926 7. MERCURIALS 



of Henle. However, this is a very high toxic dose and the maximal inhibi- 

 tion occurred at 24-48 hr, although some effect could be observed at 3 hr. 

 In doses under 10 mg Hg/kg, no inhibition could be demonstrated, so that 

 again there is no reason to relate the inhibition to diuresis. Wachstein and 

 Meisel (1954) also observed succinate dehydrogenase inhibition in the prox- 

 imal tubules of the rat following large nephrotoxic doses of meralluride. 

 Bahn and Longley (1956) confirmed these results in that diuretic doses of 

 meralluride (4 mg Hg/kg) produce insignificant inhibition of succinate de- 

 hydrogenase while toxic doses (12 mg Hg/kg) inhibit moderately, especially 

 in the terminal proximal tubules. Finally, Bickers et al. (1960) found that 

 meralluride at 3-4 mg Hg/kg does not inhibit succinate dehydrogenase, 

 whereas 5 mg Hg/kg does to some extent after 10 hr. Later changes in en- 

 zyme activity, at a period of tubular damage, may be the result of secondary 

 changes and necrosis, so have little bearing on the mechanism of the diuretic 

 action. 



a-Ketoglutarate oxidase is more sensitive to mercurials than is succinate 

 dehydrogenase, and is inhibited 64% at 3-4 hr and 91% at 6 hr in rats 

 given HgClg at 3 mg Hg/kg (Shore and Shore, 1960). In animals fed sucrose, 

 the inhibitions are less, and sucrose also protects somewhat against the 

 nephrotoxic effects of Hg++, the mechanism being unknown. But again it 

 is impossible to correlate this action with the diuretic effect, since mersalyl 

 in diuretic dose (4 mg Hg/kg) does not alter the renal concentration of 

 a-ketoglutarate, although toxic doses (10 mg Hg/kg) produce an early and 

 prolonged rise in a-ketoglutarate (Dziirik and Krajci-Lazary, 1962). No 

 changes in sorbitol dehydrogenase activity in the kidneys of rats given 

 nephrotoxic doses of mercurin are detectable, and it would probably not 

 be very significant if they were (Pietschmann et al., 1962). Moderate inhibi- 

 tions of NAD and NADP diaphorases are found after toxic doses of the 

 mercurials (Bickers et al., 1960; Wachstein and Meisel, 1957), but in all 

 cases where enzyme inhibition is seen, there is histologically demonstrable 

 damage to the tubules. Protein disulfide reductase is apparently rather 

 potently inhibited in the kidney during mercurial action, but this is un- 

 doubtedly unrelated to the diuretic effect (Shore and Shore, 1962). 



Various phosphatases have been the subject of investigation although 

 there is little reason to expect a relation to ion transport. Nephrotoxic 

 doses of HgClg inhibit renal phosphatase slightly (10-20%) without affect- 

 ing serum phosphatase, but subtoxic doses somewhat increase the phospha- 

 tase activity (Hepler et al., 1945). There is no correlation between glucosuria 

 and phosphatase inhibition (Hepler and Simonds, 1946). Very high doses 

 (175-260 mg/kg) of HgClg decrease tubular phosphatase, although not in 

 capillaries or glomeruli, but low doses (6-10 mg/kg), which are lethal in 3 

 weeks, do not alter the phosphatase (Sachs and Dulskas, 1956). Diuretic 

 doses of various mercurials do not inhibit alkaline phosphatase, |5-glycero- 



