SemOpenAlex |

SemOpenAlex

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2108542246> ?p ?o ?g. }

Showing items 1 to 100 of ±323 with 100 items per page.

W2108542246 endingPage "240" @default.
W2108542246 startingPage "222" @default.
W2108542246 abstract "[Gomez] Associate Professor.Dennis M. Fisher, M.D., EditorIN 1935, Zwillinger reported that administration of magnesium (Mg (2+)) restored sinus rhythm in patients with digitalis-induced tachyarrhythmias. [1]Since that time, Mg2+has been used for prophylaxis or therapy in a variety of cardiovascular disorders [2]: myocardial ischemia and infarction, [3]coronary spasm, [4]ventricular [5]and supraventricular [6]arrhythmias, digoxin toxicity, [7]preeclampsia-eclampsia, [8]cerebral vasospasm, [9]and stroke. [10]Chronic Mg2+deficiency and acute hypomagnesemia are associated with increased cardiovascular morbidity and mortality. [11–15]Therapeutic effects, however, have been reported after pharmacologic administration, even in the absence of known Mg2+deficiency or hypomagnesemia. Because many of the abnormalities for which Mg2+therapy has been advocated are common among patients undergoing anesthesia and surgery, the anesthesiologist should be familiar with the rational use of this cation. Accordingly, this article addresses (1) the physiology and pharmacology of Mg2+relevant to patients with cardiovascular disease;(2) evidence supporting the use of Mg2+in a variety of disease states; and (3) current applications of Mg (2+) therapy.Mg2+metabolism and its derangements have been reviewed recently. [16–19]Mg2+is the second most abundant cation in the body, the second most abundant intracellular cation after potassium (K+), and a critical cofactor in >300 enzymatic reactions involving energy metabolism and protein and nucleic acid synthesis. Total body stores of Mg (2+) average 1,000 mmol for a 70-kg individual, with >50% in bone, nearly 50% in soft tissues, and <1% in blood. [18]In contrast to the tight hormonal control of concentrations of calcium (Ca2+) in blood, the kidney is the primary regulator of Mg2+balance. Although there is some hormonal influence on the renal handling of Mg2+(primarily by parathyroid hormone, calcitonin, and antidiuretic hormone), changes in dietary intake of Mg2+or concentrations of Mg2+in blood do not evoke hormone secretion. [19]Mg2+(intra- and extracellular) exists in three states:(1) free, ionized fraction (the physiologically active form);(2) complexed to anions (citrate, phosphate, bicarbonate); and (3) protein bound. In extracellular fluid, free Mg2+composes 61% of total Mg2+, 6% is complexed, and 33% is protein bound. [20]In this article, the symbol Mg2+designates total Mg2+cation unless otherwise modified (e.g., ionized Mg2+or complexed Mg2+).The diagnosis of Mg2+deficiency (defined as a reduction in total content of Mg2+in the body [17]) is difficult to establish because (1) it may be asymptomatic [2];(2) concentration of total Mg2+in serum may be normal despite depletion in tissue [21–26]; and (3) measurement of concentrations in tissue is not readily available [22,23]and may be specific for the tissue sampled. [17,22]Nonetheless, studies reporting Mg2+assays on a variety of tissues suggest that many patients with cardiovascular disease exhibit depletion of Mg2+compared with healthy individuals. [21,25,26]For example, Haigney et al. [21]found that (1) concentrations of Mg2+in buccal mucosal cells were reduced in patients with coronary artery disease compared with healthy volunteers, despite normal concentrations in serum, and (2) concentrations of Mg2+in buccal cells correlated well with atrial concentrations of Mg2+.The diagnosis of Mg2+depletion also has been based on the percent of Mg2+retained after an intravenous infusion of Mg2+. [27,28]The Mg2+retention test requires a baseline 24-h urine collection, after which Mg2+(0.2 mEq/kg lean body weight) is infused for 4 h and urine is again collected for 24 h. Mg2+-repleteindividuals should excrete at least 60% of the administered load. [27]Although the retention test is considered highly sensitive for depletion of Mg2+, it has not been possible to correlate the percent retention with the degree of total body Mg2+deficiency. [17]The test has been used to screen critically ill patients [29]and patients with diseases in which deficiency of Mg2+has