Wolny A, Clozel J P, Rein J, Mory P, Vogt P, Turino M, Kiowski W, Fischli W
Pharma Division, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Circ Res. 1997 Feb;80(2):219-27. doi: 10.1161/01.res.80.2.219.
Blockade of the renin-angiotensin system by inhibition of angiotensin-converting enzyme (ACE) is beneficial for the treatment of hypertension and congestive heart failure. However, it is unclear how complete the blockade by ACE inhibitors is and if there is continuing angiotensin II (Ang II) formation during chronic treatment with ACE inhibitors. Indeed chymase, a serine protease, which is able to form angiotensin II from angiotensin I (Ang I) and cannot be blocked by ACE inhibitors, has been shown to be present in human heart. The goal of the present study was to evaluate the extent of renin-angiotensin system blockade and the Ang II-forming pathways in cardiac tissue of patients chronically treated with ACE inhibitors or in patients without ACE inhibition therapy. Our studies indicate an incomplete ACE inhibition in human heart tissue after chronic ACE inhibitor therapy. Moreover, ACE contributes only a small portion to the total Ang I conversion, as shown in biochemical studies in ventricular and coronary homogenates or functionally as Ang I contractions in isolated rings of coronary arteries. A serine protease was responsible for the majority of Ang II production in both the membrane preparation and Ang I-induced contractions of isolated coronary arteries. In humans, the serine protease pathway is likely to play an important role in cardiac Ang II formation. Thus, drugs such as renin inhibitors and Ang II receptor blockers might be able to induce a more complete blockade of the renin-angiotensin system, providing a more efficacious therapy.
通过抑制血管紧张素转换酶（ACE）来阻断肾素-血管紧张素系统，对治疗高血压和充血性心力衰竭有益。然而，尚不清楚ACE抑制剂的阻断效果有多彻底，以及在长期使用ACE抑制剂治疗期间是否仍有血管紧张素II（Ang II）生成。实际上，已证实在人类心脏中存在一种丝氨酸蛋白酶——糜酶，它能够将血管紧张素I（Ang I）转化为血管紧张素II，且不能被ACE抑制剂阻断。本研究的目的是评估长期接受ACE抑制剂治疗的患者或未接受ACE抑制治疗的患者心脏组织中肾素-血管紧张素系统的阻断程度以及Ang II的生成途径。我们的研究表明，长期使用ACE抑制剂治疗后，人体心脏组织中的ACE抑制并不完全。此外，如在心室和冠状动脉匀浆的生化研究中所示，或在离体冠状动脉环中通过Ang I收缩功能测定，ACE在总的Ang I转化中仅占一小部分。在膜制剂和离体冠状动脉的Ang I诱导收缩中，一种丝氨酸蛋白酶负责大部分的Ang II生成。在人类中，丝氨酸蛋白酶途径可能在心脏Ang II形成中起重要作用。因此，诸如肾素抑制剂和Ang II受体阻滞剂等药物可能能够更彻底地阻断肾素-血管紧张素系统，提供更有效的治疗。
