An endogenous ouabain-like sodium pump inhibitor was demonstrated originally in serum or plasma of acutely extracellular fluid volume (ECFV) expanded animals and humans. Since then numerous studies have confirmed the presence of ouabain-like factor(s) (OLF) in blood, urine, cerebrospinal fluid, and various tissues including the heart and hypothalamus. Some of these OLFs represent well-known endogenous compounds, eg, free unsaturated fatty acids, which in vitro exhibit inhibition of transepithelial sodium transport, direct inhibition of the Na-K-ATPase enzyme, displacement of 3H-ouabain from its membrane receptor, and crossreaction with a digoxin antibody. Small molecular weight (MW) OLFs of yet unknown peptidic or nonpeptidic nature, which may be of hypothalamic origin, were also detected in various animal models of hypertension and in hypertensive patients. They may play a pathophysiological role especially in salt- and volume-dependent forms of hypertension. Our results show that OLFs increase basal and vasopressin-stimulated intracellular Ca2+ release in rat vascular smooth muscle cells in culture and in human platelets similar to the newly discovered endothelin. In addition, a natriuretic factor (natriuretic hormone) was detected by bioassay in plasma and urine, whose activity changes in parallel with sodium intake. We found that this natriuretic factor is associated with small peptides with a MW of less than 1,000. It is, however, unlikely that the two biological properties, ie, the ouabain-like and natriuretic activities, reside in a single compound. A number of circulating OLFs is certainly not identical with a humoral natriuretic factor. Nevertheless, there is increasing evidence for multiple interactions between OLF and the atrial natriuretic peptide (ANP).(ABSTRACT TRUNCATED AT 250 WORDS)