Modulation of circulating substance P in Mg‐deficient (MgD) rats by NMDA receptor and neutral endopeptidase inhibitors

Abstract

Changes in dietary Mg intake influences rat plasma levels of the proinflammatory neuropeptide, substance P (SP), and was associated with altered cardiac tolerance to postischemic stress (Exp Biol Med 228, 2003). In this study, the impact of NMDA receptor inhibition (MK-801, 0.5 mg/kg/day, s.c. pellet) and neutral endopeptidase inhibition (phosphoramidon [PR], 5 mg/kg/day, s.c. pellet) on plasma SP levels were assessed (ELISA) in MgD (Mg = 9% RDA) rats, along with changes in in vivo oxidative stress (RBC GSH loss). During wk 1, MgD alone induced a substantial elevation in SP (0.59 ng/ml/wk) vs Mg-normal rats. PR-treatment of MgD rats during wk 1 led to a further 1.9-fold increase in SP (1.13 ng/ml/wk) and caused a 2-fold greater loss in GSH vs MgD alone. By contrast, continuous MK-801 treatment during 3 wks of MgD caused an overall 49 % reduction in SP vs untreated, but MK-801’s impact was greatest during wk 1 (89 % lower) vs wk 2 (51 %) and wk 3 (30 %). MK-801 treatment of 2 and 3 wk MgD rats led to 38 and 56 % higher GSH levels vs MgD alone, indicating attenuation of oxidative stress. Thus, in addition to a dietary approach (Mg intake), modulating plasma SP levels during MgD by targeted inhibition of neuronal SP release (MK-801) or SP degradation (PR) can also influence the severity of in vivo oxidative stress, and may ultimately impact subsequent cardiac susceptibility to secondary (postischemic) stress. NIH-HL-66226 & HL-65178.