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孕妇（约4%的孕妇），服用称为β 1受体阻滞剂的药物。这些药物改善了母亲的心脏功能，使其能够向重要器官泵送足够的血液。在英国，比索洛尔是常用于此目的的β 1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，也不知道它们对婴儿生长发育的潜在影响。胎盘中的血管为婴儿提供营养，使其能够在子宫内生长。比索洛尔穿过胎盘进入胎儿血液，当孕妇服用比索洛尔时，通过胎盘的胎儿血流减少，从而限制了婴儿正常生长所需的营养和氧气。出生时身材矮小可能会对成年后产生不利影响，因为这些婴儿患高血压和糖尿病的风险增加。因此，胎儿在子宫内的健康状况受损，在出生前后给家庭和NHS带来了重大的情感和经济负担。奈必洛尔是一种不同的β 1受体阻滞剂，在妊娠期间似乎对通过胎盘的胎儿血流几乎没有影响。我的研究旨在证明母体比索洛尔是否会通过改变胎盘血管的功能来降低婴儿的生长和损害婴儿的健康，以及奈必洛尔是否可以为患有心脏病的孕妇提供更好的药物，以改善胎盘血流，婴儿的生长和婴儿的健康。为了达到我的研究目的，将使用妊娠绵羊证明比索洛尔和奈必洛尔对妊娠期间婴儿的影响。这些动物将接受比索洛尔或奈必洛尔治疗，以检查未出生羔羊的胎盘血流量、妊娠期羔羊的生长以及心脏和主要血管的功能。我将在实验室里使用捐赠给研究的人类胎盘，测试有多少这些药物穿过胎盘从母亲一侧的器官到婴儿一侧。为了确定奈必洛尔的作用以及比索洛尔是否会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必洛尔介导的重要信号。这将涉及在微小的塑料腔室中培养胎盘血管细胞，这些塑料腔室重建天然血管：血管内部的内皮细胞和收缩或放松的平滑肌细胞，它们在胎盘中共同控制子宫内婴儿的血流供应。目前可用的其他β 1受体阻滞剂是否可以为婴儿提供比比索洛尔更好的选择，从而改善母亲的前瞻性临床实践，将需要证明。这些研究将阐明比索洛尔和奈必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后果。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β 1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孕产妇和胎儿健康研究中心（MFHRC）进行。MFHRC是欧洲最大的妊娠研究团体之一，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，共同目标是使怀孕对母亲和婴儿都更安全。此外，考虑到其在特定领域的声誉，布宜诺斯艾利斯大学药理学家的专业知识对于了解β 1受体阻滞剂的作用至关重要;动物研究将在剑桥大学进行，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.