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Published on: January 7, 2019
Inhibition of neutral endopeptidase potentiates neutrophil activation during Mg-deficiency in the rat
I T Mak1, J H Kramer, J J Chmielinska
1Department of Biochemistry & Molecular Biology, Division of Experimental Medicine, George Washington University Medical Center, 2300 Eye St. NW, Ross Hall, Rm 443, Washington, DC 20037, USA. itmak@gwu.edu
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 (approximately 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 .O(2-) 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 .O(2-) production and may promote other inflammatory activities during MgD.
Insights
Magnesium deficiency (MgD) potentiates substance P (SP) levels, and inhibiting neutral endopeptidase (NEP) further elevates SP and enhances neutrophil superoxide generation during MgD.
Area of Science:
- Biochemistry
- Physiology
- Immunology
Background:
- Neutral endopeptidase (NEP) degrades substance P (SP).
- NEP activity may influence neutrophil activation, particularly during magnesium deficiency (MgD).
Purpose of the Study:
- To investigate the role of NEP inhibition in modulating SP levels and neutrophil activation under MgD conditions.
Main Methods:
- Rats were fed Mg-deficient or Mg-sufficient diets for 7 days.
- Some rats received the NEP inhibitor phosphoramidon (PR).
- Plasma SP, neutrophil superoxide generation, PGE2-metabolite, red blood cell glutathione, and neutrophil NEP activity were measured.
Main Results:
- MgD increased plasma SP 9-fold; MgD+PR increased it 18-fold.
- Neutrophils from MgD+PR rats showed significantly higher basal superoxide generation.
- MgD+PR markedly reduced neutrophil NEP activity, while MgD or PR alone had lesser effects.
Conclusions:
- NEP inhibition potentiates SP-mediated neutrophil superoxide production during MgD.
- This suggests NEP plays a critical role in regulating inflammatory responses under magnesium-deficient states.
