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W B Weglicki

Publications and source records attributed to W B Weglicki.

At least 55 records · Page 3Linked to original sources
PubMed1992

Magnesium-deficiency elevates circulating levels of inflammatory cytokines and endothelin.

We have developed two rodent models of diet-induced magnesium-deficiency in which histologically defined cardiac lesions can be induced within two to three weeks. During the development of these lesions, the magnesium-deficient animals exhibit circulating cytokine levels which are indicative of a generalized inflammatory state. Dramatic elevations of the macrophage-derived cytokines, IL-1, IL-6, and TNF-alpha together with significantly elevated levels of the endothelial cell-derived cytokine, endothelin, were detected in the plasma of these animals. We believe that the pathophysiological effects caused by the action of these cytokines may play a role in the promotion of cardiovascular pathology associated with magnesium deficiency.

Animals↗
PubMed1992

Membrane antiperoxidative activities of D-propranolol, L-propranolol and dimethyl quaternary propranolol (UM-272).

With the isolated sarcolemmal membrane model, the antiperoxidative activities of D-propranolol, L-propranolol and the non-beta-blocker analogue UM-272 (dimethyl quaternary propranolol) were compared. Membrane lipid peroxidation induced by the Fe-catalysed, hydroxyl radical producing system (dihydroxyfumarate + Fe3+) was assessed by MDA formation. In the range of 10-200 microM, both D- and L-propranolol exhibited identical concentration-dependent inhibitory effects (20-70%), whereas UM-272 was about 2/3 as active as propranolol. In contrast, lignocaine (lidocaine), a well known membrane stabilizer, did not produce any effect. When purified rat hepatic microsomes were peroxidized by NADPH + Fe3+, comparable antiperoxidative effects were produced by the propranolol enantiomers and the dimethyl analogue. Thus, the antioxidant activities of these agents are related to their intrinsic chemical properties which might contribute to the reported beneficial effects of propranolol and UM-272 in models of ischaemia/reperfusion injury.

Animals↗
PubMed1992

Erythrocytes from magnesium-deficient hamsters display an enhanced susceptibility to oxidative stress.

Previous studies in our laboratory have indicated a role for free radical participation in magnesium deficiency cardiomyopathy. We have demonstrated the ability of various antioxidant drugs and nutrients to protect against magnesium deficiency-induced myocardial injury. In this study, we have examined erythrocytes from normal and magnesium-deficient animals and compared their susceptibility to an in vitro oxidative stress. Syrian male hamsters were placed on either magnesium-deficient or magnesium-supplemented diets. Animals from each group also received vitamin E in doses of 10 and 25 mg as subcutaneous implants. Erythrocytes obtained after 14 days on the diet were exposed to an exogenous hydroxyl (.OH) radical generating system (dihydroxyfumarate not equal to Fe3+ ADP) at 37 degrees C for 20 min. Erythrocyte crenation was observed and quantified by scanning electron microscopy. Lipid peroxidation, hemolysis (%), and intracellular glutathione levels were determined. In addition, serum lipid changes and membrane phospholipids were characterized. Our data demonstrate that erythrocytes from magnesium-deficient animals are more susceptible to free radical injury, supporting our hypothesis that magnesium deficiency reduces the threshold antioxidant capacity.

Adenosine Diphosphate↗
PubMed1992

Pathobiology of magnesium deficiency: a cytokine/neurogenic inflammation hypothesis.

During the progression of Mg deficiency in a rodent model, we have observed dramatic increases in serum levels of inflammatory cytokines [interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha)] after 3 wk on a Mg-deficient diet. Sequential analyses of these cytokine changes in the serum of rats revealed an initial rise at day 12, followed by a major elevation in all three cytokine levels by day 21. Of greater interest was an early peak in the serum level of the neuropeptide substance P after only 5 days on the diet. This "neuronal" tachykinin is thought to be released from neural tissues, and it is known to stimulate production of certain cytokines, including IL-1, IL-6, and TNF-alpha. In addition, there was a concomitant increase in histamine levels, which may have resulted from stimulation and degranulation of mast cells by substance P. Thus we hypothesize that the release of substance P may be the earliest pathophysiological event leading to stimulation of the inflammatory cytokines, which may then stimulate the free radical mechanisms of injury previously confirmed by our work.

