Received on: May 14, 2018
Accepted on: June 19, 2018
Published on: July 02, 2018
*Corresponding author: Burton M Altura, Department of Physiology and Pharmacology, State University of New York, Brooklyn, New York, USA. E-mail: email@example.com; Tel: 718-270-2194
Of all drugs, alcohol (i.e. ethanol) is the most abused drug and is responsible for countless deaths and hospitalizations worldwide each year. In the USA, alone, excessive alcohol drinking accounts for about 10,000 deaths per year. Alcohol drinking is a major risk factor for irreversible brain damage and strokes. Excessive drinking over years results, in a high-degree of dementia in human subjects. Alcoholic-induced dementia is very similar to Alzheimer’s disease. It results in poor-judgment, confusion, decreased cognitive abilities, and memory loss. One of the major effects of heavy alcohol drinking and alcohol-induced dementia is development of what has been termed, the “Wernicke-Korsakoff syndrome”. In this syndrome, the patient presents with “Korsakoff psychoses”, causing hallucinations, thought by some to be a consequence of thiamine deficiency. But, this cause is disputed by many investigators.
Of the many minerals in the body that is most affected by alcohol drinking, it is magnesium (Mg). Although numerous drugs can deplete the body’s tissues and cells of Mg, ethanol is the greatest depletory of Mg [1, 2, 3, 4, 5, 6]. It also is the number-one drug which can reduce intracellular levels of free , ionized Mg (Mg2+) in minutes, particularly in cerebral brain cells (e.g. astrocytes, endothelial cells, vascular smooth muscle cells , and all types of neurons studied to date) [4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15].
Alcohol abuse leads to primary malnutrition that is a deficient utilization of nutrients. Alcoholic beverages provide what is termed “empty” calories because ethanol does not contain significant amounts of proteins, vitamins, or minerals. An individual who consumes 5 to 30 ounces of 86-proof (43% v/v ethanol) beverage will ingest from 375 to 2,250 empty calories. In other terms, this represents from as little as 15% of the normal daily caloric requirements to 100%. The end result of such intake is a decreased intake of other foods and results in an imbalance of daily nutrient ingestion. Serum hypomagnesaemia occurs in from 30 to 60% of the alcoholic population [1, 2, 3, 4, 5, 6]. Nearly 90% of patients undergoing alcohol withdrawal are hypomagnesemic and at high-risk for strokes and hallucinations.
Overall, looking at many clinical studies, there is a clear relationship between heavy alcohol ingestion (i.e., 3-5 drinks/day), sudden –cardiac death (SCD), and dementia [16, 17, 18, 19]. However, very few of these alcoholinduced deaths are ever autopsied, so it is impossible to determine how many of these subjects had severe brain damage and underwent strokes or stroke-like events. Less than 5% of all deaths in the USA ever result in a complete autopsy. From the available data, it is also apparent there is a clear relationship between “binge drinking “and SCD. Again, since autopsies are seldom done, how many of these deaths are related to potential brain damage and stroke-like events? In those subjects that have been autopsied, the only findings often found at “post mortem” are fatty livers of typical alcohol ingestion, often leading pathologists, inaccurately, to term the SCD to alcoholinduced liver toxicity. In many of these victims, pathologists failed to make fine histological sections of key areas of the brain, e.g., medulla oblongata, cerebral hemispheres, pons, hypothalamus, etc., which might have picked-up signs of stroke-like events. “Binge drinking” (more than 80g alcohol ingested in< 24 hrs) can result in intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), and cerebral infarctions. Particularly alarming, are the numbers of reports suggesting that even moderate drinking elevates the risk for ICH and SAH [20, 21, 22, 23].
Over the past three decades, evidence has accumulated to indicate that daily dietary deficiency in Mg intake and/or errors in Mg metabolism pose serious risks for development of SCD, coronary artery spasm, myocardial infarction, and brain damage [24, 25, 26, 27, 28, 29, 30, 31, 32, 33]. Using perfused, working rat hearts, Ca2+ imaging, optical imagingspectroscopy and 31P-NMR spectroscopy, as well as invitro studies, we found that low levels of Mg2+ result in reductions in coronary flows, reduction in cardiac output, reductions in stroke volume and peak systolic pressure development, reduction in myocardial intracellular Mg2+ levels, reduction in myocardial levels of ATP, increased levels of intracellular inorganic phosphate, acidification of atrial and ventricular myocytes, Ca2+ overload, coronary vasospasm, increases in free myoglobin, rises in inorganic phosphate, increases in mitochondrial reduced cytochrome C, and generation of reactive oxygen and nitrogen species [34, 35, 36, 37, 38]. Interestingly, we reported very similar results when rat hearts were exposed to increasing concentrations of ethanol, both in-vivo and in-vitro [12, 38, unpublished findings]. Examination of rat and canine brains using 31P-NMR spectroscopy, optical spectroscopy and Ca2+- imaging, which were exposed to increasing doses of alcohol, also resulted in Mg2+ deficiency, Ca2+ overload, reduction in levels of cellular ATP, increased levels of reduced cytochrome oxidize, increased levels of inorganic phosphate, increased levels of deoxyhemoglobin, acidification of neurons, astrocytes and cerebral vascular smooth muscle cells, and generation of reactive oxygen and nitrogen species in the cerebral cortex, hippocampus, pyramidal cells, and the medulla oblongata [4, 5, 7, 9, 11, 13, 20, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, unpublished findings].