been implicated as contributory (e.g., variant angina). [30–32]Goto et al. [33]found that patients with vasospastic angina had normal concentrations of total Mg2+in serum, but they excreted only 40 +/- 5% of the Mg2+load, whereas healthy individuals excreted 64 +/- 3%(P < 0.001).In clinical practice, laboratory assessment of Mg2+status usually begins with measurement of concentration of total Mg2+in serum. Serum rather than plasma is used because the anticoagulants (e.g., citrate, ethylene-diaminetetraacetic acid) for plasma affect the assay procedure. [23]This test, however, has several limitations in the assessment of Mg (2+) status, despite its ready availability. First, hypomagnesemia (defined as concentration of Mg2+in serum less than the normal range [22];Table 1) is often not present in patients with chronic depletion of Mg2+because of very slow equilibration of Mg2+among tissue compartments and because the compartment being sampled, namely blood, contains a small fraction of total Mg2+. [17]Second, concentration of total Mg2+in serum may not reflect concentration of ionized Mg2+in serum. [31,34–36]These findings may explain at least part of the beneficial effect of administration of Mg2+in some patients who appear to be normomagnesemic.Although the Mg2+-selectiveelectrode has been commercially available for several years, [37,38]it is not widely used because the clinical utility of ionized Mg2+measurement has not been established. Some authors have recommended measuring ultrafilterable Mg2+(the combination of complexed and ionized Mg2+) to approximate ionized Mg2+, [39–41]but this method also is not widely used.Sequelae. There is substantial evidence that chronic depletion of Mg2+and acute hypomagnesemia are associated with increased cardiovascular morbidity and mortality. [11–15,26,35,42–49]Animal studies have shown that chronic depletion of Mg2+exacerbates hypertriglyceridemia, hypercholesterolemia, and decreased high-density lipoprotein concentrations. [43,44]Dogs fed a Mg2+-freediet and subjected to coronary artery occlusion develop myocardial infarcts twice as large as dogs that are fed a normal diet. [45]Similarly, chronically Mg (2+-depleted) swine have prolonged postischemic myocardial dysfunction (stunning) compared with Mg2+-repletecontrol animals. [46]Human epidemiologic studies indicate that chronic depletion of Mg2+is associated with ventricular arrhythmias [12]and increased atherosclerotic vascular disease and associated cardiovascular mortality. [11,13,14]Myocardial depletion of Mg2+is associated with an increased incidence of arrhythmias after cardiac surgery. [26]Finally, recent results suggest that early and progressive ionized hypomagnesemia during pregnancy is associated with the development of preeclampsia at term. [47]Acute hypomagnesemia in isolated hearts subjected to ischemia worsens postischemic function and arrhythmias. [48]In contrast, Madias et al. [49]found that, in patients with acute myocardial infarction (AMI), low concentrations of Mg2+in serum on admission were not associated with arrhythmias or increased hospital mortality. However, ionized and tissue concentrations of Mg2+were not measured, and patients who were hypomagnesemic in the emergency department were more likely to be treated with MgSO4(P < 0.001). [49]Landmark and Urdal [15]reported that large decreases in concentrations of total Mg2+in serum during AMI were associated with higher peak concentrations of creatine kinase. Finally, hyperventilation-induced acute ionized hypomagnesemia is associated with variant anginal episodes despite normal concentrations of total Mg2+. [35]Mechanisms. Although many patients with chronic heart disease are Mg2+depleted, [21]a variety of superimposed stressors cause additional decreases in concentrations of Mg2+in serum by redistribution (Table 2). [3]Patients presenting with AMI, for example, have a precipitous decrease in concentrations of Mg2+in serum, with the lowest concentrations seen 12–20 h after hospital admission. [50]The postulated mechanism involves catecholamine-induced lipolysis and generation of free fatty acids, which then chelate free Mg2+to form insoluble salts that are sequestered intracellularly. [3,51,52]Catecholamines increase uptake of Mg2+by adipose cells. [53,54]Other high-stress states, such as major burns, sepsis, trauma, alcohol