Neutral endopeptidase inhibition enhances substance P mediated inflammation due to hypomagnesemia.
During dietary deficiency of magnesium neurogenic inflammation is mediated, primarily, by elevated levels of substance P (SP). The enzyme most specific for degrading this neuropeptide is neutral endopeptidase (NEP). In recent studies we found that pharmacological inhibition of NEP by phosphoramidon resulted in elevated plasma levels of SP and greater oxidative stress. We also observed that hypomagnesemia reduced cardiac and intestinal expression of NEP. In these magnesium-deficient rats increased intestinal permeability and impaired cardiac contractility occurred. In our colony of genetically-engineered NEP knockout mice that have reduced ability to degrade SP, we found increased oxidative stress that was prevented by SP (neurokinin-1) receptor blockade. Thus, we submit that inhibition of NEP by pharmacological, genetic and dietary approaches (magnesium restriction), causes greater neurogenic inflammation that may result in increased intestinal and cardiac dysfunction.
The Department of Biochemistry & Molecular Biology, 439 Ross Hall, The George Washington University Medical Center, 2300 Eye ST., N.W., Washington, DC 20037, USA. phywbw@gwumc.edu
William B
WB
Weglicki
Joanna J
JJ
Chmielinska
Isabel
I
Tejero-Taldo
Jay H
JH
Kramer
Christopher F
CF
Spurney
Kandan
K
Viswalingham
Bao
B
Lu
I Tong
IT
Mak
D000818:Animals; D006020:Glycopeptides / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D007150:Immunohistochemistry; D007422:Intestines / Q000187:drug effects; D008275:Magnesium Deficiency / Q000150:complications*; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D020078:Neurogenic Inflammation / Q000209:etiology* / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D013373:Substance P / Q000378:metabolism*; D015854:Up-Regulation
D006020:Glycopeptides; D011480:Protease Inhibitors; D013373:Substance P; D015260:Neprilysin; C008890:phosphoramidon