EFFECTS ON THE KIDNEY 925 



a separation of the villi, and mitochondrial disintegration occurs. With 

 large doses, damage may be observed with the electron microscope within 

 10 min. The maximal diuretic dose of mersalyl (6 mg/kg) in the rabbit 

 produces nuclear pycnosis, mitochondrial changes, and vacuolization in the 

 convoluted tubule (Dejung, 1963). Again, these results show selective ef- 

 fects, but may be the result of differential distribution and may not relate 

 to the diuretic site of action. 



The evidence taken together suggests that various portions of the nephron 

 are affected in one way or another by the mercurials, and what portion may 

 be involved will depend on the particular transport considered. The diuretic 

 action, i.e., the inhibition of Na+ resorption, appears to be limited mainly 

 to the proximal tubule; whether this is primarily in the convoluted or ter- 

 minal segments is not known. Analyses of th6 filtrate composition through- 

 out the nephron in the presence of mercurials are very difficult to interpret, 

 but most of the data are compatible with a proximal action (Welt et al., 

 1953). More indirect evidence will be provided by studies on enzyme inhi- 

 bition in the following section, but it is clear that the basic mechanism of 

 mercurial action must be sought in the Na+ transport system of the prox- 

 imal tubules. 



Effects on Enzyme Activity in the Kidneys 



Much of the work has unfortunately been on succinate dehydrogenase, 

 presumably because the activity is easily measured, but this enzyme is 

 probably not directly involved in renal transport and, in fact, is much less 

 sensitive to the mercurials than are many other enzymes. The results, how- 

 ever, may be taken as a rough indication that the mercurials can in diuretic 

 doses inhibit various renal enzymes, and to some extent provide evidence 

 for the primary site of action. Handley and Lavik (1950) found that mer- 

 alluride injected intravenously at a dosage of 8 mg Hg/kg in dogs and rats 

 reduces the succinate dehydrogenase activity around 45% in the kidney 

 at the peak of diuresis, whereas no inhibitions were observed in the liver 

 or heart. Fawaz and Fawaz (1951), on the other hand, could detect no 

 changes in succinate oxidation by renal homogenates from rats given the 

 diuretic dose (4 mg Hg/kg) of mersalyl, and concluded that if the mercurial 

 is acting on an SH enzyme, succinate dehydrogenase is not involved. Mus- 

 takallio and Telkka (1953) reported that high doses (10-60 mg Hg/kg) of 

 mercurophylline lead to loss of succinate dehydrogenase activity in the distal 

 tubules, using a tetrazolium staining technique, and later (Telkka and Mus- 

 takallio, 1954) found some inhibition in the proximal tubules and loops of 

 Henle, their conclusion being that there is little correlation between such in- 

 hibition and transport inhibition. Somewhat different results were obtained 

 by Rennels and Ruskin (1954), who found marked inhibition of succinate 

 dehydrogenase in the proximal tubules of the rat following 40 mg Hg/kg 

 of meralluride, little or no effect being exerted on the distal tubules or loops 



