OBSERVATIONS ON THE NATURE, BIOSYNTHESIS, SECRETION AND SIGNIFICANCE OF ENDOGENOUS OUABAIN

The human circulation contains four readily distinguishable biological ly active inhibitors of the sodium pump that appear to be endogenous t o mammals. Of these, one has been purified to homogeneity and by numer ous chromatographic, mass spectral, biochemical, and physiological ana lyses has been shown to be a novel steroidal isomer of ouabain in whic h the location and orientation of two or more steroidal hydroxyl group s differ. The human endogenous ''ouabain'' (EO) is a high affinity rev ersible inhibitor of the pump with inotropic and vasopressor activity. Circulating levels of EO depend upon the adrenal cortex and metabolic events preceding and following pregnenolone formation are involved in EO biosynthesis. Within the adrenal gland, the stimulus-secretion mec hanisms for EO secretion are distinct from those for aldosterone highl ighting different regulation. Among Caucasians with essential hyperten sion, 30-45% have elevated circulating levels of EO. Sustained elevati on of plasma ouabain in rats induces chronic hypertension with charact eristics similar to those in patients and whose severity is determined by inherited factors and renal function. In conclusion, at least one of the mammalian counterparts to the cardiac glycosides is a novel ste roidal isomer of ouabain. The isomer is secreted by the adrenal cortex , and augments cardiovascular function. The observation of this entity in the human circulation, the demonstration of its biosynthesis, and the existence of specific receptors suggest to us that EO is a novel a drenocortical hormone and may be part of a broader family of novel mam malian steroids that regulate the sodium pump and other processes.