Desensitization of beta-receptor mediated responses to epinephrine in fetal lambs by prolonged ritodrine...

During prolonged administration of beta-agonists 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 micrograms/min), whereas blood PO2 and base excess were significantly decreased. After 3 d, despite continued drug infusion, all these changes had ameliorated. To examine the hypothesis that this tachyphylaxis to ritodrine also results in decreased sensitivity to endogenous catecholamines, epinephrine (1 microgram/min i.v. for 60 min, then 2 micrograms/min i.v. for a further 60 min) was infused into fetal lambs (124-130 d gestation) 1 d before, then 5 +/- 1 d after, and again 10 +/- 1 d after beginning ritodrine infusion. Before ritodrine administration, epinephrine significantly increased plasma FFA, lactate, glucose, and glucagon concentrations and decreased insulin. However, after ritodrine treatment for either 5 +/- 1 or 10 +/- 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 ritodrine. Initial responses of mean arterial pressure and heart rate to epinephrine were significantly greater during prolonged ritodrine treatment. Fetal responses to epinephrine mediated through beta-adrenergic receptor mechanisms were clearly decreased when administration of beta-agonists was prolonged beyond 24 h.