Abstract

Substance P receptor blockage has dramatic protective effects against the cardiovascular pathology observed in animals placed on a severe Mg- deficient diet (MgD9 or 9% of RDA for Mg), implicating neurogenic hyper activation as a key event associated with this pathology. Our data suggest that elevated substance P induces production of nitric oxide (NO.) and other active oxygen species which may heighten the sensitivity of MgD9 animals to ischemia/reperfusion (I/R stress. This proposal will determine the minimal dietary threshold level of Mg which continues to elicit similar neurogenic hyperactivity observed with MgD9 diet. Specifically, moderate (40% RDA) and marginal (60-85%) dietary MgD rat models will be used to examine five specific aims: 1) Establish the detection time-courses of circulating and tissue neurogenic events during prolonged Mg deficiency, and the minimal threshold of level of dietary Mg restriction which still causes the cardiovascular pathobiology observed in severe Mg-deficiency; 2) Determine if susceptibility to I/R stress is enhanced by moderate and marginal Mg restricted diets, and the contribution of elevated neuropeptides and N0. synthesis in the injury process; 3) Investigate whether endogenous NMDA receptor activation mediates release of neuropeptides during moderate and marginal MgD, and if this is a calcium-triggered mechanism; 4) Determine if Mg- restriction induces cellular up-regulation of neuropeptide receptors; and 5) Determine if the neurogenic response associated with MgD is a consequence of new synthesis of substance P from neuronal and non- neuronal sources. We hypothesize that less severe MgD diets can induce hyper activation of NMDA receptors causing excessive release of neuronal mediators which enhance cell production of superoxide and NO. in vivo, and reduce the tolerance of animal tissues to applied I/R stress. These studies will provide insight concerning the role of neurogenic inflammation in the cardiovascular pathologic consequences of clinically- achievable Mg-deficiency.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062282-03
Application #
6498988
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Massicot-Fisher, Judith
Project Start
2000-02-01
Project End
2004-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
3
Fiscal Year
2002
Total Cost
$310,591
Indirect Cost

  Institution

Name
George Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Washington
State
DC
Country
United States
Zip Code
20052

  Publications

Mak, I Tong; Kramer, Jay H; Chmielinska, Joanna J et al. (2015) EGFR-TKI, erlotinib, causes hypomagnesemia, oxidative stress, and cardiac dysfunction: attenuation by NK-1 receptor blockade. J Cardiovasc Pharmacol 65:54-61
Weglicki, William B; Kramer, Jay H; Spurney, Christopher F et al. (2012) The EGFR tyrosine kinase inhibitor tyrphostin AG-1478 causes hypomagnesemia and cardiac dysfunction. Can J Physiol Pharmacol 90:1145-9
Mak, I Tong; Chmielinska, Joanna J; Kramer, Jay H et al. (2011) Loss of neutral endopeptidase activity contributes to neutrophil activation and cardiac dysfunction during chronic hypomagnesemia: Protection by substance P receptor blockade. Exp Clin Cardiol 16:121-4
Weglicki, William B; Mak, Iu Tong; Chmielinska, Joanna J et al. (2010) The role of magnesium deficiency in cardiovascular and intestinal inflammation. Magnes Res 23:S199-206
Kramer, Jay H; Spurney, Christopher; Iantorno, Micaela et al. (2009) Neurogenic inflammation and cardiac dysfunction due to hypomagnesemia. Am J Med Sci 338:22-7
Weglicki, William B; Chmielinska, Joanna J; Tejero-Taldo, Isabel et al. (2009) Neutral endopeptidase inhibition enhances substance P mediated inflammation due to hypomagnesemia. Magnes Res 22:167S-173S
Weber, Karl T; Weglicki, William B; Simpson, Robert U (2009) Macro- and micronutrient dyshomeostasis in the adverse structural remodelling of myocardium. Cardiovasc Res 81:500-8
Mak, I T; Kramer, J H; Chmielinska, J J et al. (2008) Inhibition of neutral endopeptidase potentiates neutrophil activation during Mg-deficiency in the rat. Inflamm Res 57:300-5
Scanlan, Bradford J; Tuft, Blaine; Elfrey, Justin E et al. (2007) Intestinal inflammation caused by magnesium deficiency alters basal and oxidative stress-induced intestinal function. Mol Cell Biochem 306:59-69
Tejero-Taldo, Maria Isabel; Kramer, Jay Harlan; Mak, Iu Tong et al. (2006) The nerve-heart connection in the pro-oxidant response to Mg-deficiency. Heart Fail Rev 11:35-44

Showing the most recent 10 out of 19 publications