Early Gestation Dexamethasone Exposure Alters Coronary Artery Reactivity in Newborn Lambs.

Abstract

BACKGROUND: Exposure of the ovine fetus to glucocorticoids early in gestation programs postnatal elevation of blood pressure and enhanced coronary artery reactivity to second messenger-dependent vasoconstrictors. It is unknown whether the coronary alterations are a direct consequence of the corticosteroid exposure or related to the hypertension that evolves over the first 4 months of life. HYPOTHESIS: Early gestation glucocorticoid exposure enhances newborn lamb coronary artery vascular reactivity in the absence of systemic hypertension. METHODS: Dexamethasone (dex, 0.28 mg/kg/day iv for 48 hours) was administered to pregnant ewes at 27–28 days gestation (term being 145 days). The ewes were allowed delivery, and offspring were studied at a postnatal age of 8 ± 2 days (N = 6). Non-dex exposed age-matched control lambs were used for all comparisons (N = 6). Vascular catheters were placed 48 h prior to recording blood pressures. The contractile responses of circumflex coronary, mesenteric and femoral artery rings were then measured by wire myography. RESULTS: Exposure to dex was not associated with alterations in mean arterial blood pressure or heart rate at 8 days of life. Coronary vessels from dexamethasone-exposed sheep exhibited enhanced vasoconstriction to endothelin-1 and acetylcholine (both P < 0.05). There was no difference in maximal response of the coronary arteries to potassium chloride or angiotensin II. Dex exposure was associated with attenuation in vasodilatation to adenosine, but not sodium nitroprusside or forskolin. No differences in contractile response were detected between dex-exposed and control mesenteric or femoral arteries. CONCLUSION: Early gestation glucocorticoid exposure selectively programs postnatal alterations in coronary artery vascular reactivity prior to the development of hypertension. These findings suggest coronary artery dysfunction is a primary programming phenomenon and not secondary to alterations in blood pressure. These coronary vascular alterations may provide a mechanistic link between an adverse intrauterine environment and later coronary artery dysfunction.