Relationship of Mg to Alcohol Intoxication, Cerebral Vascular and Parenchymal Stability, Strokes and Brain Damage
From the foregoing, it is now obvious that drinking of alcohol poses serious risks not only for the heart, but the brain as well. Much of this danger appears to be a consequence of Mg depletion. It has been known for more than 40 years that ingestion of alcoholic beverages results in body depletion of Mg [17, 18]. But, what is so special and important about this mineral, Mg? Mg is a co-factor for more than 500 enzymes in the body, and is the second most abundant intracellular action after potassium. It is vital in numerous physiological, cellular and biochemical reactions including carbohydrate, lipid, protein, DNA and RNA metabolism, among many, many other pathways [26, 60]. Several epidemiological studies in North America and Europe have shown that people consuming Western-type diets are low in Mg content (i.e., 30-60% of Americans are consuming only 185-235 mg/day of Mg [61, 62, 63, 64]. In contrast, in 1900, most Americans were consuming 450- 550 mg/day of Mg . Low Mg content of drinking water, found in areas of soft-water and Mg-poor soil is associated with high incidences of IHD, atherosclerosis, coronary artery vasospasm, hypertension, strokes, and SCD [24, 25, 26, 27, 65, 66, 67, 68, 69]. The myocardial level of Mg has consistently been observed to be lower in subjects dying from IHD and SCD in soft-water areas than those living in hard-water areas [24, 25, 26, 27, 61, 65, 70]. It is of considerable interest to note, here, that we have found that strokes in humans, brain trauma (with and without alcohol intoxication) as well as Mg- deficient rats, and alcohol-induced hemorrhagic strokes in rats, all have shown deficits in brain and blood ionized Mg levels [4, 5, 7, 9, 11, 13, 20, 41, 43, 44, 47, 48, 53, 71, 72, unpublished findings]. Vink and his colleagues, in extensive animal and human studies, have also reported that brain trauma and injury resulted in deficits in brain tissue and serum Mg [73, 74]. Removal of hippocampal brain slices from Mg-deficient rats showed deficits in neuronal cell Mg, elevated Ca2+, reduced ATP, and elevated inorganic phosphate [unpublished findings]. Interestingly, headaches (including many induced by alcohol ingestion) of all types in both adult humans and children have been found to exhibit deficits in serum ionized Mg levels and are often treatable with administration of only Mg [75, 76, 77, 78, 79].
More than 45 years ago, two of us demonstrated that Mg2+ behaves as a natural calcium channel blocker in cardiac, vascular, endothelial, and cerebral vascular muscle cells as well as in hippocampal-pyramidal brain cells [61, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92]. We also showed in experimental animals, and human subjects (with type 1 and type 2 diabetes mellitus), that Mg behaves as a natural statin in that it lowers serum levels of cholesterol, triglycerides and LDL , as well act as a powerful vasodilator in the microcirculation and on coronary and cerebral arteries, and as a cardiac muscle relaxant [61, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105]. In contrast, hypomagnesemic blood levels have been shown to ameliorate hypertension, atherogenesis, atrial arrhythmias, headaches of all types, and alcohol-induced strokes as well as increase cerebral blood flow and limit cerebral tissue damage from alcohol intoxication [4, 5, 6, 11, 31, 41, 43, 44, 53, 55, 60, 61, 70, 75, 76, 77, 78, 79, 93, 94, 100, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118].
With the use of sensitive and newly-designed specific Mg2+-ion selective electrodes, our laboratories have shown that patients with alcohol intoxication, IHD, cardiac failure, ischemic and hemorrhagic strokes , diabetes types I and II, renal-induced vascular pathology, preeclampsia, and atherosclerosis exhibit significant reductions in plasma, serum/ whole blood levels of Mg2+ [5, 7, 11, 20, 44, 47, 48, 61, 70, 71, 72, 76, 76, 77, 78, 79, 93, 94, 105, 117, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128]. Our group has also found that experimentallyinduced dietary deficiencies of Mg in rats, rabbits and mice causes vascular remodeling (i.e., arteriolar wall hypertrophy and alterations in the matrices of the vascular walls) in the brain, skeletal muscle, and splanchnic microcirculations concomitant with atherogenesis, high blood pressure, and microvascular vasospasm [26, 27, 37, 70, 84, 100, 106, 129].
Low [Mg2+]0 Environments or The Presence of Increasing Concentrations of Alcohol Result in Concentration-dependent Cerebral Arterial, Venular and Arteriolar Vasoconstriction as Well as Increased Vascular Reactivity, Inflammatory Responses and Formation of Reactive Oxygen Species (ROS): Relevance to Alcohol-induced Leukocyte -Endothelial Interactions in Microcirculation, Apoptosis, Necroptosis and Ferroptosis
Almost 50 years ago, our group reported that declining levels of extracellular wresulted in concentration-dependent constriction and vasospasm of small )< 100 um in diameter) , medium and large coronary arteries excised from dogs, sheep, baboons and rats [26, 80, 81, 82, 83, 84, 85, 86, 87, 88, 95, 96, 98, 122]. Similar results were found by our group using small, medium, and large cerebral and middle cerebral vessels excised from dogs, sheep, baboons and rats [20, 61, 82, 86, 87, 88, 96, 98]. These low [Mg2+]0 -induced vasospasms could only be attenuated or inhibited with elevated concentrations of Mg2+. Further studies showed that administration of ethanol can induce similar responses on isolated cerebral vessels (from the same diverse mammals) as well as on the intact brain microcirculatory arterioles and is associated with rapidly-induced reductions in cellular [Mg2+]I coupled to movements and release of calcium ions into the vascular smooth muscle and parenchymal brain tissues [4, 7, 9, 11, 20, 39, 40, 41, 42, 43, 44, 53, 55, 57, 83]. Moreover, these low [Mg2+]0 levels enhanced vasoconstrictor responses to a variety of vasoactive and neurohumoral putative neurotransmitters (e.g., angiotensin II, serotonin, numerous vasoactive peptides, etc.). We suggested, at that time, that low dietary levels of Mg and alcohol intoxication could result in cellular calcium overload, mitochondrial dysfunction, disturbances in Ca2+ and K+ currents in brain capillary endothelial cells, arrhythmias, fibrillation, IHD, SCD, strokes and brain damage [4, 7, 11, 13, 20, 39, 40, 41, 42, 43, 44, 45, 48, 49, 50, 51, 52, 53, 54, 55, 56, 60, 91, 92, 117].
