Ontogeny of β-Adrenergic Receptors in the Rat Lung: Effects of Hypothyroidism

Abstract

((f)-[12611HYP). Binding capacity (B, , ) for (-)-I3H]DHA increased progressively from 46 + 7 on day 18 of gestation to 510 2 70 femt~moles*mg-~ protein (mean + S.D.) on postnatal day 28, at which time adult B, , was attained. An increase in (-)-i3HI DHA binding capacity of the lung was observed between postnatal days 15 and 28, during the known period of increased thyroid gland secretory activity, serum triiodothyronine (T3), and thyroxine (T4) concentrations in the rat. We therefore studied lung /?-adrenergic receptors in rat pups made hypothyroid with propylthiouracil (PTU) (in utero and postnatally) compared to normal agematched control pups and to euthyroid pups which were treated with PTU but were also injected daily with thyroxine (T4treated). Hypothyroid pups grew nearly normally until postnatal day 15 but grew poorly thereafter; by day 28 somatic and lung weight, lung DNA, and protein were markedly decreased in hypothyroid pups as compared to controls. Pulmonary Padrenergic receptors were similar in hypothyroid pups and controls on day 15, but were markedly decreased in hypothyroid pups on day 28 (294 2 57 versus 489 + 82 femtomoles*mg-' protein in T4 treated euthyroid controls). Treatment of the hypothyroid pups with T4 on day 25 significantly increased lung ~a d r e n e r~i c receptors to near normal concentrations bv dav 28. We conclude that thvroid hormones or thyroid dependent faftors enhance pulmonary b-adrenergic recep tor synthesis and that thyroid hormone is required for the normal postnatal maturation of the 8-adrenergic receptor system in the rat lung. SpeculationThyroid hormone or thyroid hormone dependent factors are required for the normal postnatal growth and maturation of the rat lung. Pulmonary &adrenergic-receptors increase markedly during the wrinatal wriod in the rat and their normal postnatal developmeit is thyroib hormone dependent. Because themtiming of increased thyroid gland activity varies among species, occurring earlier in the human than in the rat, the possible effects of thyroid hormone on pulmonary maturation in the human might also occur at an earlier time in perinatal life. Finally, it is speculated that the ontogenic increases in pulmonary /?-adrenergic receptors are also associated with developmental changes in catecholamine mediated cellular responses of ;pecific cells.Catecholamines are mediators of surfactant release (7) and smooth muscle tone in the mammalian lung. These effects are presumably the result of the interactions of adrenergic agonists with P-adrenergic receptors present on the plasma membranes of various pulmonary cells, resulting in the stimulation of adenylate cyclase thus increasing intracellular 3',5' cyclic adenosine monophosphate (CAMP) (2, 17). Studies from this laboratory have recently demonstrated that pulmonary /3-adrenergic receptors in the rat and rabbit increase dramatically during late gestation and during the suckling period, reaching adult levels by 28 days of postnatal age (26). Cheng et al. (5) have also recently demonstrated the ro...

Combined Effects of Corticosteroid, Thyroid Hormones, and β-Agonist on Surfactant, Pulmonary Mechanics, and β-Receptor Binding in Fetal Lamb Lung

“…The changes in Bmax reported here in response to hormone infusion were significantly greater than those reported in control fetal lambs during the same period of gestation. In the rabbit fetus, glucocorticoids increase the number of P-receptor binding sites (4), whereas in the rat fetus hypothyroidism decreases the number of binding sites (5). The lack of effect of corticosteroids alone on P-receptor binding capacity in the fetal lamb lung may be due either to a species difference or to the physiological concentrations of cortisol used herein in comparison with the pharmacological concentrations used in other systems (2).…”

“…Glucocorticoids and thyroid hormones act at different points in the pathways of surfactant phospholipid synthesis (2), whereas (3-agonists stimulate surfactant release and also regulate the production of fetal lung liquid (3). The maximal binding capacity of fetal lung preceptors is regulated by glucocorticoids (4) and thyroid hormones (5).…”

“…The fetuses were assigned randomly to be controls (6) or to receive cortisol infusion (5), TRH infusion (4), P-agonist infusion (6), cortisol plus P-agonist infusion (6), cortisol plus TRH infusion (4), or cortisol plus TRH plus P-agonist infusion (5).…”

Premature Weaning of Rat Pups Results in Prolongation of Neonatal Tolerance to Hyperoxia

“…Other hormonal factors that normally increase in rats around the normal time of weaning include growth hormone (32) and somatomedin C (33). P-Adrenergic receptors in the rat lung markedly increase between d 15-28, and this change in receptor density is related to the normal rise in serum T3 levels at this time (34). The rise in serum growth hormone levels at approximately 20 d of age is also dependent upon the normal rise of T3 and the rise in glucocorticoid hormones at this time (35).…”

Chronic Glucose Infusion Inhibits Development of β-Receptor Binding in Fetal Lamb Lung

“…Glucocorticoids have been reported to increase the @-receptor binding capacity of fetal rabbit lung (19), whereas hypothyroidism was shown to inhibit preceptor binding capacity in fetal rat lung (20). In addition, Maniscalco et al (14) and Warburton et al (21) have reported synergistic effects of glucocorticoid and thyroid hormones on Preceptor binding capacity in fetal rabbit lung explants in culture and in fetal lamb lung, respectively.…”