Rats maintained for 12 weeks on diets moderately or more severely deficient in magnesium showed significant elevations in arterial blood pressure compared to control animals. Examination of the mesenteric microcirculation in situ revealed that dietary magnesium deficiency resulted in reduced capillary, postcapillary, and venular blood flow concomitant with reduced terminal arteriolar, precapillary sphincter, and venular lumen sizes. The greater the degree of dietary magnesium deficiency the greater the reductions in microvascular lumen sizes. These findings may provide a rationale for the etiology, as well as treatment, of some forms of hypertensive vascular disease.

Contractility of all types of invertebrate and vertebrate muscle is dependent upon the actions and interactions of two divalent cations, viz, calcium (Ca2+) and magnesium (Mg2+) ions. The data presented and reviewed herein contrast the actions of several organic Ca2+ channel blockers with the natural, physiologic (inorganic) Ca2+ antagonist, Mg2+, on microvascular and macrovascular smooth muscles. Both direct in vivo studies on microscopic arteriolar and venular smooth muscles and in vitro studies on different types of blood vessels are presented. It is clear from the studies done so far that of all Ca2+ antagonists examined, only Mg2+ has the capability to inhibit myogenic, basal, and hormonal-induced vascular tone in all types of vascular smooth muscle. Data obtained with verapamil, nimopidine, nitrendipine, and nisoldipine on the microvasculature are suggestive of the probability that a heterogeneity of Ca2+ channels, and of Ca2+ binding sites, exists in different microvascular smooth muscles; although some appear to be voltage operated and others, receptor operated, they are probably heterogeneous in composition from one vascular region to another. Mg2+ appears to act on voltage-, receptor-, and leak-operated membrane channels in vascular smooth muscle. The organic Ca2+ channel blockers do not have this uniform capability; they demonstrate a selectivity when compared with Mg2+. Mg2+ appears to be a special kind of Ca2+ channel antagonist in vascular smooth muscle. At vascular membranes it can (i) block Ca2+ entry and exit, (ii) lower peripheral and cerebral vascular resistance, (iii) relieve cerebral, coronary, and peripheral vasospasm, and (iv) lower arterial blood pressure. At micromolar concentrations (i.e., 10-100 microM). Mg2+ can cause significant vasodilatation of intact arterioles and venules in all regional vasculatures so far examined. Although Mg2+ is three to five orders of magnitude less potent than the organic Ca2+ channel blockers, it possesses unique and potentially useful Ca2+ antagonistic properties.

In this study, we have examined the effects of variation in dietary Mg on the atherogenic process. Oral supplementation of rabbits fed a high cholesterol diet (1% or 2%) with the Mg salt magnesium aspartate hydrochloride (Magnesiocard) (i) lowers the level of serum cholesterol and triglycerides in normal (25-35%) as well as atherosclerotic (20-40%) animals and (ii) attenuates the atherosclerotic process markedly. In addition, we found that dietary deficiency of Mg augments atherogenesis markedly and stimulates (or activates) macrophages of the reticuloendothelial system. Evidence is presented to indicate that the hypercholesterolemic state may cause the loss of Mg from soft tissues to the serum, thereby masking an underlying Mg deficiency.Hypercholesterolemia has been widely accepted as a high risk factor for development of atherosclerosis and ischemic heart disease (IHD) (1-3), particularly since cholesterol-rich diets lead to deposition of lipids in blood vessel walls and an atherosclerotic-like state in experimental animals (4-6). Increased blood levels of lipoproteins are thought to eventually lead to endothelial cell injury or denudation with concomitant uptake of the former molecules (7,8), increased permeability to calcium ions (Ca2") (9), invasion of the arterial wall by macrophages (10-12), and altered smooth muscle cells (7,8,13). It is, however, not clear how the lipoproteins and Ca2+ gain access to the normally and relatively impermeable arterial walls (4-13).Approximately 20 years ago, it was suggested on the basis of epidemiologic findings that the incidence of IHD was highest in geographic regions with soft drinking water (14). Of the minerals that are deficient in soft water, magnesium (Mg) is the only element that has been found to be consistently lowered in cardiac muscle of IHD victims (for reviews, see refs. 15 and 16 (15,16,20,28).Recent emphasis on the potential importance of nutritional factors and preventive rather than palliative medicine in the approach to etiology and treatment of cardiovascular disease led us to examine the effects of a possible "hidden" Mg deficiency as well as the potential benefits of Mg supplementation on the development of atherosclerosis induced by high cholesterol diets in rabbits. We report here that dietary deficiency of Mg (compatible with the reduced dietary intake of Mg seen in the adult population of the Western World; see refs. 29-31), which often is not reflected by serum analysis, exacerbates atherogenesis and stimulates (or activates) macrophages of the reticuloendothelial system (RES). In addition, we demonstrate that pretreatment of animals with orally administered magnesium aspartate hydrochloride (Magnesiocard) (i) attenuates the atherosclerotic process markedly and (ii) lowers serum cholesterol and triglycerides in normal as well as in some atherosclerotic animals. Finally, evidence is presented to indicate that a high serum cholesterol seems to obscure the Mg deficiency that is present in the atherosclerotic animal. METHODS Animals and ...

