Effect of meralluride on solute and water excretion in hydrated man: comments on site of action.

The renal tubular site at which organomercurials exert their primary effect on salt absorption has been the subject of considerable dispute for many years. The fact that these drugs produced a consistent reduction in Tmglucose and TmPAH in man suggested that these agents exerted an influence within the proximal tubule (1, 2). The absence of such changes in the dog, despite comparable diuretic activity, emphasized the hazards of such conclusions (3). Other experimental studies indicating that distal tubular functions such as the production of ammonia and titratable acid were not influenced by the administration of mercurials, were also used to imply a primary proximal tubular effect (4). Potassium secretion, however, which represents a late distal operation was shown to be depressed by the mercurial agents (5, 6). In hydrated man, it was demonstrated that meralluride produced a prompt increase in the rate of excretion of "nonsolute obligated" water implying a proximal tubular effect on salt and water absorption (7, 8). On the other hand, other observers reported that the administration of organomercurials to hydrated man and dog did not change the rate of free water clearance (9, 10). Recently, utilizing the stop flow technique, several investigators have concluded that, in the dog, the major site of action of the organic mercurials is confined to the proximal tubule (11, 12). Alternatively, some investigators concluded that the distal tubule represented the site of mercurial action because the magnitude of the diuresis approximated the quantity of salt and water normally absorbed within the distal tubule (13). Others, who observed that the rate of excretion of * Supported by a grant from the National Institute of Arthritis and Metabolic Diseases, National Institutes of Health (Grant no. A-277). Presented in abstract form at the Fifty-Second Annual Meeting of the American Society for Clinical Investigation, May, 1960. t Public Health Service Research Fellow of the National Heart Institute. nonsolute obligated water seemed independent of the solute diuresis, also suggested a distal site of action (14). Recently acquired insight (15-19) suggests that subjects deficient in antidiuretic hormones (ADH) forming maximally dilute urine, might 1)e used to localize the site of action of an agent which alters tubular salt reabsorption. In such subjects, proximal tubular fluid remains isosmotic to plasma as the absorption of the major fraction of the filtered salt and water occurs. This absorptive process is therefore accomplished without the generation of nonsolute obligated or free water. From the tip of the loop of Henle into the collecting duct, salt is reabsorbed actively through a segment relatively impermeable to water, thereby producing free water for excretion. The available micropuncture data suggest that the major portion of this free water is formed between the tip of the loop of Henle and the beginning of the distal convolutions (15, 16). It is generally accepted that, as increasing quantities of salt are presented to this site, more salt may be absorbed with an increase in the excretion of free water. Contrariwise, an action inhibiting salt absorption at this site would be expected to decrease the rate of excretion of nonsolute obligated water. Whether the quantity of free water formed is appreciably reduced by the passive back diffusion of water through the impermeable distal tubule is not certain. On the basis of these considerations, it seems possible to localize the site at which an agent affects salt reabsorption by comparing the changes in the clearance of solute with those in the clearance of nonsolute obligated or free water. Accordingly, a variety of acute experiments was performed in normal, maximally hydrated man in an attempt to define more precisely the site of action of meralluride.1