Martin P, Tzanidis A, Stein-Oakley A, Krum H
Clinical Pharmacology Unit, Monash University, Melbourne, Australia.
J Cardiovasc Pharmacol. 2000 Nov;36(5 Suppl 1):S367-70. doi: 10.1097/00005344-200036051-00106.
Whilst endothelin (ET) receptor antagonism has been evaluated in post-myocardial infarction (MI) remodeling, endothelin-converting enzyme (ECE) inhibition has not been determined. In the study reported here female Sprague-Dawley rats underwent coronary artery ligation, then were randomized 24 h post-MI to either no therapy (control) or 7 days therapy with the highly selective ECE inhibitor, FR901533 (Fujisawa, Osaka, Japan) 100 mg/kg/day, by continuous subcutaneous infusion. Echocardiography [fractional shortening (FS), internal dimensions and relative wall thickness (RWT)] and invasive hemodynamics were performed before sacrifice on day 8, with subsequent cardiac immunohistochemistry. Plasma concentrations of ET-1 and big ET-1 (39 AA) were determined by enzyme-linked immunosorbent assay (ELISA). ECE inhibitor-treated rats [n = 6, infarct size (IS) 37 +/- 2%) were compared to control rats with similar size MI (n = 8, IS 38 +/- 3%). Values for sham-operated rats were: RWT 0.49 +/- 0.02; left ventricular end-diastolic diameter (LVEDD) 6.2 +/- 0.5 mm; left ventricular end-systolic diameter (LVESD) systolic3.5 +/- 0.5 mm; blood pressure (SBP) 119 +/- 4 mmHg; heart rate 340 +/- 21 bpm; and left ventricular end-diastolic pressure (LVEDP) 12 +/- 2 mmHg, FS 46 +/- 4%. ECE inhibition was confirmed by increased big ET-1 to ET-1 ratio (0.23 +/- 0.06 vs 0.05 +/- 0.02, ECE inhibitor vs control, p < 0.05). ECE inhibitor increased RWT (0.43 +/- 0.03 vs 0.35 +/- 0.02, p < 0.05) contributed to by reduced left ventricular (LV) internal dimensions (EDd 7.5 +/- 0.4 vs 7.9 +/- 0.3 mm, ESd 5.2 +/- 0.5 vs 5.6 +/- 0.3 mm, ECE inhibitor vs control respectively). There were also trends in ECE inhibitor rats to increased FS (31 +/- 4 vs 29 +/- 2%), decreased SBP (99 +/- 4 vs 104 +/- 4 mmHg), heart rate (355 +/- 28 vs 385 +/- 12 bpm) and LVEDP (23 +/- 2 vs 25 +/- 1 mmHg), all p = NS, ECE inhibitor vs control. Immunoreactive cardiac collagen I peptide was unchanged by ECE inhibitor, however, alpha-smooth muscle actin, a marker of myofibroblast activation, was decreased in the infarct zone of ECE inhibitor rats (35 +/- 4 vs 46 +/- 3%, ECE inhibitor vs control, p < 0.05). This study concludes that selective ECE inhibitor with FR901533 reduces the conversion of big ET-1 to ET-1 in post-MI rats and improves some parameters of cardiac remodeling early post-MI. However, longer-term studies are needed fully to assess the therapeutic potential of ECE inhibitor post-MI and in heart failure.
虽然已经对内皮素（ET）受体拮抗剂在心肌梗死后（MI）重塑中的作用进行了评估，但内皮素转化酶（ECE）抑制作用尚未确定。在本研究中，雌性Sprague-Dawley大鼠接受冠状动脉结扎，然后在心肌梗死后24小时随机分为两组，一组不进行治疗（对照组），另一组通过连续皮下输注给予高选择性ECE抑制剂FR901533（日本大阪藤泽公司）100mg/kg/天，治疗7天。在第8天处死前进行超声心动图检查[缩短分数（FS）、内径和相对室壁厚度（RWT）]以及有创血流动力学检查，随后进行心脏免疫组织化学检查。通过酶联免疫吸附测定（ELISA）测定血浆中ET-1和大ET-1（39个氨基酸）的浓度。将接受ECE抑制剂治疗的大鼠（n = 6，梗死面积（IS）37±2%）与梗死面积相似的对照组大鼠（n = 8，IS 38±3%）进行比较。假手术大鼠的值为：RWT 0.49±0.02；左心室舒张末期直径（LVEDD）6.2±0.5mm；左心室收缩末期直径（LVESD）3.5±0.5mm；血压（SBP）119±4mmHg；心率340±21次/分钟；左心室舒张末期压力（LVEDP）12±2mmHg，FS 46±4%。ECE抑制剂组大鼠的大ET-1与ET-1比值升高（0.23±
