title: Coronary constriction to angiotensin II is enhanced by endothelial superoxide production in sheep programmed by dexamethasone.
abstract: 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.
authors: Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, USA. robert-roghair@uiowa.edu
authors: Robert D
authors: RD
authors: Roghair
authors: Francis J
authors: FJ
authors: Miller
authors: Thomas D
authors: TD
authors: Scholz
authors: Fred S
authors: FS
authors: Lamb
authors: Jeffrey L
authors: JL
authors: Segar
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D009249:NADP / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012756:Sheep; D013481:Superoxides / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D005938:Glucocorticoids; D007093:Imidazoles; D011725:Pyridines; D014662:Vasoconstrictor Agents; D013481:Superoxides; D000804:Angiotensin II; C073402:PD 123319; D009249:NADP; D003907:Dexamethasone; D019808:Losartan