On further investigation, we found that both ethanol and low [Mg2+]0 induced generation of ROS (e.g., H2O2, hydroxyl radicals, ferrylmyoglobin, NO, peroxynitrite radicals as well as hypochloric acid) in the heart and on brain blood vessels [4, 5, 7, 11, 15, 36, 37, 43, 48, 53, 54, 56, 58, 61, 70, 117, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, unpublished findings]. Studying the in-situ brain microcirculation with high power (up to 3,200 x –magnification) TVimage intensification microscopy of the post-capillary venules, we noted that Mg-deficient animals or animals given increasing doses of ethanol, demonstrated rolling and adherence of leukocytes on the endothelial walls with eventual infiltration of leukocytes and macrophages across the venular walls into the brain parenchymal tissues and increased myeloperoxidase staining, suggesting clear inflammatory responses with generation of peroxidase, H 2O2, and hypochloride free radicals [4, 5, 7, 11, 43, 48, 56, 57, 59, unpublished findings].
Using a host of biochemical and molecular assays, we found that Mg deficiency (in intact animals, or primary cultured cerebral vascular smooth muscle cells), or prolonged culture of these cells with ethanol, showed clear signs of three types of cell death, i.e., apoptosis, necroptosis and ferroptosis [129, 139, 140, unpublished findings].
Use of 31P-Nuclear Magnetic Resonance Spectroscopy (31P-NMRS) in Animals Given Stroke-like Doses of Alcohol Results in Brain Declines in ATP, [Mg2+]I, and Phosphocreatine with Rises in Levels of Inorganic Phosphate and N-Acetylaspartate
In-vivo studies performed by our group, using intact rats and high-powered 31P-nuclear magnetic resonance spectroscopy (31P-NMR) to probe the intact brain, have found that increasing concentrations of ethanol resulted in rapid alterations in brain biochemistry and neurophysiology [4, 7, 9, 11, 13, 20, 44, 46, 48, 53]. We found that diverse brain cells demonstrated declines in intracellular free [Mg], rapid declines in neuronal ATP and ADP, declines in brain phosphocreatine, acidification (i.e., decreased neuronal pH), concomitant with rises of intracellular free inorganic phosphate and N- acetylaspartate, all signs of dying and/or compromised brain neuronal cells and parenchymal tissues [4, 5, 7, 9, 11, 13, 44, 48, 53, unpublished findings]. Working with primary cultured canine and baboon cerebral vascular smooth muscle cells, primary cultured rat brain astrocytes and rat brain hippocampal brain slices, we have found very similar biochemical and molecular alterations [4, 8, 10, 14, 20, 41, 44, 53]. In addition, we noted that these diverse cells demonstrated rises in [Ca2+]I concomitant with reductions in intracellular pH (i.e., intracellular acidification) and rises in inorganic phosphate levels [4, 8, 11, 42, 43, 52, 53, unpublished findings]. Moreover, ethanol exposure resulted in lipid peroxidation and activation of nuclear factor – kB [58, 59]. But, what is causing these detrimental alterations in brain biochemistry? Is it the alcohol, per se, as some investigators believe or is it some intermediate(s) molecule (s)? Using proton -NMR spectroscopy, about 20 years ago, in preliminary experiments, we noted that cerebral vascular smooth muscle cells, exposed to increasing concentrations of ethanol demonstrated rises in the sphingolipid, ceramide, and what looked like rising levels of platelet-activating factor (PAF) and PAF-like lipids [131, unpublished findings].
Roles of Ceramide, PAF and PAF-like Lipids in Alcohol-induced Strokes and Brain Damage
Ceramides are now thought to play important roles in fundamental cellular, biochemical and physiological processes such as cell proliferation, membrane-receptor functions, oxidative stress, angiogenesis, diverse microcirculatory functions, immune-inflammatory functions, cell adhesion, activation of nitric oxide synthases, alterations in membrane lipid domains, and programmed cell death, among other functions. We have reported, previously, that low extracellular Mg levels cause mitochondrial alterations, programmed cell death( discussed above), activate nitric oxide synthases, oxidative stress, and activation of all five of the major enzymes in the sphingolipid pathway leading to synthesis/release of ceramides [4, 130, 131, 132, 133].
PAF is known to play major roles in both inflammatory reactions and atherogenesis. A variety of the circulating blood-formed elements (e.g., polymorphonuclear leukocytes, platelets, basophils, and macrophages) as well as endothelial cells can elaborate PAF. Interestingly, all of these cell types play roles in hemorrhagic and ischemic strokes. We have shown, recently, that cerebral vascular smooth muscle cells, astrocytes, brain capillary endothelial cells, and hippocampal brain slices all can elaborate PAF in low Mg2+environments [141, 142, unpublished experiments].
Since preliminary studies, using isolated canine and baboon arteries, suggested that exposure of these tissues to ethanol and low Mg2+ resulted in increased levels of the sphingolipid, ceramide, and PAF, we proceeded to examine primary canine, rat, and baboon cerebral vascular smooth muscle cells exposed to increasing concentrations of ethanol. These cells demonstrated, as expected, rising levels of ceramide and PAF [142, unpubished findings]. In addition, we found that ethanol resulted in activation of N-sphingomyelinase and acid-sphingomyelinase concomitant with increasing reductions in free [Mg] [142, unpublished findings]. Preliminary studies seem to indicate that agents that inhibit the synthesis of PAF will inhibit accumulation of ceramide and PAF ; surprisingly, PAF inhibitors also seemed to markedly attenuate the ability of ethanol to reduce intracellular levels of [Mg]. Whether or not sphingolipids and PAF are critical molecules in the stroke and brain-damaging effects of ethanol will have to await further investigation.
