OBJECTIVE: We hypothesized that the endothelial-derived relaxing factor nitric oxide may contribute to low resting vascular tone and may attenuate vasoconstrictor action in the human fetal-placental circulation. STUDY DESIGN: Isolated human placental cotyledons were dually perfused in vitro, and the effects of N-monomethyl-L-arginine and N-nitro-L-arginine (3 x [10.sup.-4] mol/L), which are nonmetabolizable analogs of L-arginine, the substrate for nitric oxide synthase, on resting perfusion pressure and on the fetal-placental circulation preconstricted with U46619 ([10.sup.-8] mol/L) or endothelin-1 ([10.sup.-8] mol/L) were established. Responses before and after inhibition were compared by paired t test. The effects of glyceryl trinitrate ([10.sup.-6] mol/L), acetylcholine ([10.sup.-4] mol/L), the calcium ionophore A23187 ([10.sup.-6] mol/L), and histamine ([10.sup.-8] to [10.sup.-4] mol/L) were also determined in the preconstricted fetal-placental circulation. RESULTS: Both N-monomethyl-L-arginine and N-nitro-L-arginine (3 x [10.sup.-4] mol/L) increased resting perfusion pressure (p < 0.06), and N-nitro-L-arginine promptly and significantly increased perfusion pressure in the fetal-placental circulation preconstricted with U46619 (p < 0.0004) or endothelin-1 (p < 0.06). Nitric oxide generated by addition of glyceryl trinitrate ([10.sup.-6] mol/L) attenuated the vasoconstrictor effects of U46619 (p < 0.026) or endothelin-1 (p < 0.01). Neither acetylcholine nor the calcium ionophore A23187 had an effect on the fetal-placental circulation, whereas bradykinin further increased perfusion pressure. Histamine only relaxed the preconstricted preparations at concentrations ([10.sup.-6] to [10.sup.-4] mol/L) above those shown to release nitric oxide in other systems. CONCLUSION: The stimulus to nitric oxide generation in the fetal-placental circulation may be hydrodynamic. Nitric oxide appears to contribute to maintenance of basal vascular tone and to attenuate the actions of vasoconstrictors in this circulation. (Am J Obstet Gynecol 1992:166:224-30.)