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 ·O2- generation, but those from MgD or PR alone were not activated. Plasma PGE2-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 ·O2- production and may promote other inflammatory activities during MgD.

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Angiotensin may promote endothelial dysfunction through iron accumulation. To research this, bovine endothelial cells (ECs) were incubated with iron (30 μmol·L−1) with or without angiotensin II (100 nmol·L−1). After incubation for 6 h, it was observed that the addition of angiotensin enhanced EC iron accumulation by 5.1-fold compared with a 1.8-fold increase for cells incubated with iron only. This enhanced iron uptake was attenuated by losartan (100 nmol·L−1), D-propranolol (10 μmol·L−1), 4-HO-propranolol (5 μmol·L−1), and methylamine, but not by vitamin E or atenolol. After 6 h of incubation, angiotensin plus iron provoked intracellular oxidant formation (2′7′-dichlorofluorescein diacetate (DCF-DA) fluorescence) and elevated oxidized glutathione; significant loss of cell viability occurred at 48 h. Stimulated prostacyclin release decreased by 38% (6 h) and NO synthesis was reduced by 41% (24 h). Both oxidative events and functional impairment were substantially attenuated by losartan or D-propranolol. It is concluded that angiotensin promoted non-transferrin-bound iron uptake via AT-1 receptor activation, leading to EC oxidative functional impairment. The protective effects of D-propranolol and 4-HO-propranolol may be related to their lysosomotropic properties.

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