withdrawal, hypothermia, or cardiac surgery, also may be accompanied by catecholamine-induced hypomagnesemia. [50,55,56]Concentrations of total Mg2+in serum decrease significantly during cardiopulmonary bypass (CPB), and these concentrations persist into the post-CPB period, during which they are associated with increased morbidity. [57,58]Recent reports indicate that concentrations of ionized Mg2+also decrease during and after CPB. [34,59]Several factors have been implicated in CPB-related hypomagnesemia. First, measurable preoperative hypomagnesemia is common in patients undergoing cardiac surgery. [39,58,60,61]Second, there may be additional decreases in concentrations of Mg2+in serum after induction of anesthesia but before CPB, probably as a result of hemodilution with Mg2+-freefluids. [39,58]Increasing concentrations of catecholamines also may have contributed to the decrease. Third, during CPB, further decreases in concentrations of Mg2+in serum are caused by additional hemodilution, binding to albumin in the pump prime, and redistribution secondary to catecholamine-induced increases in concentrations of free fatty acid. [39,62]Although urinary excretion of Mg2+may increase slightly during CPB, it is probably not a major factor in CPB-related Mg2+flux unless exogenous Mg2+is administered. [63,64]Intraoperative administration of Mg2+-containingcardioplegia solutions [64](or the equivalent intravenous bolus dose of Mg2+[65]) prevents the decrease in concentrations of total Mg2+seen during and after CPB, but concentrations of ionized Mg2+may still be decreased. [34]Intracellular Mg2+. Although the important pharmacologic actions of Mg2+are primarily extracellular, free cytosolic Mg2+(Mgi2+) modulates the intracellular milieu through its influence on ion channels and transport mechanisms. [66–70]Although this area has been reviewed, [71–74]two general points are important. First, Mgi2+modulates Ca2+flux in pathophysiologic and physiologic states. [71–73]Increasing concentrations of Mgi2+during early ischemia or hypoxia [67,75]have beneficial effects on L-type Ca2+channels during stress [66,69,71,74]; i.e., Ca2+influx is inhibited. [68]Second, depletion of Mgi2+, as occurs after prolonged ischemia and reperfusion, [76]contributes to progressive Ca2+over-load and subsequent cell damage (discussed subsequently). [45]In addition, loss of Mgi2+may promote cystolic Ca2+overload from intracellular sources: Elevated concentrations of Mgi2+inhibit efflux of Ca2+from sarcoplasmic reticulum. [77,78]Extracellular Mg2+. For nearly two decades, extracellular Mg (2+)(and several other divalent cations) has been considered to be a Ca (2+) antagonist because it inhibits Ca2+current in excitable cells. This has several clinical implications because (1) virtually all excitable cells have voltage-gated Ca2+channels [79];(2) in general, these channels transduce electrical signals (that is, membrane depolarization) into various cellular actions (e.g., muscle contraction, neurotransmitter release) via modulation of Ca2+flux [80];(3) Ca2+current supports excitation in the sinoatrial and atrioventricular nodes and conduction through the atrioventricular node [81]; and (4) voltage-sensitive Ca2+channels also play important roles in arrhythmogenesis. [82]Two mechanisms are believed to be involved in inhibition of Ca2+current by extracellular Mg2+:(1) effects mediated by cationic screening of fixed negative external surface charges [83–85]; and (2) competition with permeant ions (Ca2+) for a site within the channel itself. [86]Elevated extracellular divalent cation concentrations stabilize excitable membranes and raise the excitation threshold in voltage-dependent channels. [87,88]The net result for a given voltage-sensitive channel is a shift of the current-voltage relationship so that current is diminished in response to a standard stimulus. [87,89]Divalent cations such as Mg2+effectively neutralize fixed negative charges on the outside of the cell membrane either by binding or, more likely, by electrostatic screening. [83,90]The result is a change in the effective local transmembrane potential sensed by the voltage-sensitive Ca (2+) channel. [91]This offset in the transmembrane potential across the channel, sensed by the voltage sensor, alters any voltage-dependent processes such as gating (i.e., channel activation and inactivation). [85]In addition to alterations of transmembrane potential in the vicinity of the channel, it is also possible that divalent cation screening of fixed negative charges on the channel entrance itself effectively decreases the local permeant cation (Ca2+) concentration, thereby reducing current flow. [85,92]Mg2+affects both L-type and T-type Ca2+channels. [93]Although early studies showed that, during some experimental conditions (i.e., use of Ba2+as charge carrier in the presence of Bay K8644, a Ca2+channel opener [94]), Mg2+has relatively weak direct channel blocking activity, [86]evidence to date indicates that elevated extracellular concentrations of Mg2+effectively decrease Ca (2+) current by altering the membrane surface potential in the vicinity of the Ca2+channel, rather than by lodging in the channel pore itself. [95]Mg2+and Ischemic-Reperfusion Injury. Studies in the 1970s showed that myocardial ischemia followed by reperfusion results in cytoplasmic Ca2+overload. [79,96–99]There is now general agreement that during and after periods of ischemia, transmembrane Ca2+influx occurs by several routes, [97,100–112]and that cytoprotective agents, including Mg2+, attenuate the increase in intracellular Ca2+via multiple mechanisms. [102,103,113–122]Antiischemic Effects. In animals, administration of Mg2+before permanent coronary artery occlusion is highly effective in limiting the size of myocardial infarcts. [123]Clinical management of AMI, however, involves reperfusion therapy as early as possible after the onset of ischemia. Recent attention has shifted toward identifying agents that may be administered before or concurrently with reperfusion therapy, with particular emphasis on drugs that reduce myocardial injury caused by reperfusion. [124]There is experimental evidence that Mg2+is cardioprotective. [125–127]Recent models designed to simulate the clinical setting in which Mg2+is administered during the interval beginning shortly after coronary occlusion and extending through initial reperfusion have shown significant reductions in the size of myocardial infarcts [125,126]and in the severity of regional myocardial stunning. [127]Numerous cardioprotective effects have been attributed to Mg2+(Table 3). [4,119,127–144]Mg2+Cardioplegia. Effects of cardioplegia on reperfusion injury have been reviewed recently. [145–149]A brief period of ischemia causes reversible cell injury, defined by the finding that reperfusion prevents infarction and allows eventual recovery of normal cellular structure, function, and metabolism. [146]Complete recovery, however, is not immediate; profound metabolic and functional abnormalities may persist for hours or days after as few as 5–15 min of coronary occlusion. [147]These abnormalities are manifestations of reperfusion injury and include (1) postischemic contractile dysfunction (stunning);(2) reperfusion arrhythmias (see antiarrhythmic effects); and (3) damaged microvasculature preventing continued reperfusion (no reflow). [148]Stunning occurs in many clinical settings, particularly interventional (and spontaneous) thrombolysis in acute coronary syndromes [145]and in the post-CPB period. [149]Studies using isolated perfused hearts subjected to periods of global ischemia and reperfusion have shown that Mg2+cardioplegia significantly reduces myocardial stunning and cytosolic Ca2+overload [115,116,150–153]when given concurrently with or before reperfusion. [126]Ischemic - reperfusion injury of the microvasculature results in progressive diminution of perfusion to previously ischemic tissues despite restoration of flow in the conduit arteries supplying these tissues, i.e., the noreflow phenomenon. [148]The no-reflow phenomenon is a significant clinical problem. It occurs in 2% of coronary interventions (e.g., balloon angioplasty, directional atherectomy, stent placement)[154]and in 23–27% of patients receiving thrombolytic therapy during AMI. [155,156]No reflow is associated with a higher incidence of early and prolonged congestive heart failure (CHF) compared with the absence of no reflow. [156]The primary insult in no reflow is probably reperfusion-induced (and oxygen free radical-mediated) injury to endothelium. [157–162]Circumstantial evidence suggests that Mg2+reduces endothelial injury. First, deficiency of Mg (2+) potentiates oxygen free radical-induced postischemic injury in working isolated rat hearts. [158]Second, agents that attenuate the initial ischemic injury, namely Ca2+antagonists administered before reperfusion, also reduce the severity of no reflow [163]and preserve endothelial function. [164]Finally, experimental areas of no reflow are decreased, and vascular endothelial and smooth muscle function are preserved after administration of Mg2+cardioplegia (16 mM). [165,166]Mechanisms. Despite improved understanding, pharmacologic control of cardiac arrhythmias is still largely empiric because there are few criteria to differentiate underlying mechanisms. [167]Moreover, many antiarrhythmic agents (including Mg2+) have multiple effects on the key components of arrhythmogenesis (and their interactions), namely substrate, trigger, and modulating factors. [168]The nature and severity of the substrate derangement itself can affect the specificity of antiarrhythmic drug activity. For example, in experimental models of ventricular tachycardia involving different arrhythmogenic mechanisms (e.g., ischemic, digitalis toxic, catecholamine induced), Mg2+possesses class IV (Ca2+channel inhibition [169]) and weak class I (Na+channel inhibition [169]) antiarrhythmic activities. [170]Several specific and related antiarrhythmic mechanisms involving Mg2+have been inferred after nearly seven decades of clinical and experimental observations (Table 4). [113,114,136,167,168,171–179]Electrophysiologic Effects. Administration of MgSO4during electrophysiologic evaluation of patients has demonstrated two effects of Mg (2+) relevant to the treatment of supraventricular tachyarrhythmias:(1) prolongation of atrioventricular nodal conduction time (anterograde and retrograde) and refractory period [6,180–184]; and (2) suppression of conduction in accessory pathways with and without atrioventricular node-like properties, [6,182]although conflicting results have been reported. [184]Prolongation of atrioventricular nodal conduction by Mg2+is most likely attributable to inhibition of Ca2+current, the primary mode of impulse conduction through the atrioventricular node, [81]but also may results from Mg2+-inducedattenuation of sympathetic activity at the atrioventricular node. [184,185]Other antiarrhythmic effects of Mg2+have been reported, although the underlying mechanisms have not been defined:(1) restoration of sinus rhythm in critically ill medical and surgical patients with supraventricular tachycardias [186];(2) suppression of intractable ventricular tachyarrhythmias [5];(3) control of ventricular rate in new-onset atrial fibrillation (AF)[187,188];(4) prophylaxis of AF after coronary artery bypass grafting [189,190];(5) slowing of digoxin-facilitated ventricular rate during AF in Wolff-Parkinson-White syndrome [191];(6) abolition of preexcitation (Delta wave) in patients with Wolff-Parkinson-White syndrome during normal sinus rhythm [192];(7) suppression of multifocal atrial tachycardia [193–194];(8) suppression of digoxin-induced ectopic tachyarrhythmias [1,7];(9) prevention of bupivacaine-induced arrhythmias [195]; and (10) treatment of amitriptyline-induced ventricular fibrillation. [196]Intact Individuals. Circulatory effects of rapid administration of Mg2+in awake individuals are minimal even in the presence of hypertension or moderately severe ventricular dysfunction. In several studies, Mg2+was administered as a bolus dose with or without continuous infusion, sufficient in some cases to achieve a threefold increase in concentrations of Mg2+in serum (Table 5). [141,180,197–203]The most common finding was a small decrease in blood pressure accompanied by a decrease in systemic vascular resistance and an increase in cardiac output and stroke volume. These results suggest that negative inotropic effects of moderately elevated concentrations of Mg2+are effectively counterbalanced by Mg2+-inducedafterload reduction.The few studies that have involved administration of Mg2+in anesthetized individuals (not during CPB) either have not reported hemodynamic effects [7,60]or have involved infusion of Mg2+for control of pathologic hyperdynamic states associated with pheochromocytoma [204,205]or severe tetanus. [138,139]Because volatile anesthetic agents depress intracellular Ca2+flux, [206]however, it is likely that the