Newborn lamb coronary artery reactivity is programmed by early gestation dexamethasone before the onset of systemic hypertension.
Newborn lamb coronary artery reactivity is programmed by early gestation dexamethasone before the onset of systemic hypertension.
复制标题
DOI：
10.1152/ajpregu.00369.2005
复制
发表时间：
2005-10
期刊：
影响因子：
--
通讯作者：
R. Roghair;J. Segar;Ram V. Sharma;M. Zimmerman;D. Jagadeesha;E. Segar;T. Scholz;F. Lamb
中科院分区：
文献类型：
--
作者：
R. Roghair;J. Segar;Ram V. Sharma;M. Zimmerman;D. Jagadeesha;E. Segar;T. Scholz;F. Lamb
妊娠早期绵羊胎儿暴露于外源性糖皮质激素会诱导出生后心血管生理学的器官特异性改变。为了确定妊娠早期皮质类固醇暴露是否会在发生全身性高血压之前改变冠状动脉反应性，从妊娠27天（足月，145天）开始，在48小时内通过静脉输注向怀孕母羊施用地塞米松（0.28 mg x kg（-1）x天（-1））。从 1 周龄暴露于类固醇的羔羊和年龄匹配的对照羔羊（N = 6）中分离出完整的内皮冠状动脉，评估血管反应性。在从采集的冠状动脉中加载 fura 2 的血管平滑肌细胞 (VSMC) 原代培养物中进行钙成像。妊娠早期类固醇暴露不会显着改变平均动脉血压或冠状动脉对 KCl、血栓素 A(2) 模拟物 U-46619 或 ANG II 的反应性。类固醇暴露显着增加乙酰胆碱和内皮素-1 的冠状动脉血管收缩。妊娠早期类固醇暴露后，腺苷（而非硝普钠或毛喉素）的血管舒张作用显着减弱。 Endothelin-1 或 U-46619 刺激导致从地塞米松治疗或对照动物分离的冠状动脉 VSMC 中细胞内钙浓度 ([Ca(2+)](i)) 显着增加。然而，在对照VSMC中ANG II或KCl介导的[Ca(2+)](i)增加在从地塞米松处理的羔羊收获的VSMC中显着减弱。类固醇暴露不会显着改变肌肉电压门控 L 型钙通道 α-1 亚基蛋白的冠状动脉表达，而内皮一氧化氮合酶表达减弱。这些发现表明，妊娠早期糖皮质激素暴露在全身性高血压发生之前引起冠状动脉反应性的主要改变。糖皮质激素引起的冠状动脉生理学改变可能提供不利的宫内环境与后来的心血管疾病之间的机制联系。
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 x kg(-1) x 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 alpha-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.