This study investigates the effects of prenatal corticosteroid administration on newborn sympathoadrenal mechanisms involved in postnatal adaptation. Randomly assigned preterm (122-125 days) fetal sheep were treated with hydrocortisone or saline for 60 h and delivered by cesarean section. We examined postnatal physiological adaptation, sympathoadrenal responses, cardiac beta-receptor density, and the receptor-cyclase system. We observed increased ventilatory, cardiovascular, and metabolic responses function in the corticosteroid-treated animals despite a marked attenuation in the anticipated surge of plasma catecholamine concentrations and a decrease in epinephrine secretion rate, which is normally seen at birth. Myocardial beta-adrenergic receptor density and affinity states were comparable in both groups. Basal and agonist-mediated adenylyl cyclase activity in myocardial tissue was increased in the corticosteroid-treated animals. We speculate that the increase in myocardial adenylyl cyclase activity may be accompanied by similar changes in other organ systems and that this could account for the augmentation in respiratory, cardiovascular, and metabolic responses in the corticosteroid-treated animals.

ABSTRACT. In adult animals, prolonged 8-agonist exposure leads to down-regulation of 8-adrenergic receptors and desensitization. Prior evidence from our lab suggests that this may not occur in developing animals. To study this, we measured the response to graded epinephrine infusion I2.7, 5.5, 13.6, 27.3 pmol/(kg.min), (0.5, 1.0, 2.5, 5.0 pg/ (kg. min)], myocardial 8-agonist receptor density, and components of the receptor-cyclase system in newborn lambs before (n = 6) and after (n = 5) 3 d of continuous isoproterenol administration (2 pg/kg/min). 8-Adrenergic receptors were measured by radioligand binding. Epinephrine dose-response curves were analyzed for the threshold and slope for changes in mean blood pressure, systolic blood pressure, and heart rate versus plasma epinephrine levels. Despite 3 d of continuous isoproterenol infusion, we observed no desensitization of the hemodynamic response to epinephrine. There was a reduction in receptor density when expressed per membrane protein I155.3 f 19.5 (controls) versus 73.2 f 3.8 fmol/mg protein (agonist exposed), p c 0.051, but no alteration in receptor density when expressed per g cardiac wet weight 1258.8 2 39.9 (controls) versus 406.8 + 74.0 fmol/g wet weight (agonist exposed)].There was no alteration in agonist affinity or in adenylyl cyclase activity after adjustment for membrane protein recovery. Prolonged ,8-agonist infusion in newborn lambs does not desensitize hemodynamic responses to infused epinephrine. We propose that receptor regulation in developing animals is fundamentally different than in adult animals. (Pediatr Res 31: 462-467, 1992 have demonstrated alteration of p-adrenergic-mediated responses after chronic agonist exposure. Decreased responsiveness, known as desensitization, may result from alteration in several components of the hormone-responsive adenylate cyclase system. These include down-regulation or a decrease in adrenergic receptor numbers, a shift in the ratio of affinity states of the receptor, altered coupling of the receptor and G protein, altered expression of G proteins, altered adenylyl cyclase activity, or alterations of intracellular systems distal to the second messenger (2-5). In vitro and in vivo studies in adult models have used both pharmacologic agents and physiologic stimuli to demonstrate alteration at each of these levels.In developing animals, studies on desensitization have been less confirmatory. Investigators from several laboratories have noted little or no apparent desensitization or alteration in receptor numbers after agonist administration or physiologic elevations of endogenous catecholamines (6-10). Previous in vivo data from our laboratory have shown that there is no change in Preceptor density of lamb myocardial cells or alteration in adenylyl cyclase activity after exposure to the logarithmic increases in catecholamines at birth (9) or in response to severe chronic intrauterine stress (10). In newborn rats. there is no alteration in receptor numbers, density affinity, or response to 0-agonists after s...

ABSTRACX. At birth, there is a marked increase in cir-occur both in viva and in vitro in response to both endogenous culating plasma catecholamine concentrations. This in-and exogenous receptor ligands (4-2 1). crease is critical to many of the physiologic adjustments to At birth, there is a marked increase in sympathoadrenal activpostnatal life. Because the levels observed are higher than ity reflected by changes in circulating catecholamine concentrathose seen in most other physiologic conditions in adults, tions. Plasma norepinephrine rises 5-to 10-fold and plasma previous investigators have suggested that the newborn is epinephrine 10-to 20-fold over the first several hours of life (22-less sensitive to adrenergic stimulation or that desensiti-26). We have previously demonstrated that the majority of zation to adrenergic stimulation occurs rapidly. To inves-circulating norepinephrine arises from increased postganglionic tigate this question, we designed experiments to measure sympathetic nerve activity (24), whereas the increase in plasma myocardial Sadrenergic receptor density and sensitivity epinephrine is derived almost solely from adrenal medullary before and after exposure to the catecholamine surge at secretion (25). These changes are critical to successful postnatal birth in term newborn sheep. We also measured the status physiologic adaptation and survival (25). It is unclear, however, of sympathetic innervation, reflected by myocardial nor-to what extent these changes in circulating catecholamines affect epinephrine content. At birth, plasma catecholamines in-adrenergic receptor mechanisms after birth. Because circulating creased 4-to 6-fold with associated increases in heart rate, catecholamine levels in the early newborn period are higher than blood pressure, and cardiac output. Myocardial B-adrener-those observed in most other physiologic conditions in adults gic receptor at birth (135 fmol/mg protein) did not change (22), previous investigators have suggested that the newborn is significantly by 6 h of life (157 fmol/mg protein). Myocar-less sensitive to adrenergic stimulation or that desensitization to dial adenyl cyclase activity, reflecting receptor sensitivity, adrenergic stimulation occurs rapidly (26). To examine this and myocardial sympathetic innervation also did not question, we designed experiments in newborn fetal sheep to change. These results suggest that, despite exposure to measure cardiac BAR and catecholamine-stimulated adenyl cysustained adrenergic stimulation, myocardial adrenergic clase activity in newborn sheep after exposure to the surge in effector mechanisms do not change in the newborn sheep catecholamines at birth. at birth. (Pediatr Res 29: 98-103, 1991) MATERIALS AND METHODS AbbreviationsSixteen Western mixed breed fetuses from time-dated single-BAR, @-adrenergic receptor ton, twin, or triplet pregnancies were operated on at 139 d (term GTP, guanosine triphosphate is 150 d). The details of delivery and postnatal stabilization were ECS0, half maximal concentration iden...