circulatory effects of high concentrations of Mg2+in serum are potentiated by these agents, particularly in patients with ventricular dysfunction. Recent experimental evidence suggests, however, that a 10-fold increase in concentrations of Mg2+in blood during sevoflurane-N2O or sevoflurane-fentanyl anesthesia results in minimal cardiovascular depression. [207,208]Regional Circulations. Mg2+vasodilates by inhibiting Ca2+influx at the vascular smooth muscle membrane [209–211]and possibly by interfering with release of Ca2+from intracellular sites. [212]Mg (2+) increases renal blood flow in healthy individuals, [141,213]increases uterine blood flow in pregnant patients, [214]and dilates isolated human (pregnant) uterine artery segments. [215]Experimental and clinical observations indicate that Mg2+dilates coronary arteries, particularly when coronary vasoreactivity is pathologic. Mg2+dilates preconstricted segments of human (fresh cadaver) coronary arteries, [128]decreases coronary vascular resistance (and increases coronary blood flow) moderately in healthy individuals, [200]provides rapid relief of vasospastic angina, [4,129]and prevents inducible episodes of vasospastic angina. [129–131,197]In addition, coronary artery spasm occurs in eclampsia, [216]and it is likely (albeit unproven) that one of the myriad beneficial effects of Mg2+in this potentially lethal condition is cardioprotection. [129]The cerebral circulation also responds to changes in concentrations of Mg2+. Withdrawal of Mg2+rapidly increases the tension in canine middle and basilar cerebral arteries. [217]In contrast, sudden increases in Mg2+cause rapid and concentration-dependent relaxation of basal tension in all cerebral arteries tested. [218]Mg2+relaxes preconstricted (by serotonin, prostaglandins, or Ca2+) cerebral arteries [218–220]and arteries subjected to delayed spasm secondary to subarachnoid hemorrhage. [221]Mg2+also produces dose-dependent relaxation of cerebral arterioles (17–30 [micro sign] in diameter). [218]Cerebral arteriolar dilation, with the accompanying increased cerebral blood flow, is one of the salutary effects of administration of Mg2+in severe eclampsia [222]and may account, at least in part, for the anticonvulsant effect of Mg2+in this setting. [8]Diffuse and intense cerebral vasospasm associated with preeclampsia-eclampsia has been documented angiographically. [223–225]Another potential anticonvulsant effect of Mg2+in preeclampsia, in addition to its vascular (antiischemic) actions, is attenuation of ischemia-induced neuronal Ca2+influx via channels associated with the excitatory N-methyl-D-aspartate subtype of glutamate receptor. [226–228]Endothelial Effects. Normal endothelium modulates the state of contraction of the underlying vascular smooth muscle. [229–232]Endothelial dysfunction is implicated in several disease processes, including atherosclerosis, [233]pathologic coronary vasoreactivity with and without significant coronary stenoses, [234]and preeclampsia-eclampsia. [235]Normal endothelium synthesizes the vasodilators prostacyclin and nitric oxide (NO). [236–238]Infusion of Mg2+increases endothelial release of prostacyclin, not only by cultured human endothelial cells [239]but also in healthy nonpregnant volunteers [141]and preeclamptic patients. [240]These results suggest that vascular actions of Mg2+in healthy individuals and preeclamptic patients are mediated, at least in part, by release of prostacyclin. Further, in preeclampsia, Mg2+-inducedrelease of prostacyclin antagonizes pathologic platelet adhesion, aggregation, and resulting microvascular occlusion secondary to endothelial dysfunction in this disorder. [235,239]Similar to the reciprocal or mutant antagonistic relationship between Ca2+and Mg2+at the level of the vascular smooth muscle cell membrane, [212,213,218]there appears to be a reciprocal interaction at the level of the vascular endothelial cell membrane (see subsequent section). Extracellular Ca2+is essential for endothelium-dependent vascular smooth muscle relaxation [241]; an increase in endothelial cell intracellular Ca2+accompanies basal production or release of NO and the release of NO in response to a wide variety of endothelium-dependent dilators. [242]Entry of Ca2+in endothelial cells, however, is not voltage-gated; i.e., these cells are nonexcitable. [243]Rather, Ca2+entry