Although the current focus among physicians and the public seems to be the increasing number of deaths, particularly among the youth, on “overdosing by opioids”. The most abused drug, among the youth and college students, is “alcohol”. Alcohol intoxication and abuse accounts for countless deaths worldwide, particularly in the USA and Russia. Death certificates usually list these deaths as from hepatic and respiratory failure. Unfortunately, very few complete autopsies are ever performed on these victims. Importantly, repeated ingestion of alcohol, over many years, often results in dementia, Wiernicke-Korsakoff syndrome and hallucinations. We review data and studies, herein, which suggest, rather strongly, that many of these alcohol-induced deaths are caused by brain damage (to vital areas) and hemorrhagic and ischemic strokes. Numerous experiments performed by our group on diverse mammals, using intact brains, isolated cerebral vascular, neuronal, astrocytic, and endothelial cells point to an important, overlooked role of magnesium in the responses of the brain to alcohol. Our studies on human subjects and animals demonstrate that alcohol causes rapid depletion of free, intracellular Mg ions coupled to loss of ATP, ADP, and phosphocreatine along with rises in cellular acidification, free inorganic phosphate, and N-acetylaspartate, all clear signs of either impending brain- cell death or necrosis of cells. Very recent experiments point to important roles for sphingolipids (e.g., ceramide) and platelet-activating factor (PAF) and other PAF-like lipids in the brain’s responses to alcohol. Collectively, such clinical and experimental studies point to the need for complete autopsies in alcoholinduced deaths in order to determine whether the deaths were caused by strokes or increasing brain damage over time. Our newer studies on sphingolipids and PAF point to the need for such studies in humans known to be alcoholabusers. We believe if the latter demonstrates proof for the key-involvement of sphingolipids and PAF, drugs could be designed to help alcohol-abusers and prevent brain damage, alcohol-induced dementia, Wiernicke-Korsaff syndrome, and probably prevent induction of strokes.
Some of the original experimental and clinical studies mentioned in the above were supported, in part, by research grants from The N.I.H. (National Institute on Alcoholism and Alcohol Abuse, The National Institute on Mental Health, and The National Institute on Drug Abuse to B.M.A. and B.T.A.). We also received unrestricted grant support from several pharmaceutical companies including CIBA-GEIGY, SANDOZ, and Bayer.
1. Flink EB, Omar M, Shane SR (1981) Alcoholism, liver diseases and magnesium. Magnesium Bull 3: 209-216.
2. Lieber C (1992) Medical Aspects of Alcoholism. Plenum, New York.
3. Abbott L, Nadler J, Rude RK (1994) Magnesium deficiency in alcoholism: Possible contribution to osteoporosis and cardiovascular diseases in alcoholics. Alcoholism: Clin Exp Res 18: 1076-1082.
4. Altura BM, Altura BT (1994) Role of magnesium in alcoholinduced hypertension and strokes as probed by in vivo television microscopy, digital image microscopy, optical spectroscopy, 31P-NMR spectroscopy and a unique magnesium ion-electrode. Alcohol: Clin Exp Res 18: 1057-1068.
5. Altura BM, Altura BT (1999) Association of alcohol in brain injury, headaches, and stroke with brain tissue and serum levels of ionized magnesium: a review of recent findings and mechanisms of action. Alcohol 19: 119-130.
6. Long S, Romani AM (2014) Role of cellular magnesium in human disease. Austin J Nutr Food Sci 18:1051.
7. Altura BM, Altura BT, Gupta RK (1991-1992) Alcoholintoxication results in rapid loss in free magnesium in brain and disturbances in bioenergetics: Relation to cerebrovasospasm, alcohol-induced strokes, and barbiturate-induced anesthesia induced deaths. Magnes Trace Elem 10: 122-135.
8. Altura BM, Zhang A, Cheng TP, et al. (1993) Ethanol promotes rapid depletion of intracellular free Mg in cerebral vascular smooth muscle cells: Possible relation to alcoholinduced behavioral and stroke-like effects. Alcohol 10: 563-566.
9. Altura BM, Gebrewold A, Altura BT, et al. (1995) Role of [Mg2+]I in alcohol-induced hemorrhagic stroke in a rat model: A 31P-NMR in- vivo study. Alcohol 12: 131-136.
10. Altura BM, Zhang A, Cheng TP, et al. (1995) Alcohols induce rapid depletion of intracellular free Mg2+ in cerebral vascular muscle cells: relation to chain length and partition coefficient. Alcohol 12: 247-250.
11. Altura BM, Altura BT (1996) Effects of alcohol on overall brain metabolism. In: Pharmacology of Alcohol and Alcohol Dependence, Begleiter H, Kissin B, eds. Oxford Univ Press, New York 145-180.
12. Altura BM, Zhang A, Altura BT (1996) Alcohol, myocardial bioenergetics, phospholipids, and ionic balance. In: Alcohol and The Cardiovascular System, Zakhari S, Wassef M, eds. NIAAA Research Monograph 31 US Govt Printing Office, Bethesda 279-315.
13. Altura BM, Weaver C, Gebrewold A, et al. (1998) Continuous osmotic mini-pump infusion of alcohol into brain decreases brain [Mg2+] and brain bioenergetics and enhances susceptibility to hemorrhagic stroke: An in-vivo 31P-NMR study. Alcohol 15: 113-117.
14. Babu AT, Cheng TP, Zhang A, et al. (1999) Low concentrations of ethanol deplete type-2 astrocytes of intracellular free magnesium. Brain Res Bull 50: 59-62.
15. Li W, Zheng T, Babu AT, et al. (2001) Antioxidants prevent depletion of [Mg2+]I induced by ethanol : studies on cultured cerebral vascular smooth muscle cells, type-2 astrocytes and intact brain. Brain Res Bull 55.
16. Kloner RA, Rezkalla SH (2007) To drink or not to drink? That is the question. John Wiley and Sons Inc, New York.
17. Koskinen P, Kupari M, Leinonen H, et al. (1987) Alcohol and new onset atrial fibrillation: a case-control study of a current series. Brit Heart J 57: 466-473.
18. Templeton AH, Carter KLT, Sheron N, et al. (2009) Sudden unexpected death in alcohol misuse-An unrecognized public health issue. Int Environm Res Public Health 6: 3070-3081.
19. Davidson DM (1989) Cardiovascular effects of alcohol. West J Med 151: 430-439.
20. Altura BM, Altura BT (1990) Alcohol, stroke and the cerebral circulation. Alcohol Health Research World 14: 322-331.
21. Hillbom M (1986) Neurological damage-Stroke. In : Effects of Ethanol on the Central Nervous System, Dietrich RA, Erwin RG, eds. CRC Press, New York 145-180.
22. Hillbom M, Juvela S (1996) Alcohol and risk for stroke. In: Alcohol and Cardiovascular System 31, Zakhari S, Wassef M, eds. U.S. Govt Printing Office, Wash, DC 63-84.
23. Camargo CA (1989) Moderate alcohol consumption and stroke: epidemiologic evidence. Stroke 20: 1611-1626.
24. Altura BM (1979) Sudden-death ischemic heart disease and dietary magnesium intake: Is the target site coronary vascular smooth muscle? Med Hypoth 5: 543-548.
