Glucocorticoid Metabolism in the Newborn Rat Heart

Abstract

Abstract

A relative cardiac hypertrophy has been observed in newborns chronically treated with dexamethasone. To test the hypothesis—that dexamethasone might alter steroid metabolism within the heart—rat pups were injected with vehicle, corticosterone (dosages 20 or 200 μg/pup/injection, or 1 mg/pup/injection) or dexamethasone (5 μg/pup/injection) on Day 2-6 and sacrificed on Day 7-8. Injections with dexamethasone in this dosage have induced the cardiac changes in this rat model. 11β-Hydroxysteroid dehydrogenase (11β-OHSD) activity was assessed in hearts from these adrenally intact rat pups by incubating tissues with ³H-corticosterone 10^-8 M for 60 min. On Day 7-8, controls transformed 10.3% ± 1.1% (mean ± SE) of the cortico-sterone (Compound B) to 11-dehydrocorticosterone (Compound A) generating 1.25 ± 0.35 × 10^-12 moles A/mg protein (n = 8). Tissues from pups pretreated with cortico-sterone at all three dosages were not different from controls in percent metabolized and moles A/mg generated. In contrast, hearts from dexamethasone treated pups transformed only 4.5% ± 1.0% of the corticosterone to A generating 3.19 ± 0.05 × 10^-13 moles A/mg protein (n = 10) (P <0.05 versus control in moles/mg protein metabolized). Cultured cardiomyocytes exposed to dexamethasone for 4 days in vitro also decreased their expression of 11β-OHSD mRNA. Readily metabolized endogenous glucocorticoids produced little or no effect on developing heart muscle while treatment with dexamethasone, a potent synthetic glucocorticoid, induced relative cardiac hypertrophy and downregulated 11β-OHSD mRNA expression and enzyme activity.