932 7. MERCURIALS 



The hypothesis that organic mercurial diuretics to be active must release 

 inorganic Hg++ in the kidney was proposed by Mudge and Weiner (1958) 

 and the evidence was presented by Weiner et al. (1962). This had been 

 suggested occasionally ever since the first use of the organic mercurials but 

 very little evidence either for or against was reported, and the idea generally 

 was not taken seriously because all the other metal compounds used clini- 

 cally had been shown to act directly without splitting off the metal ion. The 

 evidence now accumulated impels one to consider this possibility. If such 

 splitting occurs, it is important not only for the diuretic action but for many 

 other effects of the mercurials, even in vitro. The evidence is mainly of two 

 sorts: (1) a correlation between acid lability of organic mercurials and their 

 diuretic activity, and (2) the potentiation of diuretic activity by the acid- 

 ifying NH^Cl. 



Mudge and Weiner (1958) pointed out that mersalyl does not split* in 

 acid medium over 3 hr, but in the presence of cysteine the half-time for 

 splitting is 105 min and with dimercaprol 5 min. The acid lability of 32 

 mercurials was tested by Weiner et al. (1962) by incubating the mercurial 

 at 1 WlM with cysteine at 2 mM in an Og-free medium at pH 4 and 37° 

 for 3 hr. The diuretic activity was expressed as A CI (//moles/min/kg). All 

 of the 22 mercurials which are diuretic are acid-labile, while of the 9 non- 

 diuretic mercurials 6 are stable and 3 labile (1 mercurial is indeterminate 

 in diuretic activity). There is thus a reasonably good correlation between 

 lability and diuretic activity. The 3 labile nondiuretic mercurials are all 

 of the ether series with structures of the type R — CHg — — CH2CH2 — Hg+, 

 and possibly their distribution is such that Hg++ is not released in the 

 proper region. The pH dependence of the splitting, according to the reac- 

 tions of Benesch and Benesch (1952), indicate the rate of splitting to be 

 approximately one thousandth as fast at pH 7 as at pH 4. If one assumes 

 that X = XqC'^', where X is the amount of organic mercurial, it may be 

 calculated that at pH 7 around 0.14% splitting would occur in 3 hr, since 

 the mean splitting of the labile mercurials is about 75%. Since maximal 

 diuresis occurs in 1-2 hr, approximately 0.1% would be split in this time. 

 Now, this calculation is not very valid because one does not know the con- 

 ditions for splitting in the kidney; e.g., dimercaptides may be formed there 

 and split more rapidly than the cysteine complexes. Diuretic activity was 

 examined by injecting the mercurials with a 10-fold excess of cysteine, but 

 presumably in the kidney there would be a transfer of the mercurial from 

 cysteine to other thiols. Thus it is difficult to obtain an idea of the amount 

 of inorganic mercury which is released in the kidney. If much splitting oc- 

 curs, one might expect to find Hg++ excreted in the urine in some form. 



* The term "split" will be used to designate the dissociation of the mercurial into 

 inorganic mercury so that there will be no confusion with the term "dissociation" 

 which is used to indicate the reaction R — Hg — X ±^ R — Hg+ + X~. 



