Renal Concentration of Citrate as a Negative Modulator of Diuretic Response to Mercurials

Abstract

IN several mammalian species, including man, the potency of organomercurial diuretics depends on the acid-base status. Acidifying salts (for example, ammonium chloride) markedly enhance the diuretic response to mersalyl¹. To account for this, Weiner et al.² proposed that (a) hydrogen ions facilitate the cleavage of the carbon-mercury bond of organomer-curials and (b) the diuretic response is elicited by the interaction of mercuric ions with renal diuretic receptors. The authors based their conclusions on the excellent correlation between the liberation of mercuric ions from a given organomercurial under acidotic conditions in vitro and its diuretic potency in dogs in vivo. Recently we reported that rapid alkalinisation of urine brought about by treatment of dogs with acetazolamide decreases the diuretic response to inorganic mercury complexed with cysteine³. This observation led us to postulate that alterations in acid-base balance not only modify the rate of cleavage of the carbon-mercury bond in organo-mercurials but also must control the diuretic response to mercuric ions. Our findings are compatible with the following hypothetical chain of events. Alkalosis increases and acidosis decreases the renal concentrations of an endogenous metabolite which is capable of complexing mercury. In the kidneys the partition of mercuric ions between the diuretic receptor and the hypothetical ligand will then depend on the relative concentration of these two substances and their relative affinity for mercury. Specifically, the ratio of mercury bound to these two sites can be described by the following expression where brackets denote the renal concentration, L the hypothetical ligand, R the diuretic receptor, Hg·L and Hg·R the corresponding complexes with mercury, and K^Hg the effective stability of mercury complexes with the compound denoted in the subscript. A change in any one of the four factors on the right side of the expression will alter the partition of mercury between these two binding sites. If the concentration of the ligand increases in alkalosis, more mercury will be sequestered by the ligand and, as a consequence, a smaller number of mercuric ions would be free to react with renal diuretic receptors. The predicted result will be a decreased diuretic potency of inorganic mercury. Under acidotic conditions when the renal level of the ligand is low, the binding of mercury to the diuretic receptor would not be opposed to the same extent. Therefore the full diuretic response will ensue. The hypothesis does not require that changes in acid-base status alter either the total concentration of mercury in renal tissue or the rate of urinary excretion of mercury. In any case a large fraction of renal mercury is bound to non-specific sulphydryl groups. Many sulphydryl groups of proteins may serve as scavengers for mercury and thus do not participate in the diuretic response^1,4.