During prolonged administration of β-ago-nists such as ritodrine directly to chronically cannulated fetal lambs, the cardiovascular, metabolic, and endocrine changes observed during the 1st day of administration, lessen and return to normal within 3–4 d despite continuing drug administration. In our investigation, heart rate, plasma FFA, lactate, glucose, and insulin concentrations all increased significantly during the 1st day of ritodrine infusion (10 μg/min) whereas blood Po2and base excess were significantly decreased. After 3 d. despite continued drug infusion, all these changes had ameliorated. To examine the hypethesis that this tachyphylaxis to ritodrine also results in decreased sensitivity to endogenous catecholamines, episphrine (1 μg/min i.v. for 60 min, then 2 μ/min i.v. for a further 60 min) was infused into fetal lambs (124–130 d gestation) 1 d before, then 5 \pm 1 d after, and again 10 \pm 1 d after beginning ritodrine infusion. Before ritodrine administration. epinephrine significantly increased plasma FFA, lactate, glucose, and glucagon concentration and decreased insulin. However, after ritodrine treatment for either 5 \pm 1 or 10 \pm 1 d, epinephrine resulted in no significant increases in FFA or glucagon, and those in lactate and glucose were significantly reduced. Decreases in insulin during epinephrine administration were unchanged by vitodrine. Initial responses of mean arterial pressure and heart rate to epinephrine were significantly greater during prolonged ritodrine treatment. Fetal responses to epinephrine mediated through β-adrenergic receptor mechasms were clearly decreased when administration of β-agonists was prolonged beyond 24 h. (Pediatr Res 28:388–393, 1990)