Kidney, Salt Intake, and Na+,K+-ATPase Inhibitors in Hypertension 1990 Corcoran Lecture

In view of the finding by Mathews et al1 that oneof the circulating Na+, K+-ATPase inhibitors inhumans is ouabain, I thought it would be useful to give a brief historical outline of the background to this subject and a tentative hypothesis that tries to explain how the concentration of such a substance comes to be raised in hypertension. Historical Outline In 1961 it was found that the natriuresis caused by acute volume expansion was due mainly to a change in the concentration of a circulating natriuretic sub-stance.2 About 10 years later it was noted that acute volume expansion was also accompanied by an in-crease in the ability of plasma to inhibit sodium transport34 and that this was due to an inhibition of Na+,K+-ATPase.5 It was automatically assumed that the increased natriuretic capacity of the plasma and its increased ability to inhibit sodium transport, both of which occurred with volume expansion, were due to a change in concentration of the same substance, which was named the natriuretic hormone. The atrial natriuretic peptide was discovered in 1981.6-7 To the surprise of many of us, the atrial natriuretic peptide had no effect on Na+,K+-ATPase. It was obvious, therefore, that the increased natri-uretic capacity of the plasma and its increased ability to inhibit Na+,K+-ATPase were not necessarily due to the same substance. It followed that the structure of the substance responsible for the volume-con-trolled Na+,K+-ATPase inhibition still needed to be determined. Furthermore, we began to pay attention to the well-established but not so well-recognized fact that in a normal animal the natriuretic effect of certain well-known exogenous Na+,K+-ATPase in-hibitors, such as ouabain and digoxin, is negligible. It was therefore ironic that at about this time the atrial natriuretic peptide (an unquestionably powerful short-acting natriuretic substance) was being closely scrutinized, and only slowly accepted, as a possible physiologically relevant natriuretic substance, whil