Dual inhibition of angiotensin converting enzyme and neutral endopeptidase produces effective blood pressure control in spontaneously hypertensive rats

Abstract

Background: The synergistic effects of the combined ACE and NEP inhibition is based both on the blockade of angiotensin II synthesis and degradation of vasoactive peptides and NEP substrates (ANP, arginine, endothelial cells, guanylat cyclase etc.), including bradykinine and the natriuretic peptides, which contribute to vasodilatation, diuresis and improvement of myocardial function. Objectives: This study was undertaken to asses the hypotensive effect of a dual ACE/NEP inhibitor (omapatrilat) in comparison to a NEP inhibitor (candoxatril) and ACE inhibitor (enalapril) in SHRS. Methods: The study was performed in 130 male spontaneously hypertensive rats (SHRS) that were divided into 4 groups and treated orally by a gastric tube for 14 days according to the following dosage regimen: omapatrilat (40 mg/kg b.w./24 h); candoxatril (30 mg/kg b.w./24 h); enalapril (20 mg/kg b.w./ 24 h) and control (water). Systolic blood pressure values were determined at the beginning of the study by the tail-cuff pletysmographic method, at the 7th and 14th day of the treatment, as well as 14 days after the end of the drug administration. For evaluation of the effect of omapatrilat, candoxatril and enalapril on the investigated parameters (plasma atrial natriuretic peptide and serum ACE), 10 ani- mals from the control group were sacrificed at the beginning of the study, and afterwards 10 animals from each group were also sacrificed on the 7th and 14th day of the treatment, as well as 14 days after the end of the drug administration (28th day). Results: The dual ACE/NEP inhibitor, omapatrilat and the ACE inhibitor, enalapril lowered SBP more effectively than the NEP inhibitor, candoxatril at all time points of the experiment (p<0.01). Omapatrilat was slightly more effective than the enalapril treatment. Conclusions: Two-week treatment with the dual ACE/NEP inhibitor omapatrilat caused a significant decrease of the SBP, inhibition of the serum ACE activity and increase of the plasma ANP values, and therefore it should be considered as a new potential therapeutic agent in blood pressure management.