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CARDIOVASCULAR

N-Methyl-D-aspartate Receptor Blockade Inhibits Cardiac Inflammation in the Mg²+-Deficient Rat

Division of Experimental Medicine, Departments of Biochemistry and Molecular Biology (M.I.T., J.J.C., I.T.M., W.B.W.), Neurosurgery (G.G.), and Medicine (W.B.W.), George Washington University Medical Center, Washington, DC

Elevated plasma levels of the neuropeptide substance P (SP) precede the perivascular inflammatory infiltrate seen in hearts of Mg²⁺-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 Mg²⁺. 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 Mg²⁺ or deficient with only 9% of USDA-recommended Mg²⁺. 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 E₂ 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 Mg²⁺ deficiency.

Address correspondence to: Dr. M. Isabel Tejero, Division of Experimental Medicine, Department of Biochemistry and Molecular Biology, George Washington University Medical Center, 2300 I St., NW, Washington, DC 20037. E-mail: phymit{at}gwumc.edu

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