Mercurials

These were the first diuretic agents and were largely supplanted by the sulfonamide-based diuretics such as thiazides and loop diuretics. The structure of one of the more prominent mercurial diuretics, mersalyl, is shown in Fig. 8. Because these agents went out of use decades ago, before the advent of isolated perfused tubule techniques, we lack detailed information on their molecular mechanisms of action [10, 51]. Moreover, with different preparations, there were several variables such as the extent of secretion into the lumen in the proximal tubule and a variable degree of release of mercuric ion, which altered their mechanisms of action [10, 51]. Hg2+ binds to sufhydryl groups in a nonspecific manner and can inactivate numerous proteins [51]. Whole animal clearance and micropuncture studies on the mechanism of action of mersalyl demonstrated that it increased delivery of salt and water to the distal convoluted tubule without altering GFR or proximal tubular reabsorption [9,10,51]. Application of mersalyl to the lumina of thick ascending limb segments using the then-new isolated perfused tubule technique demonstrated that the drug directly inhibited net CI reabsorption in a manner distinct from that observed with Hg2+ [9]. Because of the toxicity of these compounds and their relatively

OCH2COONa

OCH2COONa

FIGURE 8. Structure of mersalyl, an organic mercurial compound.

FIGURE 8. Structure of mersalyl, an organic mercurial compound.

low diuretic potency when compared with that of loop diuretics, mercurials are not used as diuretic agents. Interestingly, mercurials can also inhibit water flux through aquaporins, by binding to discrete cysteine residues which are likely located near the pore [61 ]. Because of their lack of specificity and toxicity, however, these agents do not appear promising as starting points for drug discovery projects designed to obtain inhibitors of aquaporin function.

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