Effects of β-2 Agonist on Hepatic Glycogen Metabolism in the Fetal Lamb

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Abstract
To determine the effects of fetal β-2 agonist exposure on fetal hepatic glycogen metabolism, we infused ritodrine at a rate of 1.3 ± 0.4 μg/kg/min (mean ± SD) for 24 h into six chronically catheterized twin fetal lambs starting between 128 and 134 days gestation. The control twins received 0.9% saline at 1.2 ± 0.12 ml/kg/h. In addition, 15 uncatheterized fetuses were killed between 115 and 148 days gestation as unoperated controls. Ritodrine infusion produced a 1.7-fold elevation in fetal serum glucose level, from 23 ± 5 to 42 ± 15 mg/dl, and a 2-fold elevation in serum insulin level, from 16 ± 5 to 34 ± 8 mg/ml, p < 0.01. Hepatic glycogen content increased 7-fold in the uncatheterized controls between 115 and 148 days gestation (r = 0.9, p < 0.001). Ritodrine infusion reduced hepatic glycogen content by 50% from 179 ± 19 μg/mg in twin controls to 90 ± 25 μg/mg in the ritodrine-infused twins, p < 0.001. Hepatic glycogen phosphorylase kinase activity was elevated 1.3-fold from 0.149 ± 0.100 mU/mg protein in control twins to 0.186 ± 0.007 mU/mg protein in the ritodrine infused twins, p < 0.001. Glycogen phosphorylase a activity was also increased 1.4-fold from 8.60 ± 0.76 nM NADPH/min/mg protein in control twins to 11.85 ± 0.68 nM NADPH/min/mg protein in the ritodrine infused twins, p < 0.001. There were no significant differences in hepatic total glycogen phosphorylase (a + b) activity, active (I) or total I + D) glycogen synthase activity, protein, or DNA content between the ritodrine treated and control twins or between the control twins and the uncatheterized control fetuses. We conclude that β-2 agonist depletes hepatic glycogen in fetal lambs through activation of glycogen phosphorylase by glycogen phosphorylase kinase. Depletion of hepatic glycogen may be an unrecognized side effect of fetal β-2 agonist exposure.