The effect of mercurial diuretics on renal ammonia and titratable acidity production in acidotic human subjects with reference to site of diuretic action.

Experimental analysis of renal regulation of sodium and chloride excretion is complicated by the fact that the functional contributions of the proximal and the distal tubular segments to the urinary electrolyte pattern cannot be readily separated. If electrolyte transport in one of these tubular sites could be significantly depressed without affecting the other, it might be possible to clarify this tubular division of labor, particularly with regard to the suggested relationship between variations in glomerular filtration rate and electrolyte excretion (1,2). The mercurial diuretics, which reversibly inhibit tubular reabsorption of electrolytes and water, would be valuable tools for such a dissection of tubular function if it could be established that such inhibition is localized to a particular tubular segment. However, the precise renal locus of this action of mercurials has not been unequivocally demonstrated (3). In dogs, following the minimal doses of mercury which produce anatomic changes, microscopic lesions are seen only in the cells of the proximal tubule. Therefore, organic mercurials may be expected to interfere significantly with proximal tubular function (4). This surmise is supported by reports that certain presumptively proximal tubular functions, such as the secretion of diodrast and para-aminohippurate and the reabsorption of glucose, uric acid and calcium, are significantly depressed in man by therapeutic doses of mercurial diuretics (5-9). However, in the dog secretion of para-aminohippurate is not affected by diuretic doses of salyrgan (6). Moreover, renal aniso-osmotic reabsorption of water and electrolytes, which requires the major energy expenditure in electrolyte and 1 Supported in part by grants from the National Heart Institute, U. S. Public Health Service, Campbell Pharmaceutical Co., and the Martha M. Hall Foundation. water excretion, probably takes place in the distal tubule (1, 10). While it seems unlikely that a toxic heavy metal such as mercury would fail to affect the distal tubular enzyme systems involved in this process, no direct evidence has been presented as yet that mercurials in the usual therapeutic doses produce any anatomical or functional changes in the distal tubules. Therefore, the present investigation was undertaken to study in human subjects the effect of organic mercurials on the only active renal functions specifically attributed to the distal tubule: namely, ammonia and titratable acidity production (11). The significance of the data obtained is discussed in relation to the site of action of mercurial diuretics.