Blockade of cardiac inflammation in Mg2+ deficiency by substance P receptor inhibition.
In previous work we reported the elevation of circulating inflammatory cytokines in rodents maintained on a Mg(2+)-deficient diet. Within the first week of Mg2+ deficiency, significant elevation of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) occurs. The present study was designed to assess the effects of SP receptor blockade by CP-96,945 and its inactive enantiomer CP-96,344 on tissue cytokine levels and in vivo oxidative indexes. CP-96,345 had no significant effect on circulating levels of SP or CGRP; however, at the tissue level, a significant decrease (P < .01) in myocardial accumulation of SP occurred; the inactive enantiomer was only slightly effective. In addition, CP-96,345 significantly reduced (by 53%) the accumulation of tumor necrosis factor-alpha (TNF-alpha) (but not interleukin-1 and interleukin-6) within the lesions; the effect of the enantiomer was insignificant. We conclude that treatment with CP-96,345 inhibits SP and TNF-alpha tissue levels in cardiac lesions, indicating a linkage between this neuropeptide and TNF-alpha. Both SP and TNF-alpha can trigger free radical production; plasma thiobarbituric acid-reactive materials were elevated 2.5-fold and red blood cell reduced glutathione was reduced 55% during Mg2+ deficiency. In the presence of CP-96,345, both indexes of in vivo oxidation were significantly attenuated; the enantiomer was ineffective. These latter observations point to a neuropeptide/TNF-alpha/free radical-triggered mechanism that may be the major pathway of systemic oxidative injury inducing the cardiomyopathic lesions seen during Mg2+ deficiency.
Weglicki
W B
WB
Department of Medicine, George Washington University Medical Center, Washington, DC 20037.
Mak
I T
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Phillips
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TM
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D008275:Magnesium Deficiency / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000187:drug effects* / Q000378:metabolism; D013373:Substance P / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001713:Biphenyl Compounds; D016207:Cytokines; D009479:Neuropeptides; D018040:Receptors, Neurokinin-1; D017392:Thiobarbituric Acid Reactive Substances; D014409:Tumor Necrosis Factor-alpha; D013373:Substance P; D005978:Glutathione; D015740:Calcitonin Gene-Related Peptide; C066892:CP 96345