heart, suggested an indirect mechanism, 

 possibly mediated through the effect of malonate on liver metabolism. The 

 dyspnea and various central nervous system effects may result from a direct 

 action of malonate but could also arise from the ionic and acid-base im- 

 balances produced. Handler (1945) showed that malonate causes a marked 

 fall in CO2 capacity in the blood from 53 to 6 vol%. Although no study of 

 the alterations in the plasma electrolytes undoubtedly produced by mal- 

 onate has been made, Wick et at. (1956) noted that the ability of the blood 

 to coagulate is reduced, and attributed many of the actions of malonate to 

 the chelation of divalent cations. Other changes in the blood composition 

 may also be responsible for some of the toxic effects. Handler (1945) re- 

 ported that 1.6 g/kg malonate given subcutaneously to rabbits increases 

 the blood glucose 368%, blood lactate 545%, blood pyruvate 163%, serum 

 inorganic phosphate 262%, and serum organic phosphates 155%. (The keto- 

 nemia produced by malonate was discussed previously). There is thus much 

 opportunity for secondary mechanisms to play a role in the toxicity of 

 malonate. At the present state of our knowledge it is even difficult to evaluate 

 the importance of succinate oxidase inhibition in these effects. 



The kidneys have the highest concentration of malonate after administra- 

 tion and therefore the renal effects and nephrotoxicity have been investigat- 

 ed. Early arguments about the renal toxicity of glutarate were published 

 between 1907 and 1912. Rose (1924) "reinvestigated this and found that 

 glutarate is a nephrotoxic substance in rabbits, as indicated by the increases 

 in nonprotein nitrogen, urea, and creatinine, and the almost complete disap- 

 pearance of renal function as measured by the phenolsulfonphthalein test. 

 A single experiment with malonate was reported. No renal damage was 

 observed after 2 g given on successive days and 3 g 2 days later, nor was 

 there a change in the rate of dye excretion. Corley and Rose (1929) reported 

 that methylmalonate and ethylmalonate are slightly toxic to the kidneys 

 at doses of about 1 g/kg in rabbits, there being a definite increase in the 

 nonprotein nitrogen and some reduction in dye secretion, although both 

 effects are transitory. Extensive renal damage was observed by Becker and 

 Rieken (1954) following the intraarterial injection of 20 mg potassium mal- 

 onate (Fig. 1-19 a). The vessel walls become edematous, potocytosis is evi- 

 dent, and many perinuclear vacuoles appear in the loops of Henle. However, 

 it requires much higher doses to depress the respiration of kidney slices 

 prepared from injected animals, 80 mg potassium malonate giving no effect 

 and 150 mg inhibiting 30.5%. Similar histological changes occur after in- 

 cubating kidney tissue in vitro with 110 mil/ potassium malonate for 20 min 

 (Fig. 1-19 b), vacuolization being intense. Tinacci (1953) found not only 

 kidney damage but widespread degenerative changes 2-8 days after sub- 



