Keuneke C, Yacullo R, Metzger R, Hellmann T, Peters J, Ganten D
German Institute for High Blood Pressure Research, University of Heidelberg.
Eur Heart J. 1990 May;11 Suppl D:11-6. doi: 10.1093/eurheartj/11.suppl_d.11.
When inhibitors of the renin-angiotensin system (RAS) were initially developed, they were believed to act as antihypertensive agents mainly under pathophysiological conditions, in which an elevated plasma RAS contributed to the elevation and maintenance of high blood pressure (BP). However, evidence has accumulated from studies in hypertensive patients, as well as in animals, indicating that BP could be lowered by converting-enzyme inhibitors (CEIs) independently of whether or not the plasma RAS was stimulated. Several other effects had to be considered. It was thus discovered that converting enzyme (CE) is identical with the bradykinin-degrading enzyme, kininase II, and CEIs can therefore potentiate the vasodepressor effects of bradykinin and thereby interact with the prostaglandin system. Actions of CEIs possibly unrelated to inhibition of angiotensin and kininase also need to be considered. The actions of CEIs at the tissue level (brain, heart, blood vessels, kidney, adrenal gland) and their interference with the autonomic nervous system through central and peripheral actions may under certain conditions be more important than their inhibition of the circulating hormonal plasma angiotensin II. Recent clinical and experimental studies and new insights in the molecular biology of the RAS, especially gene expression of renin and angiotensinogen in tissues of the cardiovascular system, support this view. We have found that chronic CE inhibition with substances such as captopril, quinapril and lisinopril specifically affects angiotensinogen mRNA levels in cardiovascular tissues, and has marked effects on left ventricular hypertrophy, possibly through an action on cardiac angiotensin. These findings have consequences not only for the understanding of pharmacokinetics and pharmacodynamics of CEIs but also for their practical therapeutic use.
当最初开发肾素-血管紧张素系统（RAS）抑制剂时，人们认为它们主要在病理生理条件下起抗高血压作用，在这种情况下，血浆RAS升高会导致高血压（BP）的升高和维持。然而，来自高血压患者以及动物研究的证据不断积累，表明无论血浆RAS是否受到刺激，转换酶抑制剂（CEIs）都可以降低血压。还必须考虑其他几种作用。因此发现转换酶（CE）与缓激肽降解酶激肽酶II相同，因此CEIs可以增强缓激肽的血管舒张降压作用，从而与前列腺素系统相互作用。还需要考虑CEIs可能与抑制血管紧张素和激肽酶无关的作用。CEIs在组织水平（脑、心脏、血管、肾脏、肾上腺）的作用以及它们通过中枢和外周作用对自主神经系统的干扰，在某些情况下可能比它们对循环激素血浆血管紧张素II的抑制作用更重要。最近的临床和实验研究以及RAS分子生物学的新见解，特别是心血管系统组织中肾素和血管紧张素原的基因表达，支持了这一观点。我们发现，用卡托普利、喹那普利和赖诺普利等物质进行慢性CE抑制会特异性影响心血管组织中的血管紧张素原mRNA水平，并对左心室肥厚有显著影响，可能是通过对心脏血管紧张素的作用。这些发现不仅对理解CEIs的药代动力学和药效学有影响，而且对它们的实际治疗应用也有影响。
