Inhibition of neutral endopeptidase potentiates neutrophil activation during Mg-deficiency in the rat.
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.
Mak
I T
IT
Department 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
Kramer
J H
JH
Chmielinska
J J
JJ
Khalid
M H
MH
Landgraf
K M
KM
Weglicki
W B
WB
D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000737:chemistry; D008274:Magnesium / Q000737:chemistry*; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D013373:Substance P / Q000378:metabolism
D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D013373:Substance P; D015260:Neprilysin; D005978:Glutathione; D008274:Magnesium