Decreased neutral endopeptidase (NEP) activity in cardiac neurogenic inflammation due to magnesium deficiency

Abstract

Earlier studies have reported elevated levels of substance P (SP) in blood and cardiac tissues of magnesium-deficient (MgD) rodents. Since substance P is a major mediator of neurogenic inflammation we sought to examine the possible role of NEP (neprilysin), a cell surface metalloproteinase known to be the principal substance P-degrading enzyme. Rats kept on MgD diet (9%RDA) for 1 week were sacrificed, hearts removed and snap-frozen. Ventricular and atrial tissue sections were immunohistochemically stained for NEP. Neprilysin-specific staining was primarily localized to vascular and peri-vascular structures. Treatment with phosphoramidon, a specific inhibitor of NEP, resulted in substantially decreased staining in the vasculature in both treated and untreated MgD cardiac tissue. Concomitantly, we found a 3-fold (p<0.05) increase in superoxide production by WBCs isolated from the phosphoramidon treated MgD rats in comparison to controls. Prior studies have shown inactivation of NEP by reactive oxygen species. We hypothesize that the systemic oxidative stress induced by Mg-deficiency may decrease NEP activity due to oxidative damage. This study was supported by USPHS NIH grants: HL-65178, and HL-62282.