Renal Actions of Neutral Endopeptidase Inhibition and Its Effects on Gene Expression of Atrial Natriuretic Peptide and Neutral Endopeptidase in Rats with Chronic Heart Failure

Background and Aim of work: The aim of the current study is to evaluate the effectsof acute and chronic inhibition of NEP, by ONO-9902, on ANP, and NEP geneexpressions, hemodynamic and renal parameters in rats with chronic heart failure(CHF) following left coronary artery ligation (CAL). Methods: The study comprised48 male Sprague-Dawley rats (220–240 g) which were divided into sham and CALgroups. Myocardial infarction was induced by left CAL. All rats were divided intountreated and orally treated with ONO-9902 (300 mg/kg/day) from the 1st to 6th weekafter the operation At the 1st and 6th weeks after the operation, gene expression ofANP and NEP, plasma ANP, cGMP, and aldosterone concentrations, urine volume,Na and ANP excretion, creatinine clearance, renal cGMP generation, body andorgan weight were measured. Results: CAL led to sodium and water retention,increased plasma level of ANP and aldosterone, in addition to increase in ANP geneexpression as well as decrease in renal generation of cGMP. Acute treatment of ratswith CAL by NEPI, at the first week after the operation, inhibited the NEP geneexpression with increased plasma ANP concentration and gene expression, whichcaused diuresis and natriuresis and increased renal cGMP generation. Moreover,chronic treatment by NEPI caused significant decrease in lung weight, lung bodyweight ratio, NEP gene expression and PAC, non significant increase in plasmaconcentration and gene expression of ANP, diuresis and natriuresis with increasedrenal cGMP generation. GFR is not significantly changed either before or aftertreatment. Conclusions: It is concluded that gene expression and plasma level ofANP increased in CHF. Also, chronic treatment with NEP inhibitor improvespulmonary edema and decreases Na and water retention in rats with CHF bydeceasing degradative effect of NEP on ANP which leads to prolongation of itsbioactivity. So, ONO-9902 may offer a new therapeutic approach in patients withCHF.