BLOCKADE OF CARDIAC INFLAMMATION IN MG2-P RECEPTOR INHIBITION( DEFICIENCY BY SUBSTANCE)

In previous work we reported the elevation of circulating inflammatory cytokines in rodents maintained on a Mg2+-deficient diet. Within the first week of Mg2+ deficiency, significant elevation of the neuropepti des 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 signif icant effect on circulating levels of SP or CGRP; however, at the tiss ue 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 in terleukin-6) within the lesions; the effect of the enantiomer was insi gnificant. We conclude that treatment with CP-96,345 inhibits SP and T NF-alpha tissue levels in cardiac lesions, indicating a linkage betwee n this neuropeptide and TNF-alpha. Both SP and TNF-alpha can trigger f ree radical production; plasma thiobarbituric acid-reactive materials were elevated 2.5-fold and red blood cell reduced glutathione was redu ced 55% during Mg2+ deficiency. In the presence of CP-96,345, both ind exes of in vivo oxidation were significantly attenuated; the enantiome r was ineffective. These latter observations point to a neuropeptide/T NF-alpha/free radical-triggered mechanism that may be the major pathwa y of systemic oxidative injury inducing the cardiomyopathic lesions se en during Mg2+ deficiency.