25. Turlapaty PDMV, Altura BM (1980) Magnesium deficiency produces spasms of coronary arteries: relationship to etiology of sudden death ischemic heart disease. Science 208: 198-200.
26. Altura BM, Altura BT (1984) Magnesium, electrolyte transport, and coronary vascular tone. Drugs 28: 120-142.
27. Altura BM, Altura BT (1985) New perspectives on the role of magnesium in pathophysiology of the cardiovascular system. I. Clinical aspects. Magnesium 4: 226-244.
28. Altura BM (1988) Ischemic heart disease and magnesium. Magnesium 7: 57-67.
29. Kimura T, Yasue H, Sakaino N, et al. (1989) Effect of magnesium on the tone of isolated human coronary arteries. Comparison with diltiazem and nitroglycerin. Circulation 79: 1118-1124.
30. Goto K, Yasue H, Okumura K, et al. (1999) Magnesium deficiency detected by intravenous loading test in variant angina pectoris. Am J Cardiol 65: 709-712.
31. Simko F (1994) Pathophysiological aspects of the protective effect of magnesium in myocardial infarction. Acta Med Hung 50: 55-64.
32. Satake K, Lee JD, Shimizu H, et al. (1996) Relation between severity of magnesium deficiency and frequency of angina attacks in men with variant angina. J Am Coll Cardiol 28: 897-902.
33. Sueda S, Fukuda H, Watanabe K, et al. (2001) Magnesium deficiency in patients with recent myocardial infarction and provoked coronary artery spasm. Jpn J Circ J 65: 643-648.
34. Wu F, Zou LY, Altura BT, et al. (1992) Low extracellular magnesium results in cardiac failure in isolated perfused hearts. Magnes Trace Elem 10: 364-373.
35. Altura BM, Barbour RL, Dowd TL, et al. (1993) Low extracellular magnesium induces intracellular free Mg2+ deficits, ischemia, depletion of high-energy phosphates and cardiac failure in intact working rat hearts: A 31P-NMR study. Biochim Biophys Acta 1182: 328-332.
36. Wu F, Altura BT, Gao J, et al. (1994) Ferrylmyoglobin formation induced by acute magnesium deficiency in perfused rat heart causes cardiac failure. Biochim Biophys Acta 1225: 158-164.
37. Altura BM, Gebrewold A, Altura BT, et al. (1996) Magnesium depletion impairs carbohydrate and lipid metabolism and cardiac bioenergetics and raises myocardial calcium content in vivo: relationship to etiology of cardiac diseases. Biochem Mol Bio Int 40: 1183-1190.
38. Zou LY, Wu F, Altura BT, et al. (1992) Beneficial effects of high magnesium on alcohol-induced cardiac failure. Magnes Trace Elem 10: 409-419.
39. Altura BM, Altura BT, Carella A (1983) Ethanol produces coronary vasospasm. Evidence for a direct action of ethanol on vascular muscle. Br J Pharmacology 78: 260-262.
40. Altura BM, Altura BT (1983) Peripheral vascular actions of ethanol and its interaction with neurohumoral substances. Neurobehav Toxicol Teratol 5: 211-220.
41. Altura BM, Altura BT (1984) Alcohol, stroke, hypertension and the heart. Alcohol 1: 321-323.
42. Altura BM, Altura BT (1987) Peripheral and cerebrovascular actions of ethanol, acetaldehyde and acetate: relationship to divalent cations. Alcoholism: Clin Exp Res 11: 99-111.
43. Altura BM, Altura BT (1989) Cardiovascular functions in alcoholism and after acute administration of alcohol: Heart and blood vessels. In: Alcoholism: Biochemical and Genetic Aspects. Goedde HW, Agarwal DP, eds. Pergamon Press, Elmsford 167-227.
44. Altura BM, Altura BT (1991) Alcohol, stroke, and the cerebral circulation. Alcohol World Health & Research 14: 223-235.
45. Barbour RL, Gebrewold A, Altura BM (1993) Optical spectroscopy and cerebral vascular effects of alcohol in the intact brain: Effects on tissue deoxyhemoglobin, blood content and reduced cyochrome oxidase. Alcoholism: Clin Exp Res 17: 1319-1324.
46. Ludwig N, Altura BT, Fox SE, et al. (1995) The suppressant effect of ethanol, delivered via intrahippocampal microdialysis, on the firing of local pyramidal cells in freely behaving rats. Alcohol 12: 417-421.
47. Altura BM, Memon ZS, Altura BT, et al. (1995) Alcoholassociated acute head trauma in human subjects is associated with deficits in serum ionized Mg and Ca. Alcohol 12: 433-436.
48. Altura BM, Altura BT (1996) Effects of alcohol on brain circulation. In: The Pharmacology of Alcohol and Alcohol Dependence, Begleiter H, Kissin B, eds. Oxford Univ Press, New York 181-206.
49. Altura BM, Zou LY, Altura BT, et al (1996) Beneficial versus detrimental actions of alcohol on heart and coronary vascular muscle: Roles of Mg2+ and Ca2+. Alcohol 13: 499-513.
50. Altura BM, Zhang A, Cheng TP, et al. (1996) Exposure of piglet coronary arterial smooth muscle cells to low alcohol results in elevation of intracellular free Ca2+: relevance to fetal alcohol syndrome. Eur J Pharmacol 314: 9-11.
51. Zou LY, Altura BT, Wu F, et al. (1997) Roles of Mg2+ and Ca2+ in beneficial vs. detrimental actions of alcohol on heart. Advances in Magnesium Res. Smetana, ed. John Libbey, London 211-214.
52. Zhang A, Cheng TP, Altura BT, et al. (1997) Chronic treatment of cultured cerebral vascular smooth muscle cells with low concentrations of ethanol elevates intracellular calcium and potentiates prostanoid –induced rises in [Ca2+]I : relation to etiology of alcohol-induced stroke. Alcohol 14: 367-371.
