Inhibition of neutral endopeptidase potentiates neutrophil activation during Mg-deficiency in the rat

Abstract.

Neutral endopeptidase (NEP), which degrades substance P (SP), may regulate neutrophil activation during Mg-deficiency (MgD). Male Sprague-Dawley rats (180g) were fed MgD (~50 mg Mg/kg) or Mg-sufficient (MgS, 608 mg Mg/kg) diets for 7 days ± NEP inhibitor phosphoramidon (PR, 5 mg/kg/day, s.c.). MgD alone induced a 9-fold (vs. MgS, p <0.01) elevation in plasma SP; MgD+PR enhanced it further to 18-fold (p <0.001). Neutrophils from MgD+PR rats displayed a 3.9-fold higher (p <0.01) basal ${\rm O}_{2^-}$ generation, but those from MgD or PR alone were not activated. Plasma ${\rm PGE}_{2^-}$metabolite levels rose 2.67- (p <0.01) and 1.56- (p <0.05) fold, respectively, in MgD+PR and MgD groups; the corresponding red blood cell glutathione levels were decreased 21% (p <0.025) and 7% (NS). MgD+PR significantly reduced neutrophil NEP activity by 48% (p <0.02); PR or MgD alone only reduced this activity 26% and 15%, respectively. We conclude that NEP inhibition potentiates SP-mediated neutrophil ${\rm O}_{2^-}$ production and may promote other inflammatory activities during MgD.