R. E. Stafford

Role of free radicals and substance P in magnesium deficiency

In the United States the literature contains only sporadic references to clinical disorders of Mg-deficiency, compared to more recent interest in the benefits of magnesium infusion in myocardial infarction and other acute clinical conditions [1,2]. In Europe the clinical interest in Mg-deficiency was pioneered by Durlach in his book entitled Le Magnesium en Prutique Clinique; the English edition was entitled Magnesium in Clinical Practice [3]. In the conclusion of his book, Durlach stated: “This ion which is present in all the cells is involved in many different pathologies. Integrating a search for the disorders of magnesium metabolism in daily diagnostic processes allows determination of the indications and precise methods of magnesium therapy.” In the United States, Seelig authored a text in 1980 entitled Magnesium Dejicicncy in the Parhogerzesis sf Disease [4] and reviewed the literature concerning magnesium requirements in human nutrition and the association of magnesium deficiency with cardiovascular disease [s]. That same year Wacker published an excellent book entitled Mugnesium und Mm in which he emphasized the clinical relevance of magnesium 161. Six decades ago MacCollum [7l studied the effects of Mg-deficiency on development, reproduction, neuromuscular and humoral abnormalities in animals. In 1959 Bajusz and Selye published a paper describing the influence of electrolytes in the process of myocardial injury [8]. More recently, Lehr focused attention on magnesium and the process of cardiac necrosis [9], or cardiomyopathic lesions which had been described earlier [lo]. B.T. Altura and B.M. Altura published a series of papers which postulated

Neurogenic peptides and the cardiomyopathy of magnesium-deficiency: Effects of substance P-receptor inhibition

Dietary deficiency of magnesium (Mg) in rodents results in cardiomyopathic lesion formation. In our rat model, these lesions develop after 3 weeks on the Mg-deficient diet; significant elevation of several cytokines, IL-1, IL-6 and TNFα also occurs. In probing the mechanisms of lesion formation, we obtained data supporting the participation of free radicals (Freedman AMet al.: Bioch Biophys Res Commun 1990; 170: 1102). Recently, we identified an early elevation of circulating substance P and proposed a role of neurogenic peptides during Mg-deficiency (Weglicki WB, Phillips TM: Am J Phys 1992; 262: R734). The present study was designed to evaluate the contribution of neurogenic peptides to the pathogenesis of Mg-deficiency. In the blood, substance-P and calcitonin gene related peptide (CGRP) are elevated during the first week on the diet. During the second week, circulating histamine, PGE2 and TBAR-materials were elevated and red cell glutathione was reduced, all prior to the elevation of the inflammatory cytokines during the third week. When the rats were treated with the substance P-receptor blocker [CP-96,345], the levels of substance P and CGRP remained elevated; however, increases in histamine, PGE2, TBAR-materials, and the decrease in red cell glutathione were inhibited; also, the development of cardiac lesions was inhibited significantly. These data support a central role for neurogenic peptides, especially substance P, in the development of cardiomyopathic lesions during Mg-deficiency.

Cytokines, Neuropeptides, and Reperfusion Injury during Magnesium Deficiency a

In summary, hypomagnesemia enhances reperfusion injury. We postulate that neurogenic inflammation, which occurs very early during hypomagnesemia, predisposes the myocardium to reperfusion injury by depleting endogenous antioxidants and recruiting inflammatory cells, which can participate in enhanced free radical production during postischemic reperfusion. Vitamin E supplements can prevent the occurrence of this enhanced injury possibly through the restoration of endogenous antioxidant defenses.

Marked alterations in circulating inflammatory cells during cardiomyopathy development in a magnesium-deficient rat model

Rodents fed on a Mg-deficient (Mg-D) diet develop cardiomyopathic lesions, as well as other types of cardiovascular dysfunction. In the rat, inflammatory cell infiltration of the myocardium begins to occur by week 1, and the lesions develop extensively in the third and fourth weeks on the Mg-D diet. Although the aetiologic mechanisms of Mg-D cardiomyopathy are unknown, we have previously reported that once plasma Mg is markedly reduced, one of the earliest molecular markers of the pathophysiological process is elevation of plasma substance P, calcitonin gene-related peptide and prostaglandin E2, followed by histamine and the inflammatory cytokines (interleukin-1, interleukin-6, and tumor necrosis factor-alpha). In order to evaluate the potential role of specific circulating inflammatory cell subpopulations in the mechanisms underlying pathophysiological changes observed in Mg-deficiency-induced cardiomyopathy, we analysed these cells by flow cytochemistry. Leucocyte subpopulation pools increased progressively in the Mg-D rats. Elevated circulating levels of neutrophils and lymphocytes appeared to contribute to both the acute (week 1-2) and chronic phases (week 3-4) of the inflammatory responses; monocytes, eosinophils, basophils and large unstained cells which are lymphoid in stained smears, on the other hand, increased significantly in the third and fourth weeks and thus contributed to the chronic inflammatory phase. Changes in the circulating leucocyte subpopulations paralleled the chronological progression of the cardiomyopathic lesions, particularly in weeks 3 and 4. Since a pronounced neutrophilia preceded leucocyte infiltration and deposition within the myocardial tissue, modifications of the microvascular barrier may be a prerequisite for cardiomyopathy in this model of neurogenic inflammation.

Inhibition of tumor necrosis factor-alpha by thalidomide in magnesium deficiency.

The effect of thalidomide on circulating cytokines and myocardial lesion formation was investigated in Mg-deficient rats. After two weeks on a Mg-deficient diet, rats show an increase in circulating levels of tumor necrosis factor-alpha and interleukin 1. Thalidomide (1 mg/day) caused a complete inhibition of the increase in circulating tumor necrosis factor-alpha levels, without having an effect on interleukin 1. However, a marked increase in cardiomyopathic lesion formation was observed in Mg-deficient animals treated with thalidomide; possible mechanisms for thalidomides enhancement of myocardial injury are discussed. (Mol Cell Biochem129: 195–200, 1993)

Role of Tissue and Circulating Substance P in Cardiovascular Injury Associated with Mg-Deficiency

Hypomagnesemia is a common electrolyte deficiency found among hospitalized patients and is particularly prevalent in selected patient populations, such as alcoholics, diabetics, and those receiving diuretics and other magnesium-wasting drugs. Clinical complications as a result of magnesium deficiency were documented in a recent prospective study in which hypomagnesemia, which was present at the time of admission of critically ill patients, was associated with a statistically significant higher mortality rate [1]. Magnesium deficiency has also been associated with adverse cardiovascular conditions, such as sudden death, ventricular and atrial arrhythmias, coronary spasm, and cardiomyopathies. In one study of patients with heart disease, 45% of patients with myocardial infarction were reported to be hypomagnesemic [2].