Animals↗
PubMed1992

Antioxidant effects of calcium channel blockers against free radical injury in endothelial cells. Correlation of protection with preservation of glutathione levels.

The effects of four calcium channel blockers (nicardipine, nifedipine, verapamil, and diltiazem) on free radical injury in cultured endothelial cells were studied and compared with those of butylated hydroxytoluene. When the cultured cells were exposed to a superoxide and hydroxyl radical generating system for up to 60 minutes, lipid peroxidation occurred, and cellular viability decreased by 60% at 30 minutes. Concomitantly, total cellular glutathione decreased by 40%, whereas total protein thiols changed minimally. Preincubation of the cells with each of the calcium blockers (5 and 20 microM) before free radical addition resulted in various degrees of significant protection against cell death, and losses of glutathione correlated significantly (r = 0.89, p less than 0.001). The order of efficacy was nicardipine greater than nifedipine greater than verapamil greater than diltiazem; butylated hydroxytoluene was about fourfold more potent than nicardipine. Because none of the agents affected the level of hydroxyl radicals generated in the aqueous phase, the data suggest that the protective mechanisms were mediated by their lipid antiperoxidative activities, which also prevented the glutathione decrease caused by inhibition of peroxide generation.

Animals↗
PubMed1992

Antioxidants and the cardiomyopathy of Mg-deficiency.

For several decades the animal models of Mg-deficiency have been studied with particular attention to the cardiomyopathy that develops due to dietary deficiency. In recent years we have studied the effects of nutrients and drugs with antioxidant properties on the development of the cardiomyopathy. We have found that treatment of the Mg-deficient animals with alpha-tocopherol, a naturally-occurring antioxidant, significantly diminishes the number and size of lesions. In addition, treatment with lipophilic drugs with antioxidant properties (probucol, propranolol) or water-soluble drugs that scavenge hydroxyl radicals (captopril, epicaptopril), also provided significant protection. In view of these findings, we suggest that chronic hypomagnesemia results in a pro-inflammatory condition leading to excessive production of oxygen-derived free radicals. Subsequently, the tissue antioxidant capacity is overwhelmed and oxidative tissue destruction results.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Beta-blockers, calcium channel blockers and the sulfhydryl-ACE inhibitors demonstrate protection against free-radical-mediated injury of cardiovascular cells and membranes.

During reperfusion of previously ischemic cardiac tissue, oxygen-centered free radicals are generated and may result in peroxidative injury of cardiovascular cells and membranes. Since the occurrence of reperfusion injury in patients is unpredictable, particularly in those patients with chronic ischemic coronary artery disease, silent ischemia and those predisposed to significant coronary spasm, it would be advantageous to provide continuing therapy with antioxidant agents.

Adrenergic beta-Antagonists↗
PubMed1991

Propranolol reduces anoxia/reoxygenation-mediated injury of adult myocytes through an anti-radical mechanism.

The effects of propranolol (PRO) and atenolol (ATE) on adult canine myocytes exposed to 30 min anoxia (A:95% N2/5% CO2) and subsequent reoxygenation (R:95% O2/5% CO2) for up to 20 min was investigated. In some studies, comparison of effects were made with that of superoxide dismutase (SOD). Although anoxia alone produced only minimal injury, reoxygenation in the absence of the beta-blockers or SOD was associated with significant losses of cellular viability, elevated release of cellular lactate dehydrogenase, and increased formation of lipid peroxidation products. Myocytes exposed to A/R in the presence of d,1-PRO (20, 200 microM) were afforded substantial, concentration-dependent protection during 20 min reoxygenation. Significant protection was also observed in the presence of 2 microM d-PRO (non-active beta-blocker), but only after a longer preincubation period (2 h). SOD (10 micrograms/ml) provided equi-potent protection to that of 200 microM d,1-PRO. By contrast, the more water-soluble beta-blocker, ATE (200 microM), offered only minor protection. Electron Spin Resonance spin trapping studies using alpha-phenyl-tert-butylnitrone (PBN) were also performed with A/R myocytes in the presence or absence of drug treatment. Short-term (10 min) exposure to d,1-PRO (200 microM) prior to A/R, or to SOD, resulted in a 71-84% reduction in total PBN lipid radical adduct formation (alkoxyl; alpha H = 2.0-2.5 G, alpha N = 13.5-13.75 G); long-term exposure (2 h) to 2 microM d-PRO resulted in a 51% reduction. These data suggest that the superoxide anion was an initiator of events leading to subsequent lipid radical formation and that the anti-peroxidative properties of PRO appear to be independent of beta-receptor blockade.

