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