Effects of natriuretic peptides on the mechanisms of atherosclerosis

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Neutral Endopeptidase 24.11 (NEP), widely distributed in the body, hydrolyzes and inactivates a number of endogenous vasoactive peptides, some of which could alter the functions of smooth muscle cell or macrophage in the arterial wall. The aim of this study was to assess the influence of chronic NEP inhibition by daily administration of UK79300 (Candoxatril ; UK), an orally active inhibitor of NEP,on the development of atherosclerotic changes in high cholesterol-fed rabbits. Male New Zealand White rabbits were fed for 8 weeks : normal rabbit diet (Nor, n=15), 1.5% cholesterol diet (Chol, n=15), or 1.5% choresterol diet containing UK (20 mg/kg/day) (UK +Chol, n=15). At the end of dietary period, UK-treatment suppressed surface area of the aorta covered by plaques (% surface area : Chol 48 + 7% vs UK + chol 11 + 3, p<0.05) and decreased contents of cholesterol and cholesterol ester in the aortas. UK also reduced plasma total cholesterol by 15 + 4% of Chol (1680 + 180 mg/dl). UK-treatment preserved endothelium-dependent relaxation of the isolated thoracic aortic rings suspended in the organ chamber in response to acetylcholine (ACh) (EC50, nM ; concentrations of ACh causing 50% inhibition of contractions with 0.3 mM of phenylephrine : Nor 12 + 4, Chol 360 + 20 +, UK + Chol 56 + 9^*, +p<0.01 vs Nor, ^*p<0.01 vs Chol). UK-treatment decreased plasma NEP enzymatic activity by 27 + 3% of Chol and prevented the atherosclerotic impairment of relaxation of the isolated thoracic aortic rings in the organ chamber in response to atrial natriuretic peptide, one of NEP substrates (EC50, pM : Nor 50 + 4, Chol 290 + 20 +, UK + Chol 65 + 8, +p<0.01 vs Nor, ^*p<0.01 vs Chol). The results suggest that NEP plays a significant role in atherogenesis and NEP inhibitors might be therapeutically useful in the prevention of atherosclerosis.