Coronary constriction to angiotensin II is enhanced by endothelial superoxide production in sheep programmed by dexamethasone.

Roghair RD, Miller FJ, Scholz TD, Lamb FS, Segar JL
Pediatr Res. 2008 63 (4): 370-4

PMID: 18356741 · PMCID: PMC3663587 · DOI:10.1203/PDR.0b013e3181659bfa

Early gestation dexamethasone (dex) administration is an ovine model of fetal programming associated with increased coronary reactivity to angiotensin II (Ang II). NADPH oxidase-dependent superoxide production plays an important role in both Ang II signaling and coronary disease. We sought to determine whether early gestation dex-exposure increases coronary reactivity to Ang II by enhancing endothelial NADPH oxidase-dependent superoxide production. Dex (0.28 mg/kg/d for 48 h) was administered to pregnant ewes at 27-28 d gestation. Dex-exposed and control offspring were studied at 4 mo of age. Coronary superoxide production was measured by lucigenin-enhanced chemiluminescence and dihydroethidium fluorescence. Coronary arteries from dex-exposed sheep had significantly enhanced vasoconstriction to Ang II, an effect abolished by either endothelial removal or preincubation with membrane-permeable superoxide dismutase and catalase. Ang II significantly increased endothelial superoxide production and NADPH oxidase activity in coronaries from dex-exposed offspring, but not controls. This programmed alteration in superoxide production was accentuated by PD123319 (AT2 antagonist), but abolished by losartan (AT1 antagonist). In conclusion, early gestation dex-exposure programs coronary reactivity to Ang II by enhancing Ang II-stimulated endothelial superoxide production. This programming effect may predispose to progressive coronary endothelial dysfunction and coronary artery disease.

MeSH Terms (19)

Angiotensin II Angiotensin II Type 1 Receptor Blockers Angiotensin II Type 2 Receptor Blockers Animals Coronary Vessels Dexamethasone Endothelium, Vascular Female Glucocorticoids Imidazoles Losartan NADP Pregnancy Prenatal Exposure Delayed Effects Pyridines Sheep Superoxides Vasoconstriction Vasoconstrictor Agents

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