Natriuretic and renoprotective effect of chronic oral neutral endopeptidase inhibition in acute renal failure

The prevalence of chronic renal disease is increasing worldwide. Most chronic nephropathies lack a specific treatment and progress relentlessly to end-stage renal disease. However, research in animals and people has helped our understanding of the mechanisms of this progression and has indicated possible preventive methods. The notion of renoprotection is developing into a combined approach to renal diseases, the main measures being pharmacological control of blood pressure and reduction of proteinuria. Lowering of blood lipids, smoking cessation, and tight glucose control for diabetes also form part of the multimodal protocol for management of renal patients. With available treatments, dialysis can be postponed for many patients with chronic nephropathies, but the real goal has to be less dialysis-in other words remission of disease and regression of structural damage to the kidney. Experimental and clinical data lend support to the notion that less dialysis (and maybe none for some patients) is at least possible.

The atrial natriuretic peptide (ANP) plays an important role in chronic heart failure (CHF), delaying the progression of the disease. However, despite high ANP levels, natriuresis falls when CHF progresses from a compensated to a decompensated state, suggesting emergence of renal resistance to ANP. Several mechanisms have been proposed to explain renal hyporesponsiveness, including decreased renal ANP availability, down-regulation of natriuretic peptide receptors and altered ANP intracellular transduction signal. It has been demonstrated that the activity of neutral endopeptidase (NEP) is increased in CHF, and that its inhibition enhances renal cGMP production and renal sodium excretion. In vitro as well as in vivo studies have provided strong evidence of an increased degradation of intracellular cGMP by phosphodiesterase in CHF. In experimental models, ANP-dependent natriuresis is improved by phosphodiesterase inhibitors, which may arise as new therapeutic agents in CHF. Sodium-retaining systems likely contribute to renal hyporesponsiveness to ANP through different mechanisms. Among these systems, the renin-angiotensin-aldosterone system has received particular attention, as angiotensin II and ANP have renal actions at the same sites and inhibition of angiotensin-converting enzyme and angiotensin-receptor blockade improve ANP hyporesponsiveness. Less is known about the interactions between the sympathetic nervous system, endothelin or vasopressin and ANP, which may also blunt ANP-induced natriuresis. To summarize, renal hyporesponsiveness to ANP is probably multifactorial. New treatments designed to restore renal ANP efficiency should limit sodium retention in CHF patients and thus delay the progression to overt heart failure.

To determine the renal, endocrine and haemodynamic effects of an orally active inhibitor of the neutral endopeptidase EC 3.4.24.11 in essential hypertension.