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Antenatal dexamethasone enhances endothelin-1 synthesis and gene expression in the heart in congenital diaphragmatic hernia in rats.

Abstract：

BACKGROUND/PURPOSE:Although high levels of endothelin-1 (ET-1) in plasma may be relevant in certain pathophysiologic states, such as pulmonary hypertension accompanying congenital diaphragmatic hernia (CDH), experimental evidence favors a local, paracrine, or autocrine role for ET-1 in most tissues. Evidence of ET-1 production has been documented in fetal heart tissue where it exerts growth-enhancing and mitogenic effects. ET-1 also has a potent positive inotrope action on cardiac muscle. ET-1 -/- homozygous mice display a wide variety of cardiac anomalies, which also are features of the human and of the experimental CDH. Autopsy reports have shown that total heart weight is reduced significantly in the presence of CDH, and animal models have documented the presence of cardiac hypoplasia associated with CDH. Experimental and clinical studies have shown that prenatal exposure to corticosteroids improves cardiovascular function in the immediate newborn period. The aim of this study was to determine cardiac gene expression of ET-1 and of its receptor ET(A) and the cardiac ET-1 content in the heart of nitrofen-induced CDH in rats and to evaluate the effect of antenatal Dexamethasone (Dex) treatment. METHODS:A CDH model was induced in pregnant rats after administration of 100 mg of nitrofen on day 9.5 of gestation (term, 22 days). Dex (0.25 mg/kg) was given by intraperitoneal injection on days 18.5 and 19.5 of gestation. Cesarean section was performed on day 21 of gestation. The fetuses were divided into 3 groups: group I, control (n = 8); group II, nitrofen-induced CDH (n = 8); group III, nitrofen-induced CDH with antenatal Dex treatment (n = 8). ET-1 protein was measured using ELISA. RT-PCR was performed to evaluate the relative amount of ET-1 and ET(A) mRNA expression. RESULTS:There was a reduction in ET-1 mRNA (P <.05) and in ET(A) mRNA (P <.01) in the heart of CDH group compared with controls. ET-1 protein level also was reduced in heart of CDH compared with controls. Antenatal Dex treatment increased significantly both ET-1 mRNA and protein levels in the heart of CDH animals (P <.05 and P <.01, respectively). CONCLUSIONS:The reduced cardiac ET-1 gene expression and ET-1 synthesis may be responsible for the heart hypoplasia associated with CDH. Prenatal corticosteroids increase the cardiac production of ET-1, and this may enhance heart growth and cardiac inotropism at birth.

journal_name

J Pediatr Surg

journal_title

Journal of pediatric surgery

authors

Guarino N,Puri P

doi

10.1053/jpsu.2002.36185

subject

Has Abstract

pub_date

2002-11-01 00:00:00

pages

1563-7

issue

eissn

0022-3468

issn

1531-5037

pii

S0022346802001628

journal_volume

pub_type

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Antenatal dexamethasone enhances endothelin-1 synthesis and gene expression in the heart in congenital diaphragmatic hernia in rats.