In several previous experiments to determine the composition of interstitial fluid, the results varied depending on the collecting technique, and the electrolyte concentrations differed from those of a hypothetical ultrafiltrate of plasma. In our approach, since a change of position from standing to supine is accompanied by hemodilution with interstitial fluid, we used the changes in hematocrit and composition of plasma in 20 subjects before and after lying down to calculate the composition of added interstitial fluid. The estimated protein concentration was 20.6 g/L, and the concentrations of total calcium and magnesium were low, in accord with a lower concentration of protein-bound calcium and magnesium. The activity of free cations was also lower, in agreement with a Donnan equilibrium potential of 1 mV across the endothelium. The concentration of leukocytes and platelets decreased according to the hemodilution, implying no escape or mobilization of these elements.

To investigate alterations of magnesium metabolism in Type 2 (non-insulin-dependent) diabetes mellitus, we utilized a new magnesium-specific selective ion electrode apparatus to measure serum ionized magnesium (Mg-io) in fasting subjects with and without Type 2 diabetes, and compared these values to levels of serum total magnesium, and of intracellular free magnesium (Mgi) analysed by 31P-NMR spectroscopy. Both Mg-io (0.630 +/- 0.008 vs 0.552 +/- 0.008 mmol/l, p < 0.001) and Mgi (223.3 +/- 8.3 vs 184 +/- 13.7 mmol/l, p < 0.001), but not serum total magnesium, were significantly reduced in Type 2 diabetes compared with non-diabetic control subjects. Furthermore, a close relationship was observed between serum Mg-io and Mgi (r = 0.728, p < 0.001). We suggest that magnesium deficiency, both extracellular and intracellular, is a characteristic of chronic stable mild Type 2 diabetes, and as such, may predispose to the excess cardiovascular morbidity of the diabetic state. Furthermore, by more adequately reflecting cellular magnesium metabolism than total serum magnesium levels, Mg-io measurements may provide a more readily available tool than has heretofore been available to analyse magnesium metabolism in a variety of diseases.

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In this review, a rationale is presented for how hypercholesterolemia, hypertension, diabetes mellitus (DM), end-stage renal disease (ESRD), prolonged stress, and exposure to magnesium (Mg)-wasting drugs can lead to atherosclerosis, ischemic heart disease, and stroke. The data, accumulated so far, indicate that Mg defi ciency caused either by a poor diet or errors in Mg metabolism may be a missing link between diverse cardiovascular risk factors and atherogenesis. Early data from our laboratory and others indicate that reduction in extracellular free Mg ions can induce an entire array of pathophysiological phenomena known to be important in atherogenesis, that is, vasospasm, hypoxia, increased vascular reactivity, and elevation in intracellular calcium (Ca). More recent data has demonstrated molecular events, pointing the way to atherogenesis: that is, formation of pro-infl ammatory agents, generation of free radicals, platelet aggregation, modulation of macrophage and leukocyte mobility, and emigration across the endothelial wall. Finally, oxidation of lipoproteins, changes in membrane fatty acid saturation, changes in membrane plasmalogens, and N-phospholipids suggest alterations in intracellular lipid signals. It has been shown that Mg defi ciency can modulate membrane sphingomyelinase, generate vasoactive and pathogenic sphingolipids, which could alter multiple intracellular signaling pathways, modulate transcription factors, and thus cause intimal plaque formation.Hypercholesterolemia, hypertension, DM, immune injury, ESRD, renal dialysis, prolonged stress, obesity, and smoking are widely accepted as risk factors for atherosclerosis. No common link has been identifi ed that forms a rational basis to these disorders and atherogenesis. Moreover, it is not clear how lipoproteins, Ca 2+ , and macrophages gain access to the normally impermeable arterial walls or what allows plyable, physiological vascular smooth muscle (VSM) cells to change their state (phenotype) from a contractile to a noncontractile, synthetic cell, 1,2 and how these diverse risk factors lead to ischemic heart disease (IHD) and stroke.Until relatively recently, it was not believed that Mg, a common essential dietary element and electrolyte, played any role in maintaining normal cardiovascular dynamics. This lack of understanding is most likely a refl ection 239

Ethyl alcohol produced graded contractile responses in rat cerebral arterioles and venules in vivo and in isolated canine basilar and middle cerebral arteries at a concentration range (10 to 500 milligrams per deciliter) which parallels that needed for its graded effects of euphoria, mental haziness, muscular incoordination, stupor, and coma in humans. Two specific calcium antagonists, nimodipine and verapamil, prevented or reversed the alcohol-induced cerebrovasospasm and thus may prove valuable in treating the hypertension and stroke observed in heavy users of alcohol.