Wegner M, Hirth-Dietrich C, Stasch J P
Bayer AG, Wuppertal, Germany.
Cardiovasc Res. 1996 Jun;31(6):891-8.
The aortovenocaval fistular (AVF) rat represents a model of heart failure caused by increased cardiac volume overload and reduced renal function. Both circulating vasoconstrictors like the renin-angiotensin-aldosterone system and vasodilators like atrial and brain natriuretic peptides (ANP and BNP) are activated in this animal model of heart failure. In addition, neutral endopeptidase 24.11 (NEP) in plasma and urine is elevated in AVF rats. In the present investigation we examined the renal and hormonal effects of the NEP inhibitor, ecadotril, in acute and chronic studies in rats with an aortovenocaval fistula (AVF).
Sprague Dawley rats (350-430 g) were prepared by introducing a shunt between abdominal aorta and the vena cava.
Acute administration of the neutral endopeptidase inhibitor, ecadotril (30 mg/kg p.o.), significantly improved the reduced renal excretion of sodium in AVF rats (83 +/- 10 to 145 +/- 14 mumol/kg/h, P < 0.01) but had no significant effect in sham-operated rats. However, neutral endopeptidase activity in urine was significantly decreased after ecadotril in both groups. Plasma ANP was increased after ecadotril only in AVF rats (275 +/- 83 to 748 +/- 187 pg/ml, P < 0.05), whereas the increase in plasma BNP was not statistically significant. After 4 weeks of observation the ANP and BNP plasma levels, renin activity (PRA), angiotensin I, and neutral endopeptidase activity were significantly higher in AVF rats than in sham-operated rats. Four weeks on ecadotril (30 mg/kg p.o., b.i.d.) increased plasma ANP (245 +/- 48 as opposed to 450 +/- 77 pg/ml, P < 0.05) and decreased PRA (11.3 +/- 1.5 as opposed to 6.8 +/- 1.2 ng/ml/h, P < 0.005) in AVF rats. Plasma NEP activity was inhibited in both groups. Ventricle weight was significantly higher in AVF rats than in sham-operated controls, and ecadotril treatment over 4 weeks decreased ventricular hypertrophy to a slight extent.
These results indicate that in the AVF rat model of heart failure the neutral endopeptidase inhibitor, ecadotril, improves the reduced kidney function in AVF rats by raising natriuretic peptides in plasma and probably in urine. NEP inhibition with ecadotril could therefore offer useful therapeutic possibilities in the treatment of heart failure.
主动脉腔静脉瘘（AVF）大鼠是一种因心脏容量负荷增加和肾功能减退导致心力衰竭的模型。在这种心力衰竭动物模型中，诸如肾素 - 血管紧张素 - 醛固酮系统等循环血管收缩剂以及诸如心房和脑利钠肽（ANP和BNP）等血管舒张剂均被激活。此外，AVF大鼠血浆和尿液中的中性内肽酶24.11（NEP）升高。在本研究中，我们在患有主动脉腔静脉瘘（AVF）的大鼠的急性和慢性研究中，研究了NEP抑制剂依卡多曲对肾脏和激素的影响。
通过在腹主动脉和腔静脉之间建立分流来制备Sprague Dawley大鼠（350 - 430 g）。
急性给予中性内肽酶抑制剂依卡多曲（30 mg/kg口服）可显著改善AVF大鼠降低的钠肾排泄（从83±10至145±14 μmol/kg/h，P < 0.01），但对假手术大鼠无显著影响。然而，两组大鼠在给予依卡多曲后尿液中的中性内肽酶活性均显著降低。依卡多曲仅使AVF大鼠的血浆ANP升高（从275±83至748±187 pg/ml，P < 0.05），而血浆BNP的升高无统计学意义。观察4周后，AVF大鼠的ANP和BNP血浆水平、肾素活性（PRA）、血管紧张素I和中性内肽酶活性均显著高于假手术大鼠。给予依卡多曲4周（30 mg/kg口服，每日两次）可使AVF大鼠的血浆ANP升高（从245±48升至450±77 pg/ml，P < 0.05）并降低PRA（从11.3±1.5降至6.8±1.2 ng/ml/h，P < 0.005）。两组的血浆NEP活性均受到抑制。AVF大鼠的心室重量显著高于假手术对照组，4周的依卡多曲治疗在一定程度上减轻了心室肥厚。
这些结果表明，在AVF大鼠心力衰竭模型中，中性内肽酶抑制剂依卡多曲通过提高血浆中可能还有尿液中的利钠肽来改善AVF大鼠降低的肾功能。因此，依卡多曲抑制NEP可能为心力衰竭的治疗提供有用的治疗可能性。
