Newborn lamb coronary artery reactivity is programmed by early gestation dexamethasone before the onset of systemic hypertension

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 289; no. 4; pp. R1169 - R1176
• Main Authors: Roghair, Robert D, Segar, Jeffrey L, Sharma, Ram V, Zimmerman, Matthew C, Jagadeesha, D. K, Segar, Emily M, Scholz, Thomas D, Lamb, Fred S
• Format: Journal Article
• Language: English
• Published: United States 01.10.2005
• Subjects: Animals; Animals, Newborn; Coronary Vessels - drug effects; Coronary Vessels - embryology; Coronary Vessels - physiopathology; Dexamethasone - administration & dosage; Dexamethasone - adverse effects; Disease Susceptibility - chemically induced; Disease Susceptibility - embryology; Disease Susceptibility - physiopathology; Female; Gestational Age; Hypertension - chemically induced; Hypertension - congenital; Hypertension - embryology; Maternal Exposure - adverse effects; Pregnancy; Prenatal Exposure Delayed Effects; Sheep
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00369.2005

Departments of 1 Pediatrics and 2 Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa Submitted 25 May 2005 ; accepted in final form 13 June 2005 Exposure of the early gestation ovine fetus to exogenous glucocorticoids induces organ-specific alterations in postnatal cardiovascular physiology. To determine whether early gestation corticosteroid exposure alters coronary reactivity before the development of systemic hypertension, dexamethasone (0.28 mg·kg –1 ·day –1 ) was administered to pregnant ewes by intravenous infusion over 48 h beginning at 27 days gestation (term, 145 days). Vascular responsiveness was assessed in endothelium-intact coronary arteries isolated from 1-wk-old steroid-exposed and age-matched control lambs ( N = 6). Calcium imaging was performed in fura 2-loaded primary cultures of vascular smooth muscle cells (VSMC) from the harvested coronary arteries. Early gestation steroid exposure did not significantly alter mean arterial blood pressure or coronary reactivity to KCl, thromboxane A 2 mimetic U-46619, or ANG II. Steroid exposure significantly increased coronary artery vasoconstriction to acetylcholine and endothelin-1. Vasodilatation to adenosine, but not nitroprusside or forskolin, was significantly attenuated following early gestation steroid exposure. Endothelin-1 or U-46619 stimulation resulted in a comparable increase in intracellular calcium concentration ([Ca 2+ ] i ) in coronary VSMC isolated from either dexamethasone-treated or control animals. However, the ANG II- or KCl-mediated increase in [Ca 2+ ] i in control VSMC was significantly attenuated in VSMC harvested from dexamethasone-treated lambs. Coronary expression of muscle voltage-gated L -type calcium channel -1 subunit protein was not significantly altered by steroid exposure, whereas endothelial nitric oxide synthase expression was attenuated. These findings demonstrate that early gestation glucocorticoid exposure elicits primary alterations in coronary responsiveness before the development of systemic hypertension. Glucocorticoid-induced alterations in coronary physiology may provide a mechanistic link between an adverse intrauterine environment and later cardiovascular disease. calcium imaging; endothelium; endothelial nitric oxide synthase; fetal programming Address for reprint requests and other correspondence: R. D. Roghair, Associate in Pediatrics, Div. of Neonatology, Children's Hospital of Iowa, Iowa City, IA 52242 (e-mail: robert-roghair{at}uiowa.edu )