The involvement of endogenous oxytocin (OT) in the renal natriuretic response to an intravenous load of hypertonic and isotonic saline was investigated in anesthetized male rats with use of a selective OT-receptor antagonist [Mpa1,D-Tyr(Et)2,Thr4,Orn8]-OT (OT-ant). NaCl was infused (0.05 mmol.min-1.kg body wt-1 iv for 120 min) as a hypernatremic (HNa) solution or as an isotonic solution producing volume expansion (VE). HNa markedly increased sodium excretion from 0.25 +/- 0.06 to 10.04 +/- 0.62 mumol/min, whereas VE yielded only a moderate increase from 0.25 +/- 0.04 to 1.64 +/- 0.15 mumol/min. The increase in potassium excretion and urine flow rate during HNa was similar to that during VE. There were no significant changes in mean arterial pressure in either case. Administration of OT-ant delayed the natriuresis induced by HNa and reduced it by 60% but did not affect that induced by VE. Plasma OT concentration was significantly increased from 10.2 +/- 1.7 to 18.8 +/- 1.8 pg/ml at the end of HNa stimulation. In conclusion, the natriuresis in response to the intravenous sodium load was much more pronounced when NaCl was administered as a hypertonic solution than as an infusion inducing isotonic VE. Direct evidence was produced to assert that endogenous OT and its receptors are highly involved in the natriuresis elicited by systemic hypernatremic stimulation.