Abstract
Problem statement: We aim to evaluate the effects of acute and chronic inhibition of Neutral EndoPeptidase (NEP), by ONO-9902, on plasma and renal NEP gene expression, hemodynamic and renal parameters in rats with Chronic Heart Failure (CHF) following left Coronary Artery Ligation (CAL). Approach: Forty eight male Sprague-Dawley rats (220-240 g) were divided into sham and CAL groups. Myocardial infarction was induced by left CAL. All rats were further subdivided into untreated and orally treated with ONO-9902 (300 mg kg-1 day-1) from the 1st to 6th weeks after the operation. At the 1st and 6th weeks after the operation, gene expression of plasma and renal NEP, plasma ANP, cGMP and aldosterone concentrations, urine volume, Na and ANP excretion, creatinine clearance and renal cGMP generation were measured. Results: CAL leads to sodium and water retention, increased renal NEP gene expression, plasma ANP and aldosterone and decreased renal cGMP generation and plasma NEP gene expression. Acute treatment of CAL rats by ONO-9902, at the 1st week after the operation, inhibited plasma and renal NEP gene expression with increased plasma ANP, which caused diuresis, natriuresis and increased renal cGMP generation. Moreover, chronic treatment of those rats by ONO-9902 decreased plasma and renal NEP gene expression, plasma aldosterone, increased plasma ANP but non significantly, and caused diuresis, natriuresis with increased renal cGMP generation. GFR was not significantly changed before or after treatment. Conclusion: Chronic treatment with NEP inhibitor decreases Na and water retention in rats with CHF by enhancing ANP action and suppressing aldosterone secretion. So, ONO-9902 may offer a new therapeutic approach in patients with CHF.
Highlights
Chronic Heart Failure (CHF) is a pathophysiological condition characterized by avid sodium retention with increased cardiac volume and pressure overload, peripheral edema, activation of the Renin-Angiotensin-Aldosterone System (RAAS), adrenergic system and reduced renal function despite elevation of endogenous natriuretic peptides (Palazzuoli and Nuti, 2010)
Acute treatment of Coronary Artery Ligation (CAL) rats with NEPI significantly decreased plasma Neutral EndoPeptidase (NEP) gene expressions (Fig. 1) and increased plasma Atrial Natriuretic Peptide (ANP) level and cGMP whereas it caused no significant change in heart rate, Mean Arterial Pressure (MAP) and Plasma Aldosterone Concentration (PAC)
In rats with CAL after one week, despite the non significant decrease in Glomerular Filtration Rate (GFR), urine volume and sodium excretion significantly decreased which confirmed avid sodium retention (Table 1). In those rats, renal NEP gene expression increased (Fig. 3), urinary ANP non significantly changed whilst renal cGMP generation decreased significantly
Summary
Chronic Heart Failure (CHF) is a pathophysiological condition characterized by avid sodium retention with increased cardiac volume and pressure overload, peripheral edema, activation of the Renin-Angiotensin-Aldosterone System (RAAS), adrenergic system and reduced renal function despite elevation of endogenous natriuretic peptides (atrial and brain natriuretic peptides: ANP and BNP) (Palazzuoli and Nuti, 2010). Plasma concentration of ANP and BNP is elevated (Wei et al, 1993). Previous studies demonstrated that cardiac ANP and BNP mRNA was induced in heart failure. Both peptides become important to counteract the water and sodium retention and to decrease the peripheral vasoconstriction, which are induced in heart failure by an activated reninangiotensin-aldosterone system and by vasopressin (Arnolda et al, 1991)
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