Adrenergic beta-Antagonists↗
PubMed1991

Propranolol preserves ultrastructure in adult cardiocytes exposed to anoxia/reoxygenation: a morphometric analysis.

The protective effect of d,l-propranolol was studied using freshly isolated canine ventricular cardiocytes (1.5 x 10(6)/mL) exposed to 30 min anoxia (95% N2/5% CO2) and 0, 3, 20, and 45 min of reoxygenation (95% O2/5% CO2). In addition to preventing lipid peroxide formation, propranolol maintained cellular viability, and minimized ultrastructural alterations. In the absence of propranolol, the outer mitochondria become swollen and rounded up within the first few minutes of reoxygenation. The perinuclear mitochondrial area increased only slightly. We observed that the cellular injury process proceeded differentially from the exterior to the interior, with a mitochondrial area increase and outer membrane rupture. Sarcolemmal damage was also observed with prevalent blebbing and membrane loss. The Z-lines became wider and more diffuse with reoxygenation. Injury to the nuclear double membrane was observed. Incubation with propranolol showed significant protection during postanoxia reoxygenation. In contrast, the more water soluble beta-blocker atenolol only exhibited slight protection. In addition, d-propranolol (the non beta-blocking isomer) and the antioxidant enzymes, SOD and catalase, showed significant protection. These data support previous findings concerning the antioxidant properties of propranolol which appear to be independent of beta-receptor blockade.

Animals↗
PubMed1991

Free radical-induced injury to C6 glioma cells.

Scanning electron microscopic studies revealed that the cell bodies of cultured C6 cells were densely covered with villi and that membrane blebs were rare. Exposure to a hydroxyl radical generating system resulted in rapid ultrastructural changes. Within 2.5 minutes, 98% of the cells lost their villi. The number of blebbed cells increased during the first 7.5 minutes of exposure, until virtually all cells were blebbed. After 20 and 30 minutes of exposure, the plasma membrane of the blebs ruptured, resulting in the escape of cell contents and cell necrosis. Trypan blue exclusion, a measure of cell viability, decreased between 1 and 7.5 minutes of exposure. No further significant decline in viability was observed for the remainder of the experiment. The hydroxyl radical generating system also initiated a rapid onset of membrane lipid peroxidation, as measured by accumulation of thiobarbiturate reactive material. After a short lag period, thiobarbiturate reactive material increased rapidly, with maximum lipid peroxidation occurring by 20 minutes. Increasing the concentration of the radical generating system components shortened the time course but not the level of maximal thiobarbiturate reactive material production. These data suggest that plasmalemmal lipid peroxidation plays a role in rapid morphological changes and necrosis that occur after free radical insult.

Animals↗
PubMed1991

Postischemic free radical production in the venous blood of the regionally ischemic swine heart. Effect of deferoxamine.

