Sherman R C, Langley-Evans S C
Institute of Human Nutrition, University of Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK.
Clin Sci (Lond). 2000 Mar;98(3):269-75.
Epidemiological evidence from diverse human populations, supported by experimental evidence from animal models, suggests that maternal nutrition during pregnancy is an important fetal programming influence upon cardiovascular disease. Experiments with a low-protein-diet model of rat pregnancy suggest a role for the renin-angiotensin system in the programming mechanism, since fetal undernutrition permanently elevates pulmonary and plasma angiotensin-converting enzyme activity. Long-term beneficial effects of captopril on blood pressure in this model require further investigation in order to clarify the role of angiotensin II. Pregnant rats were fed a control diet containing 18% (w/w) casein as the protein source or a low-protein diet containing 9% (w/w) casein. Between the ages of 2 and 4 weeks postnatally, mothers and their pups were treated with losartan or nifedipine. All pups in the study had blood pressure determined at 4 and 12 weeks of age using a tail cuff. Animals exposed to the low-protein diet in utero and not subjected to drug treatment had elevated blood pressure relative to control rats (mean increase of 27 mmHg; P<0.001). Treatment of rats exposed to the control diet in utero with either nifedipine or losartan between 2 and 4 weeks of age did not alter their blood pressure. Nifedipine had no effect upon the blood pressure of low-protein-exposed pups, but losartan prevented the blood pressure elevation in these animals. Between 4 and 12 weeks of age, blood pressure increased significantly in all groups (P<0.001). The pattern of blood pressure among the groups was identical to that observed at 4 weeks, suggesting that the observed early effects of losartan would be maintained into adult life. The data are consistent with the hypothesis that angiotensin II plays a major role in the prenatal programming of hypertension. The action of angiotensin II at the AT(1) receptor between 2 and 4 weeks of age may be critically up-regulated by fetal factors, including exposure to glucocorticoids of maternal origin.
来自不同人群的流行病学证据，再加上动物模型的实验证据，表明孕期母亲的营养状况是胎儿编程影响心血管疾病的一个重要因素。用低蛋白饮食大鼠妊娠模型进行的实验表明，肾素-血管紧张素系统在编程机制中起作用，因为胎儿营养不足会永久性地提高肺和血浆血管紧张素转换酶的活性。卡托普利对该模型血压的长期有益作用需要进一步研究，以阐明血管紧张素II的作用。给妊娠大鼠喂食含18%（w/w）酪蛋白作为蛋白质来源的对照饮食或含9%（w/w）酪蛋白的低蛋白饮食。在产后2至4周龄期间，对母鼠及其幼崽用氯沙坦或硝苯地平进行处理。研究中的所有幼崽在4周和12周龄时使用尾套测定血压。子宫内暴露于低蛋白饮食且未接受药物治疗的动物，其血压相对于对照大鼠有所升高（平均升高27 mmHg；P<0.001）。在2至4周龄期间，用硝苯地平或氯沙坦对子宫内暴露于对照饮食的大鼠进行处理，并未改变它们的血压。硝苯地平对低蛋白暴露幼崽的血压没有影响，但氯沙坦可防止这些动物血压升高。在4至12周龄期间，所有组的血压均显著升高（P<0.001）。各组间的血压模式与4周时观察到的相同，这表明氯沙坦早期观察到的作用将持续到成年期。这些数据与血管紧张素II在高血压产前编程中起主要作用的假设一致。血管紧张素II在2至4周龄时对AT(1)受体的作用可能会被包括母体来源的糖皮质激素暴露在内的胎儿因素显著上调。