is capacitative: It is activated by depletion of intracellular Ca2+stores. [244]Although the effect of Mg2+on capacitative entry of Ca2+in endothelial cells has not been addressed specifically, elevated extracellular Mg2+has been shown to inhibit capacitative Ca2+entry in other cells. [245]Experimental studies have shown that (1) removal of extracellular Mg2+causes a potent, endothelium-dependent vasodilatory response [246–249];(2) in contrast, removal of Mg2+in arteries with disrupted endothelium leads to vasoconstriction; and (3) both responses are reversible with readdition of Mg2+. [246–249]When concentrations of Mg2+or Ca2+are increased to higher than the physiologic range (>1.2 and >1.5 mM, respectively), the direct endothelium-independent effects dominate. When the concentration of Ca2+is >1.5 mM in the presence of a normal concentration of Mg2+, endothelium-intact rings contract; when the concentration of Mg2+is >1.2 mM, endothelium-intact rings relax. [248]Because Ca2+is obligatory for smooth muscle contraction and basal NO formation or release, and because Mg2+opposes the action of Ca (2+) at both sites, these studies suggest that the responsiveness of vascular smooth muscle to changes in concentrations of Mg2+and Ca2+reflects the sum of responses at the endothelial and smooth muscle cells. [248]Studies of the effects of Mg2+on agonist-induced, NO-mediated relaxation of arteries have produced contradictory results. [250–253]The clinical significance of these results is not clear for two reasons. First, these studies used different types of isolated blood vessels from a variety of species. Second, and more important, most of these studies used extracellular concentrations of Mg2+outside the physiologic range (e.g., Mg2+-freeperfusate). In one study, however, human pial arteries were used to show that even slight changes in extracellular concentration of Mg2+within the physiologic range (i.e., 1.2 mM to 0.8 mM) resulted in relaxation of endothelium-intact arteries and constriction of endothelium-disrupted arteries. [249]These results suggest that normal endothelium protects against the vasospastic effect of low extracellular concentrations of Mg2+. [249]In 1991, Teo et al. [254]reported a metaanalysis of seven small randomized, placebo-controlled trials of Mg2+in AMI conducted during the previous decade. They found a reduction in mortality from AMI of 53% and a significant reduction in serious arrhythmias with Mg2+. A second metaanalysis of eight trials, which included the studies analyzed by Teo et al., yielded similar results. [255]Two additional randomized trials found that Mg2+-treatedpatient groups had significantly lower in-hospital [256]and 30-day mortality. [257]Recently, however, two large randomized trials of Mg2+in AMI yielded conflicting results. It is worthwhile to comment on these trials because significant methodologic differences may account for the disparate findings. Woods et al. [258]studied 2,316* patients in the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2), which showed that doubling the concentration of Mg2+in serum in the acute phase of AMI improved outcome significantly. Mortality at 28 days, the primary trial end point, was reduced by 24% in the Mg2+group compared with the placebo group (7.8% mortality vs. 10.3% respectively; two-tailed P = 0.04). LIMIT-2 was a single-center, double-blinded trial, and the median interval from onset of symptoms to administration of the study drug was 3 h. Other treatments for AMI were given as clinically indicated; therefore, some patients received a thrombolytic agent, aspirin, or both immediately after receiving the study drug. Analysis of these subgroups and others, including those receiving previous [Greek small letter beta]-adrenergic blocker, diuretic, nitrate, or Ca2+antagonist, showed that Mg2+improved survival significantly in all subgroups. Reduction in mortality was accompanied by a 25% reduction in the incidence of left ventricular failure (two-tailed P = 0.009" @default.
W2108542246 created "2016-06-24" @default.
W2108542246 creator A5012244933 @default.
W2108542246 date "1998-07-01" @default.
W2108542246 modified "2023-10-05" @default.
W2108542246 title "Magnesium and Cardiovascular Disease " @default.
W2108542246 cites W101547108 @default.
W2108542246 cites W105247614 @default.
