Ecadotril

Abstract: Combined inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) is a candidate therapy for hypertension and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the effects of NEP inhibition and combined NEP and ACE inhibition on Ang and BK levels in rats with myocardial infarction. We administered the NEP inhibitor ecadotril (0, 0.1, 1, 10, and 100 mg/kg/day), either alone or together with the ACE inhibitor perindopril (0.2 mg/kg/day) by 12-hourly gavage from day 2 to 28 after infarction. Ecadotril increased urine cyclic GMP and BK-(1–9) excretion. Perindopril potentiated the effect of ecadotril on urine cyclic GMP excretion. Neither perindopril nor ecadotril reduced cardiac hypertrophy when administered separately, whereas the combination of perindopril and 10 or 100 mg/kg/day ecadotril reduced heart weight/body weight ratio by 10%. Administration of ecadotril to perindopril-treated rats decreased plasma Ang-(1–7) levels, increased cardiac BK-(1–9) levels, and increased Ang II levels in plasma, kidney, aorta, and lung. These data demonstrate interactions between the effects of NEP and ACE inhibition on remodeling of the infarcted heart and on Ang and BK peptide levels. Whereas increased cardiac BK-(1–9) levels may contribute to the reduction of cardiac hypertrophy, the reduction in plasma Ang-(1–7) levels and increase in Ang II levels in plasma and tissues may compromise the therapeutic effects of combined NEP/ACE inhibition.

Abstract: The effect of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) inhibition on microvascular plasma leakage (extravasation) was evaluated in a rat model. Progressive inhibition of ACE using captopril caused increased extravasation when lung ACE was inhibited by >55%. In contrast, the selective inhibition of renal NEP by >90% using ecadotril did not increase extravasation. In NEP-inhibited rats, extravasation produced by the ACE inhibitors captopril and lisinopril was markedly enhanced. The dual ACE and NEP inhibitor omapatrilat, at oral doses of 0.03, 0.1, and 0.3 mg/kg, selectively inhibited lung ACE by 19, 61, and 76%, respectively, and did not cause significant extravasation. Doses of 1 and 10 mg/kg omapatrilat, which produced >90% inhibition of ACE and also inhibited renal NEP by 54 and 78%, respectively, significantly increased extravasation. In this model, bradykinin and substance P produced extravasation that could be abolished by the bradykinin 2 (B2) receptor antagonist Hoe 140 (icatibant) or the neurokinin1 (NK1) antagonist CP99994 [(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine], respectively. Bradykinin induced extravasation was also partially (∼40%) inhibited by CP99994, indicating that a portion of the response involves B2 receptor-mediated release of substance P. In conclusion, this study is the first to relate the degree of ACE and/or NEP inhibition to extravasation liability in the rat model. Our data clearly demonstrate that ACE inhibitor-induced plasma extravasation is enhanced by concomitant inhibition of NEP. In addition, this study provides further evidence for the role for B2 and NK1 receptors in mediating plasma extravasation in the rat.

Abstract: Objective: 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). Methods: Sprague Dawley rats (350–430 g) were prepared by introducing a shunt between abdominal aorta and the vena cava. Results: 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 μmol/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. Conclusion: 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.

Abstract: —Heart-transplant recipients (Htx) generally present with body fluid and sodium handling abnormalities and hypertension To investigate whether neutral endopeptidase inhibition (NEP-I) increases endogenous atrial natriuretic peptide (ANP) and enhances natriuresis and diuresis after heart transplantation, ecadotril was given orally to 8 control subjects and 8 matched Htx, and levels of volume-regulating hormones and renal water, electrolyte, and cyclic guanosine monophosphate (cGMP) excretions were monitored for 210 minutes Baseline plasma ANP, brain natriuretic peptide (BNP), and cGMP were elevated in Htx, but renin and aldosterone, like urinary parameters, did not differ between groups NEP-I increased plasma ANP (Htx, 206±23 to 332±59 pmol/L, P P =001), cGMP, and water excretions were observed in Htx and urinary cGMP positively correlated with natriuresis in 6 of the Htx subjects Consistent with a normal circadian rhythm of blood pressure, without excluding a possible effect of NEP-I, mean systemic blood pressure increased similarly in both groups at the end of the study (69±20% versus 74±28% in controls and Htx) Thus, systemic hypertension, mild renal impairment, and raised plasma ANP levels are possible contributory factors in the enhanced natriuresis and diuresis with NEP-I in Htx These results support a physiological role for the cardiac hormone after heart transplantation and suggest that long-term studies may be useful to determine the potential of NEP-I in the treatment of sodium retention and water retention after heart transplantation