Endogenous sodium pump inhibition: current status and therapeutic opportunities

One might ask, given the number of false trails that have been pursued, why we, and so many others, have continued to pursue the elusive digitalis-like factor? The answer can be found in the many review articles cited above [4-13]. In animal models of volume-dependent hypertension, evidence favoring sodium pump inhibition as at least a contributing factor, is essentially overwhelming. These observations are supported by multiple lines of less direct evidence in humans which are also compatible with a contribution of a circulating sodium pump inhibitor. Indeed, if multiple premature claims announcing the isolation of the digitalis-like factor had not appeared, this would be one of a large number of interesting scientific areas in which identification of a responsible vector was expected momentarily. The disenchantment so often expressed, we believe, reflects a response to those premature claims. We echo a recent review on the digoxin-like sodium pump inhibitor story from one of the productive groups in this area. "Now that there is little doubt that endogenous digoxin-like inhibitors of sodium transport exist..., the link between these substances, salt intake and vascular tone must be pursued with increasing vigor" [12]. That pursuit, of course, will be easier if the criteria concerning the responsible mediator are employed systematically. Because the current situation resembles so strikingly the situation late in the nineteenth century--when efforts focused on the attempt to identify a specific microorganism as the agent responsible for specific disease--we employed Koch's Postulates as the organizing principle. The challenge faced by Robert Koch over a century ago is identical to the challenge that those of us who are interested in digitalis-like factors face today. Passionate advocacy and equally impassioned denial can be seen as a stage in the scientific process when the problem is important and has proven to be more intractable than anticipated. Substantial, but still circumstantial evidence supports strongly a role for a circulating digitalis-like factor not only in normal sodium homeostasis and in the pathogenesis of salt-sensitive hypertension, but also in the pathogenesis of a wide array of processes that have an uncertain etiology. Although supported by many lines of evidence, this intriguing concept remains controversial, in large part because the responsible factor has proven to be very elusive. Informed opinion today ranges from arguments that the agent does not exist to contrary arguments that the agent has been identified. A very large number of candidates from a wide range of chemical classes have been proposed. Indeed, the large number of candidates, none supported by absolutely definitive evidence, has contributed to the controversy. In this essay, we have attempted to define and illustrate the information that will be required before a candidate becomes widely accepted.