Studies on Diuretics. I. The Site of Action of Mercurial Diuretics 1

Abstract

Although it is generally accepted that organic mercurial diuretics depress the renal tubular absorption of sodium,2 precise localization of their site of action within the tubule has not been accomplished. If one administers graded doses of such diuretics to the dog it becomes apparent that, above a certain level, further increases in dosage yield progressively diminishing increments of sodium excretion. This pattern of response suggests that these agents depress some specific fraction of total sodium absorption, and that this fraction might be quantitated and the mechanism itself thereby identified by the administration of doses of mercurial diuretics sufficient to block it completely.The micropuncture studies of administered, they may well act on the distal tubule. This latter conclusion, in contrast to the first, is not incontestable. It is, of course, possible that there might be two or more distinct mechanisms for sodium absorption in the proximal tubule, only one of which is mercury sensitive. That mechanism might account for 16 to 33% of the total of 67 to 87%o of filtered sodium normally absorbed in the proximal tubule. Since no evidence of functional differentiation of sodium absorption in this segment exists, we incline to the former and simpler interpretation. Our findings demonstrate (a) that there is a specific mechanism for sodium absorption which can be completely blocked by large doses of mercurial diuretics; and (b) because it accounts for 17.1 to 21.4%o of total absorption, this mechanism probably resides in the distal tubule. METHODSExperiments were performed on trained, unanesthetized dogs. Animals were used in the fasting state, at intervals of not less than one week. Glomerular filtration rate was measured by the creatinine clearance and sodium was determined in plasma and urine with an internal standard flame photometer. Other methods have been described in previous communications (3). RESULTSThe unprepared, normally hydrated dog 3 is not suitable for this study. Presumably the loss of excessive quantities of sodium and water in the urine or the cardiac and vascular toxicity of the diuretic per se so compromises circulatory function that the animal cannot for long maintain a stable renal hemodynamic state. Consistently, the onset of diuresis is followed shortly by a fall in glomerular filtration rate such that the ap-

The Effect of Mercurial Diuretics on Renal Ammonia and Titratable Acidity Production in Acidotic Human Subjects With Reference to Site of Diuretic Action 1

“…Duggan and Pitts (27) recently have concluded that in dogs mercurials act by depressing distal tubular reabsorption of electrolytes and water. This conclusion was based chiefly on the fact that despite massive doses of mercurials, the sodium excreted never exceeded 21 %o of that filtered, whereas, 67%o to 87%o of filtered sodium is generally considered to be reabsorbed proximally.…”

THE RELATIONSHIP OF PLASMA pH AND ANION PATTERN TO MERCURIAL DIURESIS 1

“…After two control periods 160 mg. of mercury as mercuhydrin were administered intravenously. The high rate of infusion of saline protects the animal against the acute circulatory collapse which often follows large doses of mercurial diuretics and also produces a prolonged, sustained mercurial diuresis (15). Phosphate was given to stabilize urine pH and to avoid the disturbing fluctuations often ob- served when the urine is poorly buffered.…”

Effect of Meralluride on Solute and Water Excretion in Hydrated Man: Comments on Site of Action*

“…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.…”