53. Altura BM, Gebrewold A, Zhang A, et al. (1999) Alcoholinduced vascular injury: Role of oxygen-derived radicals, antioxidants, cellular bioenergetics, divalent cations, transcription factors and protein kinase C. Int J Cardiovasc Med Sci 2: 7-24.
54. Altura BM, Gebrewold A (1996) Alpha-tocopherol attenuates alcohol-induced cerebral vascular damage: possible role of oxidants in alcohol brain injury and strokes. Neurosci Lett 220: 207-210.
55. Ema M, Gebrewold A, Altura BT, et al. (1998) Alcoholinduced vascular damage of brain is ameliorated by administration of magnesium. Alcohol 15: 95-103.
56. Altura BM, Gebrewold A (1998) Pyrrlidine dithicarbamate attenuates alcohol-induced leukocyte-endothelial cell interaction and cerebral vascular damage in rats: possible role of activation of transcription factor NF-kappa B in alcohol brain. Alcohol 16: 25-28.
57. Altura BM, Gebrewold A, Zhang A, et al. (2002) Role of leukocytes in the rat brain in situ: potential role in alcohol brain pathology and strokes. Eur J Pharmacol 448: 89-94.
58. Altura BM, Gebrewold A, Zhang A, et al. (2002) Ethanol induces rapid lipid peroxidation and activation of nuclear factorkappa B in cerebral vascular smooth muscle: relation to alcoholinduced brain damage. Neurosci Lett 325:
59. Altura BM, Gebrewold A (2002) Inhibitor of nuclear factor-kappa B activation attenuates venular constriction, leukocyte adhesion and microvessel rupture in intact rat brain microcirculation: relation to ethanol-induced brain injury. Neurosci Lett 334: 21-24.
60. De Baaj JHE, Henderop JG, Bindels R (2015) Magnesium in man: Implications for health and disease. Physiol Rev 95: 1-46.
61. Altura BM, Altura BT (2007) Magnesium: forgotten mineral in cardiovascular biology. In: New Perspectives in Magnesium Research. Springer, New York 239-260.
62. Mosfegh A, Goldman J, Abuja J, et al. (2009) What We Eat in America. NHANES 2005-2006: usual Nutrient Intakes from Food and Water Compared to 1997 Dietary Reference Intakes for Vitamin D, Calcium, Phosphorus, and Magnesium. US Department of Agricultural Research, Wash, DC.
63. NHANES (2017) Dietary Reference Intakes for Vitamin D, Calcium, Phosphorus, and Magnesium. U.S. Department of Agricultural Research, Wash, DC.
64. Ford ES, Mokdad AH (2003) Dietary magnesium intake in a national sample of US adults. J Nutr 133: 2879-2882.
65. Chipper Field B, Chipper Field JR (1979) Relation of nyocardial metal concentration to water hardness and deathrates from ischemic heart disease. Lancet 2: 709-712.
66. Leary WP (1983) Content of magnesium in drinking water and deaths from ischaemic heart disease in white South Africans. Magnesium 5: 150-153.
67. Marier JR, Neri LC (1985) Quantifying the role of magnesium in the interrelationship between human mortality/morbidity and water hardness. Magnesium 5: 53-59.
68. Marx A, Neutra RR (1997) Magnesium in drinking water and ischaemic heart disease. Epidemiol Rev 19: 258-272.
69. Rubenowitz E, Molin I, AXelsson G, et al. (2000) Magnesium in drinking water in relation to mortality and morbidity from acute myocardial infarction. Epidemiology 11: 416-421.
70. Altura BM, Altura BT (1995) Magnesium and cardiovascular biology: an important link between cardiovascular risk factors and atherogenesis. Cell Mol Biol Res 41: 347-359.
71. Memon ZI, Altura BT, Benjamin JL, et al. (1995) Predictive value of serum ionized but not total magnesium levels in head injuries. Scand J Clin Lab Invest 55: 671-677.
72. Altura BT, Altura BM (1995) Ionized magnesium measurements in serum, plasma and whole blood in health and disease. In: Magnesium and Physical Activity, Vecchiet L, ed. Lancs, UK 129-146.
73. Heath DL, Vink R (1999) Brain free magnesium concentration is predictive of motor outcome following traumatic axonal brain injury in rats. Magnes Res 12: 269-277.
74. Cernak I (2000) Characterization of plasma magnesium concentration and oxidative stress following graded traumatic brain injury in humans. J Neurotrauma 17: 53-68.
75. Mauskop A, Altura BT, Cracco RQ, et al. (1993) Deficiency in serum ionized magnesium but not total magnesium in patients with migraines. Possible role of ICa2+/Mg2+ ratio. Headache 33: 135-139.
76. Mauskop A, Altura BT, Cracco RQ, et al. (1994) Chronic daily headache-one disease or two? Diagnostic role of serum ionized magnesium. Cephalagia 14: 24-28.
77. Mauskop A, Altura BT, Cracco RQ, et al. (1995) Intravenous magnesium sulfate relieves cluster headaches in patients with low serum ionized magnesium levels. Headache 35: 597-600.
78. Mauskop A, Altura BT, Cracco RQ, et al. (1995) Intravenous magnesium sulfate rapidly relieves migraine attacks in patients with low serum ionized magnesium levels. A pilot study. Clin Sci 89: 633-636.
79. Mauskop A, Altura BT, Cracco RQ, et al. (1996) Intravenous magnesium sulfate rapidly alleviates headaches of various types. Headache 36: 154-160.
80. Altura BM, Altura BT (1971) influence of magnesium on drug-induced contractions and ion content in rabbit aorta. Am J Physiol 220: 938-944.
81. Altura BM, Altura BT (1974) Magnesium and contraction of arterial smooth muscle. Microvasc Res 7: 145-155.
82. Altura BM, Altura BT (1981) Role of magnesium ions in contractility of blood vessels and skeletal muscles. Magnesium Bulletin 3: 102-114.
83. Altura BM, Altura BT (1981) General anesthetics and magnesium ions as calcium antagonists. In: New Perspectives on Calcium Antagonists, Weiss GB, ed. Am Physiol Soc, Bethesda 131-145.
