N-methyl-D-aspartate receptor blockade inhibits cardiac inflammation in the Mg2+-deficient rat.
Elevated plasma levels of the neuropeptide substance P (SP) precede the perivascular inflammatory infiltrate seen in hearts of Mg(2+)-deficient (MgD) animals. The N-methyl-d-aspartate (NMDA) receptor is found in neurons, and activation of this receptor participates in SP release; under normal circumstances, this release can be blocked by Mg(2+). Therefore, we reasoned that blockade of the NMDA receptor with dizolcipine maleate (a noncompetitive NMDA receptor antagonist) would prevent SP release from C-fibers due to MgD. In this study, animals were implanted with slow-release pellets containing dizolcipine or placebo and were fed with diet sufficient in Mg(2+) or deficient with only 9% of USDA-recommended Mg(2+). SP immunostaining of dorsal root ganglia showed a time-dependent depletion of SP in the MgD animals, with a dramatic decrease of SP by week 2; this depletion was prevented by pretreatment with dizolcipine maleate. The significant increase in plasma prostaglandin E(2) levels during MgD was prevented by dizolcipine, and the loss of total red blood cell glutathione content was significantly attenuated by NMDA blockade after 3 weeks of MgD (p < 0.01 versus controls). Immunohistochemical and Western blot analyses of ventricular tissue demonstrated that NMDA receptor blockade abolished MgD-related increase of endothelium adhesion molecule CD54 (weeks 1 and 2; p < 0.05), and of monocyte/macrophage surface protein CD11b expression (week 3; p < 0.05). We conclude that NMDA receptor blockade with dizolcipine maleate prevented SP depletion and reduced perivascular inflammatory infiltrates, thus decreasing cardiac injury due to Mg(2+) deficiency.
Tejero-Taldo
M Isabel
MI
Division of Experimental Medicine, Department of Biochemistry and Molecular Biology, George Washington University Medical Center, 2300 I St., NW, Washington, DC 20037, USA. phymit@gwumc.edu
Chmielinska
Joanna J
JJ
Gonzalez
Grace
G
Mak
I Tong
IT
Weglicki
William B
WB
D000818:Animals; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology / Q000627:therapeutic use*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D005455:Fluorescent Antibody Technique; D006331:Heart Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007249:Inflammation / Q000517:prevention & control; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008275:Magnesium Deficiency / Q000150:complications*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013312:Stress, Physiological / Q000209:etiology; D013373:Substance P / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D018799:Intercellular Adhesion Molecule-1; D013373:Substance P; D016291:Dizocilpine Maleate