van Geel P P, Pinto Y M, Buikema H, van Gilst W H
Department of Clinical Pharmacology, University of Groningen, The Netherlands.
Eur Heart J. 1998 Jul;19 Suppl G:G13-7.
Peptides produced by the renin-angiotensin system play a major role in the development and progression of various cardiovascular diseases. One of these peptides, angiotensin II, is a potent vasoconstrictor that exerts most of its effects through the human AT1 receptor. Following the discovery of a functional variation in the angiotensin-converting enzyme gene, research has identified other genetic variations in the renin-angiotensin system that may contribute to cardiovascular disorders. Of the described polymorphisms in the AT1-receptor gene, the A1166C transversion is associated with human essential hypertension. We have used the TGR(alpha MHC-h AT1) rat model, which overexpresses the human AT1 receptor in the myocardium, to study some of the associations between an increased AT1-receptor number and cardiovascular disorders. Our results suggest that under physiological conditions overexpression of the AT1 receptor causes no changes in cardiovascular structure; however, pressure and volume overload lead to hypertrophic growth in this model. While the AT1-receptor polymorphism may not cause cardiovascular disorders directly, it can perhaps contribute to a process that is started by other factors, such as increased activity or uptake by tissues of plasma renin, which leads to local activation of the renin-angiotensin system. Our data indicate that the AT1-receptor polymorphism is probably associated with an increased responsiveness to angiotensin II. Under basal conditions, this increased responsiveness does not seem to affect the heart, but it may exert adverse effects under loading or high-renin conditions.
肾素 - 血管紧张素系统产生的肽在各种心血管疾病的发生和发展中起主要作用。这些肽之一，血管紧张素II，是一种强效血管收缩剂，其大部分作用通过人类AT1受体发挥。在发现血管紧张素转换酶基因存在功能变异后，研究已确定肾素 - 血管紧张素系统中的其他基因变异可能与心血管疾病有关。在所述的AT1受体基因多态性中，A1166C转换与人类原发性高血压相关。我们使用了TGR(αMHC - h AT1)大鼠模型，该模型在心肌中过表达人类AT1受体，以研究AT1受体数量增加与心血管疾病之间的一些关联。我们的结果表明，在生理条件下，AT1受体的过表达不会导致心血管结构发生变化；然而，压力和容量超负荷会导致该模型出现肥厚性生长。虽然AT1受体多态性可能不会直接导致心血管疾病，但它可能会促成由其他因素引发的过程，例如血浆肾素活性增加或组织对其摄取增加，从而导致肾素 - 血管紧张素系统的局部激活。我们的数据表明，AT1受体多态性可能与对血管紧张素II的反应性增加有关。在基础条件下，这种增加的反应性似乎不会影响心脏，但在负荷或高肾素条件下可能会产生不利影响。