84. Altura BM, Altura BT (1978) Magnesium and vascular tone and reactivity. Blood Vessels 15: 5-16.
85. Turlapaty PDMV, Weiner R, Altura BM (1981) Interactions of magnesium and verapamil on tone and contractility of vascular smooth muscle. Eur J Pharmacol 74: 263-272.
86. Altura BM, Altura BT, Carella A, et al. (1982) Ca2+ coupling in vascular smooth muscle: Mg2+ and buffer effects on contractility and membrane Ca2+ movements. Canad J Physiol Pharmacol 60: 459-482.
87. Altura BM, Altura BT (1981) Magnesium modulates calcium entry and contractility in vascular smooth muscle. In: The Mechanism of Gated Calcium Transport across Biological Membranes, Ohnishi SY, Endo M. Academic Press, New York 137-145.
88. Altura BM, Altura BT, Carella A, et al. (1987) Mg2+-Ca2+ interaction in contractility of vascular smooth muscle: Mg2+ versus calcium channel blockers on myogenic tone and agonistinduced responsiveness of blood vessels. Canad J Physiol Pharmacol 65: 729-745.
89. Zhang A, Altura BT, Altura BM (1993) Mg2+ and caffeine – induced intracellular Ca2+ release in human vascular endothelial cells. Brit J Pharmacol 109: 135-138.
90. Zhang A, Fan SH, Cheng TP, et al. (1996) Extracellular Mg2+ modulates intracellular Ca2+ in acutely isolated hippocampal CA1 pyramidal cells of the guinea-pig. Brain Res 728: 204-208.
91. Delpiano M, Altura BM (1996) Modulatory effect of extracellular Mg2+ ions on K+ and Ca2+ currents of capillary endothelial cells from rat brain. FEBS Lett 394: 335-339.
92. Delpiano M, Altura BM (1997) Transmembrane currents in capillary endothelial cells are modulated by Mg2+ ions. Adv Exp Med Biol 410: 115-118.
93. Djurhuus S, Henriksen JE, Kligaard NA, et al. (1999) Effect of moderate improvement in metabolic control on magnesium and lipid concentrations in type 1 diabetes. Diabetes Care 22: 546-554.
94. Djurhuus S, Kligaard NA, Pedersen KK, et al (2001) Magnesium reduces insulin-stimulated glucose uptake and serum lipid concentrations in type 1 diabetes. Metabolism 50: 1409-1417
95. Altura BM, Altura BT (1974) Magnesium and contraction of arterial smooth muscle . Microvasc Res 7: 145-155.
96. Altura BT, Altura BM (1980) Withdrawal of magnesium causes vasospasm while elevated magnesium produces relaxation of tone in cerebral arteries. Neurosci Lett 20: 323-327.
97. Altura BM, Altura BT (1981) Magnesium and contraction of vascular smooth muscles: Relationship to some vascular diseases. Federation Proc 40: 2672-2679.
98. Altura BM, Altura B T, Carella A, et al. (1981) Hypomagnesemia and vasoconstriction: Possible relationship to etiology of sudden death ischemic heart disease and hypertensive vascular diseases. Artery 9: 212-231.
99. Altura BM, Altura BM (1983) Influence of magnesium on vascular smooth muscle and serum biochemical parameters from diabetic and hypertensive rats. Magnesium: Exp Clin Res 2: 253-266.
100. Altura BT, Brust M, Bloom S, et al. (1990) Magnesium dietary intake modulates blood lipid levels and atherogenesis. Proc Nat Acad Sci USA 87: 1840-1844.
101. Altura BM, Altura BT (1990) Magnesium and the cardiovascular system: Experimental and clinical aspects. Metals in Biological Systems 26: 359-416.
102. Nagai I, Gebrewold A, Altura BT, et al. (1988) Magnesium salts exert direct vasodilator effects on rat cremaster muscle microcirculation. Arch Int Pharmacodyn Ther 294: 194-215.
103. Nishio A, Gebrewold A, Altura BT, et al. (1988) Comparative effects of magnesium salts on reactivity of arterioles and venules to constrictor agents. An in situ on microcirculation. J Pharmacol Exp Ther 246: 859-865.
104. Nishio A, Gebrewold A, Altura BT, Altura BM (1989) Comparative vasodilator effects of magnesium salts on rat mesenteric arterioles and venules. Arch Int Pharmacodyn Ther 298: 139-163.
105. Markell MS, Altura BT, Barbour RL, et al. (1993) Ionized and total magnesium levels in cyclosporine-treated renal transplant recipients: relationship with cholesterol and cyclosporine levels. Clin Sci 75: 315-318.
106. Altura BM, Altura BT, Gebrewold A, et al. (1984) Magnesium deficiency and hypertension: correlation between magnesium deficiency diets and microcirculatory changes in situ. Scince 223: 1315-1317.
107. Altura BM, Altura BT (1985) New perspectives on the role of magnesium in pathophysiology of the cardiovascular system. I. Clinical aspects. Magnesium 4: 220-244.
108. Luthringer C, Rayssiguier Y, Giueux E, Berthelot A (1988) Effect of moderate magnesium deficiency on serum lipids, blood pressure and cardiovascular reactivity in health and disease. Brit J Nutr 59: 243-250.
109. Seelig MS (1989) Cardiovascular consequences of Mg deficiency and loss: pathogenesis, prevalence and manifestationsMgCl loss in refractory potassium repletion. Am J Cardiol 63: 4-21.
110. Rasmussen HS (1993) Justification for magnesium therapy in acute ischemic heart disease. Clinical and experimental studies. Danish Med J 40: 84-89.
111. Orlov MW, Brodsky MA, Douban S (1994) A review of magnesium, acute myocardial infarction and arrhytnmia. J Am Coll Nutr 13: 127-132.
112. Satur CM (1997) Magnesium and cardiac surgery. An Roy Coll Surg Engl 79: 349-354.
113. Saris NE, Mervaala E, Karppanen H, et al. (2000) Magnesium : an update on physiological, clinical and analytical aspects. Clin Chim Acta 294: 1-26.
