Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure - Role of kinins and angiotensin II type 2 receptors
Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure - Role of kinins and angiotensin II type 2 receptors
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DOI：
10.1172/jci119360
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发表时间：
1997-04-15
影响因子：
15.9
通讯作者：
Carretero, OA
中科院分区：
文献类型：
--
作者：
Liu, YH;Yang, XP;Carretero, OA
血管紧张素转换酶抑制剂（ACEi）改善心功能和重塑，延长心力衰竭（HF）患者的生存期。用血管紧张素II型1受体拮抗剂（AT(1)-ant）阻断肾素-血管紧张素系统（RAS）可能具有类似的有益效果。除了抑制RAS外，ACEi还可能通过抑制激肽破坏而起作用，而AT(1)-ant可能在AT(1)受体水平上阻断RAS并激活血管紧张素II型2 （AT(2)）受体。采用大鼠心肌梗死（MI）致HF模型，研究了激肽在ACEi的心脏保护作用中的作用。我们还研究了AT(1)-蚂蚁是否具有类似的作用，以及这些作用是否部分归因于AT(2)受体的激活。心肌梗死后2个月，给大鼠治疗2个月：(a)载药；(b) ACEi雷米普利，含或不含b -2受体拮抗剂（b -2-ant）；或(c)有或不含AT(2)拮抗剂的AT(1)-蚂蚁（AT(2)-蚂蚁）或b -2-蚂蚁。给药大鼠左室舒张末期（LVEDV）和收缩末期体积（LVESV）、间质胶原沉积和心肌细胞大小显著增加，射血分数降低。ACEi和AT(1)-ant均能改善左室重构和心功能。b -2-蚂蚁阻断了ACEi的大部分心脏保护作用，而AT(1)-蚂蚁的作用被AT(2)-蚂蚁阻断。由AT(1)-蚂蚁引起的LVEDV和LVESV的下降也被b -2-蚂蚁部分阻断。我们得出结论(a)在HF中，ACEi和AT(1)-ant都具有心脏保护作用，这可能是由于对心脏的直接作用或继发于血液动力学的改变，或两者兼有；(b) ACEi的作用部分由激肽介导，而AT(1)-ant的作用是由AT(2)受体激活触发的，也部分由激肽介导。我们推测在心衰中，阻断AT(1)受体会增加肾素和血管紧张素；这些血管紧张素刺激AT(2)受体，这反过来可能通过激肽和其他类血管素在AT(1)-蚂蚁的治疗效果中发挥重要作用。
Angiotensin-converting enzyme inhibitors (ACEi) improve cardiac function and remodeling and prolong survival in patients with heart failure (HF). Blockade of the renin-angiotensin system (RAS) with an angiotensin II type 1 receptor antagonist (AT(1)-ant) may have a similar beneficial effect. In addition to inhibition of the RAS, ACEi may also act by inhibiting kinin destruction, whereas AT(1)-ant may block the RAS at the level of the AT(1) receptor and activate the angiotensin II type 2 (AT(2)) receptor. Using a model of HF induced by myocardial infarction (MI) in rats, we studied the role of kinins in the cardioprotective effect of ACEi. We also investigated whether an AT(1)-ant has a similar effect and whether these effects are partly due to activation of the AT(2) receptor. Two months after MI, rats were treated for 2 mo with: (a) vehicle; (b) the ACEi ramipril, with and without the B-2 receptor antagonist icatibant (B-2-ant); or (c) an AT(1)-ant with and without an AT(2)-antagonist (AT(2)-ant) or B-2-ant. Vehicle-treated rats had a significant increase in left ventricular end-diastolic (LVEDV) and end-systolic volume (LVESV) as well as interstitial collagen deposition and cardiomyocyte size, whereas ejection fraction was decreased. Left ventricular remodeling and cardiac function were improved by the ACEi and AT(1)-ant. The B-2-ant blocked most of the cardioprotective effect of the ACEi, whereas the effect of the AT(1)-ant was blocked by the AT(2)-ant. The decreases in LVEDV and LVESV caused by the AT(1)-ant were also partially blocked by the B-2-ant. We concluded that (a) in HF both ACEi and AT(1)-ant have a cardioprotective effect, which could be due to either a direct action on the heart or secondary to altered hemodynamics, or both; and (b) the effect of the ACEi is mediated in part by kinins, whereas that of the AT(1)-ant is triggered by activation of the AT(2) receptor and is also mediated in part by kinins. We speculate that in HF, blockade of AT(1) receptors increases both renin and angiotensins; these angiotensins stimulate the AT(2) receptor, which in turn may play an important role in the therapeutic effect of the AT(1)-ant via kinins and other autacoids.