Abstract
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.
Footnotes
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This study was supported by the National Institutes of Health National Heart, Lung, and Blood Institute Grant HL-62282. Results from this study were partially presented at the International Society for Heart Research 2003 North American Section meeting in Mystic, CT: Tejero-Taldo MI, Chmielinska J, Gonzalez G, Ghouse RR, Mak IT, and Weglicki WB (2003) NMDA receptor blockade abolishes cardiac inflammation in the Mg-deficient rat (Abstract). J Mol Cell Cardiol35:A21.
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doi:10.1124/jpet.104.070003.
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ABBREVIATIONS: MgD, Mg2+ deficiency; RDA, recommended daily allowance; DRG, dorsal root ganglion; NMDA, N-methyl-d-aspartate; PGE2, prostaglandin E2; RBC, red blood cell; ICAM, intercellular adhesion molecule.
- Received April 15, 2004.
- Accepted May 27, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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