Absence of direct effects of prostaglandins on sodium chloride transport in the mammalian nephron

A multitude of factors appear to regulate the transport of sodium chloride in the mammalian nephron. Considerable effort has been spent over the past 15 years in attempting to characterize the mechanisms of action of the various humoral, neurogenic, and "physical" factors that interact to regulate renal salt excretion. Included in this list are the renal prostaglandins. The observation that prostaglandins are natriuretic under certain experimental circumstances [11 has stimulated investigation directed at elucidating whether the renal prostaglandins have a direct effect on membrane transport of sodium chloride. The attractiveness of demonstrating such an effect lies in the fact that the existence of a locally acting hormone produced by the kidney itself could explain many of the enigmas related to the regulation of salt excretion by invoking feedback regulation linked to segmental delivery and blood flow distribution. With the wisdom of hindsight, it has become evident that much research in this area has been misdirected. Inappropriate prostaglandins, often used in pharmacologic doses, delivered to areas of renal parenchyma unaccustomed to their presence, together with the confusing effects of hemodynamic alterations in conscious versus anesthetized animals, have produced an array of conflicting data that are open to alternative interpretations [21. The solution to this confusion is obviously to design an "ideal experiment." The question we would like to answer, stated in its simplest terms, is as follows: Do prostaglandins directly stimulate or inhibit transport of sodium chloride in one or more segments of the nephron? physical factors that alter sodium chloride transport. Studies on substances that directly alter membrane transport of sodium chloride such as diuretics [3], vasopressin [41, or the uremic natriuretic factor [5] would suggest that an in vitro preparation of perfused or nonperfused renal tubules is an ideal model for this purpose. Such systems allow for precise control of the peritubular and luminal environment and permit "control" and "experimental" measurements of fluxes to be made in the same tubule. Next, it is important to establish whether or not the tubule manufactures its own prostaglandins (P0's). If it does not, it is conceivable that its transport could be regulated by PG's produced by extratubular cells, such as those that exist in the renomedullary interstitium [61. If the tubules do manufacture their own PG's, it would be necessary to determine whether alteration of endogenous synthesis by the tubule results in an altered rate of sodium chloride transport. If exogenous PG's are used as probes, they must show effects at concentrations that approximate those which exist in vivo (1O to iO-' M) [7] in order to be able to relate their effects to combination with specific binding sites or receptors. At higher concentrations, their effects as lipid solute acids may relate more to their lipid solubility and/or their acidity and may be entirely nonspecific. Finally, any demonstrable effects should be completely reversible in order to exclude from consideration possible "toxic" effects of these substances. It is evident, therefore, that the following issues must be addressed: (1) identification of nephron