Earlier studies from these laboratories have demonstrated that prostaglandins (PG's) of the A and E series are potent uterine vasodilators whereas PGF's do not significantly alter uterine vascular resistance. In addition, PGE's and PGF's are also able to modify adrenergic vasoconstrictor responses in the canine uterus. In the present study the role of endogenous prostaglandins in regulating uterine vascular resistance and adrenergic neurotransmission was evaluated. Intra-arterial infusion of the prostaglandin synthesis inhibitor meclofenamate resulted in a significant reduction in PGE levels in uterine venous plasma and increased vascular resistance. Uterine vasoconstrictor responses produced by sympathetic nerve stimulation and norepinephrine were enhanced when endogenous PG synthesis was inhibited. During sympathetic nerve stimulation, uterine venous plasma levels of radioimmunoassayable prostaglandins of the E of F series did not change, suggesting that the adrenergic activation of PG synthesis is not detectable in uterine venous efferent. These data suggest that endogenous prostaglandins of the E series appear to play an important role in regulating uterine blood flow (I) by relaxing uterine vascular smooth muscle and (2) by depressing adrenergic vasoconstrictor responses.