The effectiveness of the beta-adrenergic receptor agonist ritodrine as a tocolytic agent is limited by the tachyphylaxis that occurs with its sustained usage. In order to understand the nature of this tachyphylaxis, we investigated the effect of ritodrine on uteroplacental prostaglandin (PG)F2 alpha production in pregnant sheep. Using general anesthesia in five pregnant sheep, we placed catheters in the aorta and vena cava and in the uterine vein from the uterine horn. In random order on different days, we infused ritodrine (4 micrograms/kg/minute) or physiologic saline into the maternal vena cava at a rate of 0.184 mL/minute. Uterine venous and maternal arterial blood was sampled 60 minutes before and immediately before the infusion and then at 60, 120, 180, and 240 minutes during the infusion. After centrifugation, the serum was frozen and then assayed for the metabolite of PGF2 alpha (PGFM). Uterine venous PGFM increased significantly after 60 minutes of ritodrine infusion (mean increase 1.164 ng/mL; P less than .05), and this increase was sustained during the 4-hour infusion. The PGFM gradient across the uteroplacental bed (uterine vein - aorta) was also significantly elevated during the infusion, suggesting a uteroplacental or fetal membrane source of the PG. Saline had no effect on uterine venous PGFM or the PGFM gradient. These results suggest that ritodrine stimulates PGF2 alpha production, and this may contribute to the tachyphylaxis that occurs with ritodrine and limits its long-term effectiveness as a tocolytic agent.