Yang X P, Liu Y H, Peterson E, Carretero O A
Department of Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA.
J Cardiovasc Pharmacol. 1997 Feb;29(2):250-6. doi: 10.1097/00005344-199702000-00014.
Angiotensin-converting enzyme inhibitors (ACEi) protect the heart against ischemia/reperfusion injury. Part of this cardioprotective effect may be mediated through kinins. Because kinins are also metabolized by neutral endopeptidase (NEP) 24.11 in vivo, we hypothesized that (a) inhibition of NEP-24.11 would afford cardioprotection similar to that of ACEi and potentiate the effect of ACEi; and (b) these effects are mediated by kinins or atrial natriuretic peptide (ANP) or both. In Lewis inbred rats, the left anterior descending coronary artery (LAD) was occluded for 30 min, followed by 120-min reperfusion. Immediately before reperfusion rats received vehicle, the ACEi ramiprilat, the NEP-24.11 inhibitor (NEPi) CGS24592, or both. To test whether the effect of NEPi could be suppressed by blocking kinins or ANP, the kinin-receptor antagonist icatibant or ANP antagonist HS-142-1 was administered before LAD occlusion. In controls, infarct size/risk area was 69 +/- 4%; NEPi reduced this to 24 +/- 4% (p < 0.001) and ramiprilat to 20 +/- 3% (P < 0.001). NEPi did not potentiate the effect of ramiprilat (infarct size/risk area, 18 +/- 4%). The protective effect of NEPi was blocked by icatibant; infarct size/risk area, 61 +/-4%, significantly larger than NEPi along (p < 0.001) but no different from controls. The effect of NEPi was slightly diminished by the ANP antagonist HS-142-1 (infarct size/risk area, 35 +/- 3%; NS vs. NEPi alone). Thus NEP-24.11 participates in catabolism of kinins in the heart; inhibition of NEP-24.11 may increases cardiac kinins, which are responsible for the cardioprotective effect of NEPi.
血管紧张素转换酶抑制剂（ACEi）可保护心脏免受缺血/再灌注损伤。这种心脏保护作用的一部分可能是通过激肽介导的。由于激肽在体内也会被中性内肽酶（NEP）24.11代谢，我们推测：（a）抑制NEP-24.11会产生与ACEi类似的心脏保护作用，并增强ACEi的效果；（b）这些作用是由激肽或心房利钠肽（ANP）或两者共同介导的。在近交系Lewis大鼠中，左冠状动脉前降支（LAD）闭塞30分钟，随后再灌注120分钟。在再灌注前，大鼠立即接受溶剂、ACEi雷米普利拉、NEP-24.11抑制剂（NEPi）CGS24592或两者。为了测试阻断激肽或ANP是否能抑制NEPi的作用，在LAD闭塞前给予激肽受体拮抗剂艾替班特或ANP拮抗剂HS-142-1。在对照组中，梗死面积/危险区为69±4%；NEPi将其降至24±4%（p<0.001），雷米普利拉将其降至20±3%（P<0.001）。NEPi没有增强雷米普利拉的作用（梗死面积/危险区，18±4%）。艾替班特阻断了NEPi的保护作用；梗死面积/危险区为61±4%，明显大于单独使用NEPi时（p<0.001），但与对照组无差异。ANP拮抗剂HS-142-1使NEPi的作用略有减弱（梗死面积/危险区，35±3%；与单独使用NEPi相比无统计学差异）。因此，NEP-24.11参与心脏中激肽的分解代谢；抑制NEP-24.11可能会增加心脏激肽，这是NEPi产生心脏保护作用的原因。