W2108542246 cites W120359137 @default.
W2108542246 cites W140776867 @default.
W2108542246 cites W1460290523 @default.
W2108542246 cites W1490746554 @default.
W2108542246 cites W1501936762 @default.
W2108542246 cites W1504468632 @default.
W2108542246 cites W1536233348 @default.
W2108542246 cites W1555165785 @default.
W2108542246 cites W1568387799 @default.
W2108542246 cites W1571274258 @default.
W2108542246 cites W1580444077 @default.
W2108542246 cites W1606576717 @default.
W2108542246 cites W1823411753 @default.
W2108542246 cites W1830447029 @default.
W2108542246 cites W1855918737 @default.
W2108542246 cites W1857508511 @default.
W2108542246 cites W1882996137 @default.
W2108542246 cites W1899097043 @default.
W2108542246 cites W1899877571 @default.
W2108542246 cites W1923896920 @default.
W2108542246 cites W1953419063 @default.
W2108542246 cites W1964441909 @default.
W2108542246 cites W1964586793 @default.
W2108542246 cites W1964686850 @default.
W2108542246 cites W1965293353 @default.
W2108542246 cites W1966182601 @default.
W2108542246 cites W1967144137 @default.
W2108542246 cites W1967309809 @default.
W2108542246 cites W1967333077 @default.
W2108542246 cites W1967554202 @default.
W2108542246 cites W1969620472 @default.
W2108542246 cites W1971831443 @default.
W2108542246 cites W1972014816 @default.
W2108542246 cites W1972641551 @default.
W2108542246 cites W1972971875 @default.
W2108542246 cites W1973860118 @default.
W2108542246 cites W1974248633 @default.
W2108542246 cites W1974386299 @default.
W2108542246 cites W1974426390 @default.
W2108542246 cites W1974815604 @default.
W2108542246 cites W1975019237 @default.
W2108542246 cites W1976283130 @default.
W2108542246 cites W1977350873 @default.
W2108542246 cites W1979490534 @default.
W2108542246 cites W1979546330 @default.
W2108542246 cites W1980849503 @default.
W2108542246 cites W1982427280 @default.
W2108542246 cites W1982852481 @default.
W2108542246 cites W1982877152 @default.
W2108542246 cites W1983687348 @default.
W2108542246 cites W1983725994 @default.
W2108542246 cites W1983986458 @default.
W2108542246 cites W1984795028 @default.
W2108542246 cites W1984862252 @default.
W2108542246 cites W1986213568 @default.
W2108542246 cites W1986728006 @default.
W2108542246 cites W1986888244 @default.
W2108542246 cites W1987355981 @default.
W2108542246 cites W1988434628 @default.
W2108542246 cites W1988818855 @default.
W2108542246 cites W1992561821 @default.
W2108542246 cites W1992718978 @default.
W2108542246 cites W1993368967 @default.
W2108542246 cites W1994904265 @default.
W2108542246 cites W1996867040 @default.
W2108542246 cites W1997561902 @default.
W2108542246 cites W1997568797 @default.
W2108542246 cites W1998347917 @default.
W2108542246 cites W1998689607 @default.
W2108542246 cites W2000191381 @default.
W2108542246 cites W2000331325 @default.
W2108542246 cites W2000711773 @default.
W2108542246 cites W2000851848 @default.
W2108542246 cites W2001468299 @default.
W2108542246 cites W2003788012 @default.
W2108542246 cites W2005261621 @default.
W2108542246 cites W2005785764 @default.
W2108542246 cites W2005905514 @default.
W2108542246 cites W2008545116 @default.
W2108542246 cites W2008927736 @default.
W2108542246 cites W2009242844 @default.
W2108542246 cites W2009519343 @default.
W2108542246 cites W2010309809 @default.
W2108542246 cites W2010322323 @default.
W2108542246 cites W2010625490 @default.
W2108542246 cites W2012955910 @default.
W2108542246 cites W2013876824 @default.
W2108542246 cites W2014551842 @default.
W2108542246 cites W2016556619 @default.
W2108542246 cites W2017936170 @default.