Objectives:Fetuses of diabetic women exhibit hypoxemia, elevated catecholamine concentrations at birth, and increased incidence of death. Our previous findings suggested that experimental fetal hyperinsulinemia results in a surge in catecholamines with cardiovascular changes supported by increased β-adrenergic activity. The present experiments were designed to assess the contributions of α-adrenergic stimulation to the hemodynamic changes in the hyperinsulinemic ovine fetus.
Methods:Combined ventricular output, regional organ blood flow, vascular resistance, metabolism, and catecholamine concentrations were measured before and during an infusion of insulin and during continued infusion with α-adrenergic blockade (phentolamine) in eight chronically catheterized fetal sheep.
Results:Fetal insulin infusion produced hyperinsulinemic-hypoglycemia, a surge in epinephrine and norepinephrine concentration, and increases in the combined ventricular output (blood flow to the fetus plus placenta) and regional blood flow to the fetus, heart, stomach, gastrointestinal tract, fat, and carcass. In the hyperinsulinemic state, α-adrenergic blockade was associated with additional increases in fetal norepinephrine concentration and no major changes in combined ventricular output or blood flow to the body of the fetus, except for decreased blood flow to the stomach and lungs, and a decrease in stroke volume.
Conclusions:Because vasodilation characterizes the hyperinsulinemic state, α-adrenergic stimulation contributes less to compensatory cardiovascular changes in the hyperinsulinemic fetus then that which we previously have shown for β-adrenergic stimulation.
1. Mimouni F, Miodovnik M, Siddiqi TA, Knoury J, Tsang RC. Perinatal asphyxia in infants of insulin-dependent diabetic mothers. J Pediatr1988;133:345-353.
2.
2. McFarlane CM, Tsakalakos N. Evidence of hyperinsulinemia and hypoxaemia in the cord blood of neonates born to mothers with gestational diabetes. S Afr Med J1985;67:81-84.
3.
3. Young JB, Cohen WR, Rappaport EB, Landsberg L. High plasma norepinephrine concentrations at birth in infants of diabetic mothers. Diabetes1979;28:697-699.
4.
4. Cowett RM, Schwartz R. The infant of the diabetic mother. Pediatr Clin North Am1982;29:1213-1231.
5.
5. Gutgesell HP, Speer ME, Rosenburg HS. Characterization of the cardiomyopathy in infants of diabetic mothers. Circulation1980;61:441-450.
6.
6. Reller MD, Tsang RC, Meyer RA, Braun CP. Relationship of prospective diabetes control in pregnancy neonatal cardio-respiratory function. J Pediatr1985;106-86-89.
7.
7. Pederson J, Bojsen-Moller B, Poulsen H. Blood sugar in newborn infants of diabetic mothers. Acta Endocrinol1954;15:33-36.
8.
8. Stonestreet BS. Effects of prolonged fetal hyperinsulinemia on plasma catecholamines, circulation and oxygen metabolism in utero. Dev Pharmacol Ther1990;15:35-344.
9.
9. Milley JR. Effect of insulin on the distribution of cardiac output in the fetal lamb. Pediatr Res1987;22:168-172.
10.
10. Milley JR, Rosenberg AA, Philipps AF, Molteni RA, Jones MD Jr, Simmons MA. The effect of insulin on ovine fetal oxygen extraction. Am J Obstet Gynecol1984;149:673-678.
11.
11. Stonestreet BS, Piasecki GJ, Susa JB, Jackson BT. Effects of insulin infusion of plasma catecholamine concentration in fetal sheep. Am J Obstet Gynecol1989;160:740-745.
12.
12. Stonestreet BS, Le E, Berard DJ. Circulatory and metabolic effects of β-adrenergic blockade in the hyperinsulinemic ovine fetus. Am J Physiol1993;564:H1098-H1106.
13.
13. Barrett CT, Heymann MA, Rudolph AM. Alpha and beta adrenergic receptor activity in fetal sheep. Am J Obstet Gynecol1972;112:1114-1121.
14.
14. Vapaavouri EK, Shinebounne EA, Williams RL, Heymann MA, Rudolph AM. Development of cardiovascular responses to autonomic blockade in intant fetal and neonatal lambs. Biol Neonate1973;22:177-178.
