Prostaglandin A2 (PGA2) was suggested to function as a circulating hormone due to its ability to largely escape pulmonary metabolism, potent vasodilator and natriuretic effects, with radioimmunoassay estimating its levels in human peripheral venous blood as 1.6 ng/ml on random sodium intake and 2.1 ng/ml on sodium depletion. However, previous gas chromatography-mass spectrometry (GC/MS) studies revealed that PGA2 in rabbit and human kidney was not a biosynthetic product but rather an in vitro dehydration product of prostaglandin E2 (PGE2). To investigate the possible role of PGA2 as a hormone, a GC/MS assay with improved specificity and sensitivity (allowing measurement of plasma levels 10-fold lower than those from radioimmunoassay) was developed. Plasma samples from 12 normal volunteers on random sodium intake (23 samples) and 6 volunteers after acute sodium depletion were analyzed. Results showed that PGA2 levels in random sodium intake samples were 0.056 ± 0.134 ng/ml, which was not different from zero. After sodium depletion, plasma renin activity increased, but PGA2 levels (0.025 ± 0.085 ng/ml) were not different from those on random sodium intake or zero. The study concluded that PGA2 levels in human plasma are less than 1/10 of those reported by radioimmunoassay, below the range of accurate quantification by the present GC/MS method, and do not increase to levels greater than 0.2 ng/ml on sodium depletion.