Activation of pulmonary neutral endopeptidase in experimental congestive heart failure

Neutral Endopeptidase 24.11 (NEP) is a zinc metalloprotease which degrades the Natriuretic Peptides, ANP, BNP, and CNP and may limit their biological actions which include natriuresis, renin inhibition, vasodilitation and anti-mitogenesis. While inhibition of NEP has been proposed as a novel pharmacological approach in the treatment of hypertension and congestive heart failure (CHF), little information exists regarding the presence and activity of NEP in normal and diseased tissue. The objective of the current study is to quantify NEP activity in the left ventricle (LV) and lung under normal conditions and in experimental CHF utilizing a canine model of rapid ventricular pacing, and to visualize NEP activity by immunohistochemistry. NEP activity (pmol/min/mg protein) was measured utilizing a combined enzymatic-fluorometric assay. CHF (n=5) was characterized by LV dysfunction (EF 21±2%) LV dilatation (LVEDd 48±1 mm), increased LV mass-index (4.5±0.1 gr.kg.) and decreased mean arterial pressure (85±3 mmHg.). In control tissue (n=4), NEP activity was present in LV (16±10 pmol/min/mg protein) and lung (31±8 pmol/min/mg protein, p=n.s.). While NEP activity in LV tissue demonstrated a tendency to decrease during CHF (4.3±0.5 pmol/min/mg protein, p=n.s.), pulmonary NEP activity increased (65±11, p=0.05 vs control). Immunohistochemistry revealed that staining in CHF is localized to ventricular myocytes and pulmonary endothelial and epithelial cells. These studies support the concent of a differential regulation of NEP activity in cardiopulmonary tissue during CHF.