15.
15. Edelstone DI, Merick RE, Caritis SN, Mueller-Heubach E. Umbilical venous blood flow and its distribution before and during autonomic blockade in fetal lambs. Am J Obstet Gynecol1980;138:703-707.
16.
16. Reuss ML, Pater JT, Harris JL, Krueger TR. Hemodynamic effects of alpha-adrenergic blockade during hypoxia in fetal sheep. Am J Obstet Gynecol1982;142:410-445.
17.
17. Gilman AG, Rall TW, Nies AS, Taylor P, Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed.New York: Pergamon Press, 1990.
18.
18. Papparella A, Berard D, Stonestreet BS. Circulatory and metabolic effects of anemia in hyperinsulinemia ovine fetuses. Am J Physiol1994;266:H250-H257.
20. Bergmeyer HU, Bernt E, Schmidt F, Stork H. Methods of enzymatic analysis. In: Bergmeyer HU, ed. Verlag Chemic International, New York and London: Academic Press, Inc., 1974:1196-1201.
21.
21. Hales CN, Randle PJ. Immunoassay of insulin with insulinantibody precipitate. Biochem J1963;88:137-146.
22.
22. Hjemdahl PM, Daleskog M, Kahan T. Determination of plasma catecholamines by high-performance liquid chromatography with electrochemical detection: Comparison with a radioenzymatic method. Life Sci1979;25:131-138.
23.
23. Widness JA, Susa JB, Garcia JF, et al. Increased erythropoiesis and elevated erythropoietin in infants born to diabetic mothers and in hyperinsulinemic rhesus fetuses. J Clin Invest1981;67:637-642.
24.
24. Carson BS, Philipps AF, Simmons MA, Battaglia FC, Meschia G. Effects of a sustained insulin infusion upon glucose uptake and oxygenation of the ovine fetus. Pediatr Res1980;14:147-152.
25.
25. Milley JR, Papacostas JS, Tabata BK. Effect of insulin on uptake of metabolic substrates by the sheep fetus. Am J Physiol1986;251:E349-E356.
26.
26. Cohen WR, Piasecki GJ, Cohn HE, Susa JB, Jackson BT. Sympathoadrenal responses during hypoglycemia, hyperinsulinemia, and hypoxemia in the ovine fetus. Am J Physiol1991;261:E95-E102.
27.
27. Coustan DR, Reece A, Sherwin RS, et al. A randomized clinical trial of the insulin pump vs intensive conventional therapy in diabetic pregnancies. JAMA1986;255:631-636.
28.
28. Padbury JF, Polk DH, Newnham JP, Lam RM. Neonatal adaptation: Greater sympathoadrenal response in preterm than full-term fetal sheep at birth. Am J Physiol1985;248:E443-E449.
29.
29. Shaul PW, Magness RR, Muntz KH, DeBeltz D, Buja LM. α1-adrenergic receptors in pulmonary and systemic vascular smooth muscle: Alternations with development and pregnancy. Circ Res1990;67:1193-1200.
30.
30. Fedida D, Shimoni Y, Giles WR. A novel effect of norepinephrine on cardiac cells is mediated by α1-adrenoreceptors. Am J Physiol1989;256:H1500-H1504.
31.
31. Hay WW Jr, DiGiacomo JE, Meznarich HK, Hirst K, Zerbe G. Effects of glucose and insulin on fetal glucose oxidation and oxygen consumption. Am J Physiol1989;256:E704-E713.
32.
32. Hay WW Jr, Meznarich HK. The effect of hyperinsulinemia on glucose utilization and oxidation on oxygen consumption in the fetal lamb. Q J Exp Physiol1986;71:689-698.
33.
33. Hay WW Jr, Meznarich HK, DiGiacomo JE, Hirst K, Zerbe G. Effects of insulin and glucose concentrations on glucose utilization in fetal sheep. Pediatr Res1988;23:381-387.
34.
34. Hay WW, Meznarich HK, Sparks JW, Batraglia FC, Meschia G. Effects of insulin on glucose uptake in near-term fetal lambs. Proc Soc Exp Biol Med1985;178:557-564.
