The relationship between natriuretic activity of neurohypophysial peptides and renal prostaglandins (PGs) was investigated in anesthetized rats under water diuresis and on kidney homogenates. Over the course of water diuresis, urinary sodium excretion increased steadily, reaching a 3.5-fold increase in 90 min, but there was no significant change in PGE2 and PGF2 alpha excretion. Inhibition of PG synthesis by naproxen sodium abolished the increase in sodium excretion. Oxytocin (OT) and vasopressin, in submaximal antidiuretic doses, produced marked natriuresis to 2139% and 345% of the control rate, respectively, without a concomitant increase in PG excretion. [Leu4]OT, which is devoid of antidiuretic activity, produced natriuresis and diuresis also without a significant effect on PG excretion. Inhibition of PG synthesis by naproxen attenuated the natriuretic response but enhanced the antidiuretic response to OT. Both the natriuretic and diuretic responses to [Leu4]OT were attenuated. Although the possibility that naproxen may have antinatriuretic activity independent of its PG synthesis inhibitory action cannot be excluded, the data obtained are consistent with our postulate that the natriuretic effect of OT-peptides may be mediated in part via a renal PG mechanism. This postulate is strengthened further by our findings that natriuretic peptides, OT, vasopressin and [Leu4]OT stimulated PG synthesis in kidney homogenates in a dose-dependent manner. Their order of potency is in the same order of their relative natriuretic potencies. [Penicillamine1,Phe(Methyl)2,Thr4,Orn8]OT, an OT antagonist and non-natriuretic, had no significant PG synthesis stimulating activity in the kidney homogenates.