Harm and benefit of second and third generation beta1-blockers on placental vascular function, fetal growth and fetal cardiovascular function.

患有心脏和血管疾病的怀孕母亲(约4%的怀孕)，服用被称为β1受体阻滞剂的药物。这些药物改善了妈妈心脏的功能，将足够的血液输送到重要器官。在英国，比索洛尔是经常用于这一目的的β1受体阻滞剂。这些药物在使用时并不知道它们对胎盘的副作用，对婴儿生长发育的潜在影响的信息也很有限。胎盘中的血管提供营养物质，使婴儿在子宫中成长。比索洛尔通过胎盘进入胎儿血液，当孕妇服用比索洛尔时，通过胎盘的胎儿血液流量减少，从而限制了正常婴儿生长所需的营养和氧气。出生时身材矮小可能会在成年后产生有害的后果，因为这些婴儿患高血压和糖尿病的风险会增加。因此，婴儿在子宫中的健康受损，在出生前和出生后都会给家庭和国民健康保险制度带来巨大的情感和经济负担。奈比洛尔是一种不同的β-1受体阻滞剂，在怀孕期间似乎对通过胎盘的胎儿血液流动几乎没有影响。我的研究旨在证明，母亲比索洛尔是否通过改变胎盘血管功能来减少婴儿的生长并损害婴儿的健康，以及奈比洛尔是否可能为患有心脏病的孕妇提供更好的药物来改善胎盘血流，婴儿的生长和婴儿的健康。为了达到我的研究目标，比索洛尔和奈比洛尔的效果证据将在怀孕期间用怀孕的绵羊来证明。这些动物将接受比索洛尔或奈比洛尔治疗，以检查胎盘血流到未出生的羔羊，它的生长以及怀孕期间心脏和主要血管的功能。我将使用实验室中捐赠给研究的人类胎盘来测试这些药物中有多少从器官的母亲一侧穿过胎盘进入婴儿一侧。为了确定奈比洛尔的疗效以及比索洛尔是否导致胎盘血管无法正常工作，将使用尖端技术来识别比索洛尔和奈比洛尔介导的重要信号。这将涉及在重建自然血管的微小塑料腔中培养胎盘血管细胞：排列在血管内部的内皮细胞，以及收缩或松弛的平滑肌细胞，它们在胎盘中共同作用，控制子宫内婴儿的血液供应。目前可用的其他β-1受体阻滞剂是否能为婴儿提供比比索洛尔更好的选择，从而改善产妇的前瞻性临床实践，还需要得到证实。这些研究将阐明比索洛尔和奈比洛尔如何影响胎盘滋养婴儿的功能，以及这些影响对婴儿生长和健康的影响。在这些研究中进行的实验将提供第一个证据基础，证明母亲在怀孕期间服用不同的β1受体阻滞剂的危害和益处，最终目的是保护婴儿的生长。这项工作将在曼彻斯特大学的母婴健康研究中心(MFHRC)举行。MFHRC是欧洲最大的妊娠研究组织之一，被公认为世界级的产科研究机构。该中心由科学家、临床医生和助产士组成，他们共同努力，共同致力于让母亲和婴儿更安全地怀孕。此外，考虑到在其特定领域中应有的声誉，布宜诺斯艾利斯大学的药理学家的专业知识将对了解β1受体阻滞剂的影响至关重要；动物工作将在剑桥大学进行，使用细胞方法的研究将涉及与利兹大学和卡塔尼亚大学的合作。

Pregnant mums with heart and blood vessel disease (~4% of pregnancies), take medications known as beta1-blockers. These drugs ameliorate the function of mum's heart to pump sufficient blood to vital organs. In the UK, bisoprolol is the beta1-blocker often given for this purpose. These drugs are used with no knowledge of their side effects on the placenta and with limited information on their potential effects on baby's growth and development.Blood vessels in the placenta supply nutrients to enable baby's growth in the womb. Bisoprolol crosses the placenta into the fetal blood and when pregnant women take bisoprolol, fetal blood flow through the placenta is diminished, thus limiting nutrients and oxygen needed for normal baby's growth. Being born small may have detrimental consequences in the adulthood, as these babies have increased risk of developing high blood pressure and diabetes. Thus, compromised health of the baby in the womb is responsible for a significant emotional and financial burden on families and the NHS, before and after birth. Nebivolol is a different beta1-blocker which appears to cause little disturbance to fetal blood flow through the placenta during pregnancy. My studies aim to demonstrate whether maternal bisoprolol reduces the growth and compromises the health of the baby by altering the function of placental blood vessels, and whether nebivolol may suggest a better medication for pregnant mums with heart disease to improve placental blood flow, baby's growth and baby's health. To meet the aims of my studies, evidence of the effects of bisoprolol and nebivolol will be proven on the baby during pregnancy using pregnant sheep. These animals will be treated with bisoprolol or nebivolol to check placental blood flow to the unborn lamb, its growth and the function of its heart and major blood vessels in pregnancy. I will test how much of these drugs crosses the placenta from mum's side of the organ to the baby's side, using human placentas in the laboratory that have been donated to research. To determine effects of nebivolol and whether bisoprolol causes placental blood vessels to fail to work properly, cutting-edge technologies will be used to identify important signals mediated by bisoprolol and nebivolol. This will involve growing placental blood vessel cells in tiny plastic chambers that recreate the natural blood vessel: endothelial cells that line the inside of blood vessels, and smooth muscle cells that contract or relax, which work together in the placenta to control blood flow supply to the baby in the womb. Whether other beta1-blockers currently available may provide a better option than bisoprolol with respect to the baby, to then improve maternal prospective clinical practice, will need to be proven. These studies will shed a light on how bisoprolol and nebivolol may affect the function of the placenta to nourish the baby, and the consequences of these effects on the growth and the health of the baby. The experiments performed in these studies will provide the first evidence base of harm and benefit of different beta1-blockers taken by mums during pregnancy with the ultimate aim of preserving baby's growth. This work will be hosted at the Maternal and Fetal Health Research Centre (MFHRC) at the University of Manchester. The MFHRC is one of the largest pregnancy-based research group in Europe and is acknowledged as a world-class research facility for obstetric research. The centre consists of scientists, clinicians and midwives, all of whom work together with a combined aim of making pregnancy safer for both mum and baby. In addition, considering the deserved reputation in their specific field, the expertise of pharmacologist at the University of Buenos Aires will be essential to understand the effects of beta1-blockers; the animal work will be undertaken at the University of Cambridge, and studies using cell approach will involve the collaborations with the Universities of Leeds and Catania.