Effect of a highly selective endothelin-converting enzyme inhibitor on cardiac remodeling in rats after myocardial infarction

Whilst endothelin (ET) receptor antagonism has been evaluated in post-myocardial infarction (MI) remodeling, endothelin-converting enzyme (ECE) inhibition has not been determined. Tn 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-I (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) 3.5 +/- 0.5 mm; systolic blood pressure (SBP) 119 +/- 3 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 <plus/minus> 0.03 vs 0.35 +/- 0.02, p < 0.05) contributed to by reduced left ventricular (LV) internal dimensions (EDd 7.5 <plus/minus> 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 SEP (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.