114. Seelig MS, Rosanoff A (2003) The Magnesium Factor. The Penguin Group, New York.
115. Emila S, Swaminathan S (2013) Role of magnesium in health and disease. J Exp Sci 4: 32-43.
116. Grober U, Schmidt J, Kisters K (2015) Magnesium in prevention and therapy. Nutrients 7: 8199-8226.
117. Altura BM, Shah NC, Shah GJ, et al. (2016) Why is alcoholinduced atrial arrhythmias and sudden cardiac death difficult to prevent and treat: Potential roles of unrecognized ionized hypomagnesmia and release of ceramides and platelet-activating factor. Cardiovasc Pathol: Open Access 1: 1000112.
118. Dean C (2017) The Magnesium Miracle, 4th ed. Ballantine Books, New York.
119. Altura BM, Lewenstam A (1994) Unique Magnesiumsensitive Ion Selective Electrodes. Scand J Clin Lab Invest 54: 1-100.
120. Altura BM, Altura BT (1974) Magnesium and contraction of arterial smooth muscle. Microvasc Res 7: 145-155.
121. Altura BM (1979) Sudden-death ischemic heart disease and dietary magnesium intake: is the target site coronary vascular smooth muscle? Med Hypoth 5: 843-849.
122. Turlapaty PDMV, Altura BM (1980 ) Magnesium deficiency produces spasms of coronary arteries; relation to sudden death ischemic heart disease. Science 208: 198-200.
123. Altura BT, Altura BM (1990) Measurement of ionized magnesium in whole blood, plasma and serum with a new novel ion-selective electrode. Magnes Trace Elem 9: 311-319.
124. Altura BT, Altura BM (1992) Measurement of ionized magnesium in whole blood, plasma and serum with a new ionselective electrode in healthy and diseased human subjects. Magnes Trace Elem 10: 90-98.
125. Markell MS, Altura BT, Sarn YS, et al. (1993) Deficiency of serum ionized magnesium in patients on hemodialysis or peritoneal dialysis. ASAIO J 39: 801-804.
126. Resnick LM, Altura BT, Gupta RK, et al. (1993) Intracellular and extracellular magnesium depletion in Type 2 (non-insulin dependent) diabetes mellitus. Diabetologia 36: 767-770.
127. Handwerker SM, Altura BT, Chi DS, et al. (1995) Serum ionized magnesium levels during intravenous MgSO4 therapy of preeclamptic women. Acta Obstet Gynecol Scand 74: 517-519.
128. Scott VL, DeWolf AM, Kang Y, et al. (1996) Ionized hypomagnesemia in patients undergoing orthotropic liver transplantation: A complication of citrate intoxication. Liver Transpl Surg 2: 341-347.
129. Altura BM, Shah NC, Jiang XC, et al. (2009) Shortterm magnesium deficiency results in decreased levels of sphingomyelin, lipid peroxidation, and apoptosis in cardiovascular tissues. Am J Physiol Heart Circ Physiol 297: 86-92.
130. Altura BM, Kostellow AB, Zhang A, et al (2003) Expression of nuclear factor-kB and the proto-oncogenes c-fos and c-jun are induced by low extracellular Mg2+ in aortic and cerebral vascular smooth muscle: possible links to hypertension, atherogenesis and stroke. Am J Hypertens 16: 701-707.
131. Morrill GA, Gupta RK, Kostellow AB, et al. (1997) Mg2+ modulates membrane lipids in vascular smooth muscle cells. FEBS Lett 408: 191-194.
132. Morrill GA, Gupta RK, Kostellow AB, et al. (1998) Mg2+ modulates membrane sphingolipids and lipid second messenger levels in vascular smooth muscle cells. FEBS Lett 440: 167-711.
133. Shah NC, Liu JP, Iqbal J, et al. (2011) Mg deficiency results in modulation of serum lipids , glutathione, and NO synthase isozyme activation in cardiovascular tissues: relevance to de novo synthesis of ceramide, serum Mg2+ and atherogenesis. Int J Clin Exp Med 4: 103-118.
134. Li JF, Li W, Altura BT, et al. (2007) Peroxynitrite induces apoptosis and decline of intracellular free Mg with concomitant elevation in [Ca2+]I in rat aortic smooth muscle cells : possible roles of extracellular and intracellular magnesium ions in peroxynitrie-induced cell death. Drug Metab Lett 1: 85-89.
135. Yang ZW, Gebrewod A, Nowakowski M, et al. (2000) Mg2+- induced endothelium-dependent relaxation of blood vessels and blood pressure: role of NO. Am J Physiol Regul Comp Physiol 278: 628-639.
136. Altura BT, Altura BM (1987) Endothelium-dependent relaxation on coronary arteries requires magnesium ions. Br J Pharmacol 91: 449-451.
137. Chand N, Altura BM (1981) Acetylcholine and bradykinin relax intrapulmonary arteries by acting on endothelial cells: Role in lung vascular diseases. Science 213: 1376-1379.
138. Altura BM, Shah NC, Shah GJ, et al. (2018) Magnesium deficiency, spuingolipids and telomerase: Relevance tp atherogenesis, cardiovascular diseases and aging. In: Starvation and Famine. Springer, Berlin.
139. Altura BM, Shah NC, Shah GJ, et al. (2018) Regulated RIPK3 necroptosis is produced in cardiovascular tissues and cells in dietary magnesium deficiency; roles of cytokines and their potential importance in inflammation and atherogenesis. J Med Surg Pathol 2:104.
140. Altura BM, Gebrewold A, Carella A, et al. (2018) Regulated ferroptosiss cell death is produced in cardiovascular tissues and cells in dietary magnesium deficiency: Initiation of roles of glutathione, mitochondrial alterations and lipid peroxidation in inflammation and atherogenesis. EC Pharmacol Toxicol.
141. Altura BM, Li W, Zhag A, et al. (2016) The expression of platelet-activating factor is induced by low extracellular Mg2+ in aortic, cerebral and neonatal coronary vascular smooth muscle: Cross-talk with ceramide production, NF-kB and proto-oncogenes : possible links to atherogenesis and sudden cardiac death in children and infants, and aging: hypothesis and viewpoint. Int J Cardiol and Res 3: 47-67.
142. Altura BM, Li W, Zheng T, et al. (2018) Alcohol causes elevation of ceramides and PAF concomitant with decline in intracellular free calcium in astocytes, brain slices, and brain capillary endothelial cells.