BACKGROUND: We tested the hypothesis that secondarily produced free radicals can be detected in venous coronary effluent without the need for direct exposure of postischemic tissue to the spin trapping agent alpha-phenyl-tert-butylnitrone (PBN). METHODS AND RESULTS: The left anterior descending coronary artery (LAD) of pigs was ligated for 15, 30, 40, or 60 minutes, and the tissue was subsequently reperfused for 60 minutes. Venous effluent (6.5 ml) from the risk area was withdrawn sequentially at 1.5-minute intervals during reperfusion. The effluent blood was immediately infused (4.5 ml/min) with an isotonic saline solution containing 120 mM PBN: Preischemic control effluent samples were collected in an identical fashion. Plasma from each sample was extracted in organic solvent and subsequently analyzed by electron spin resonance (ESR) spectroscopy. Another group of pigs received an infusion of the metal chelator deferoxamine mesylate (25 mg/kg/hr) into the right atrium starting 1 hour before the 40-minute ligation and continuing throughout ligation and reperfusion. We were able to demonstrate the postischemic production of ESR signals for PBN adduct(s) from untreated hearts having spectral characteristics similar to an alkoxyl adduct (PBN-RO.; hyperfine splitting constants for beta-hydrogen [alpha H] = 2.0-2.25 G; nitrogen [alpha N] = 13.5-13.75 G). The reperfusion time course of PBN adduct production had a unique pattern: 1) multiple low-level bursts during the initial 15 minutes of reperfusion, and 2) a prominent PBN adduct signal during a relatively late time (20-25 minutes) of reperfusion. Total postischemic PBN adduct production rose with increasing duration (15-60 minutes) of ischemia and was associated with a progressive elevation of total lactate dehydrogenase in the effluent. Infusion of deferoxamine markedly diminished PBN adduct production as well as total release of lactate dehydrogenase. CONCLUSIONS: These data suggest the potential feasibility of using an ex vivo ESR spin trapping technique in blood-perfused models of cardiovascular injury and that chelatable free iron contributes to the production of alkoxyl radicals.

Alcohols↗
PubMed1991

Captopril protects against myocardial injury induced by magnesium deficiency.

We have previously reported that antioxidant drug intervention protects against magnesium deficiency-induced myocardial lesions. In the present study, Golden Syrian male hamsters were fed either a magnesium-deficient diet or a magnesium-supplemented diet. Animals from each group received sulfhydryl-containing angiotensin converting enzyme inhibitors: captopril, epi-captopril (a stereoisomer of captopril), and zofenopril* (arginine blend of zofenopril containing a free SH group); another group of animals received the non-sulfhydryl-containing angiotensin converting enzyme inhibitor enalaprilat. The animals were killed after 14 days, and their hearts were isolated for morphological and morphometric analyses. Hematoxylin and eosin-stained sections were examined by a computer image analysis system for a morphometric determination of the severity of myocardial injury. Captopril reduced both the density of lesions, from 0.32 to 0.08 lesions/(mm2) (p less than 0.01), and the area fraction of lesions, from 7.42 x 10(-4) to 2.03 x 10(-4) lesion area/(mm2) (p less than 0.01), as well as the degree of inflammatory infiltration around the blood vessels. Epi-captopril and zofenopril* were virtually equipotent to captopril, but enalaprilat afforded only slight (nonsignificant) protection. These results indicate that a significant component of the protective effect of captopril in this model was attributable to its sulfhydryl moiety, rather than solely due to the inhibition of the angiotensin converting enzyme. These data further support our previous findings of possible free radical participation in cardiomyopathy due to magnesium deficiency.

Analysis of Variance↗
PubMed1990

Protective effects of sulfhydryl-containing angiotensin converting enzyme inhibitors against free radical injury in endothelial cells.

The effects of SH-containing (captopril, epi-captopril, and the free-SH form of zofenopril) and non-SH-containing (enalaprilat and lisinopril) angiotension converting enzyme (ACE) inhibitors on free radical injury in cultured endothelial cells were studied. When cultured endothelial cells were exposed to a superoxide and hydroxyl radical generating system (dihydroxyfumarate + Fe3(+)-ADP) for 30 min, lipid peroxidation [malondialdehyde (MDA) formation] occurred, and cellular viability (trypan blue exclusion) decreased to 41%; concomitantly, plasma membrane blebbing, assessed by scanning electron microscopy, occurred in 65% of the cells. Preincubation of the cells with each of the SH-agents before free radical addition resulted in an equipotent concentration-dependent (10-200 microM) inhibition (15-60%) of MDA formation; both losses in cellular viability and percent blebbed cells were reduced significantly (P less than 0.05) by concentrations as low as 10 microM of each SH-agent. However, neither of the non-SH agents up to 200 microM produced any major effect. When the effects on hydroxyl radical formation in the system were assessed by ESR spin-trapping with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), concentrations of 10 and 50 microM of the SH-agents reduced the intensity of the DMPO-OH adducts 20 and 50% respectively. Similar results were observed when the hydroxyl radical was generated from the Fenton-reagents (Fe2+ + H2O2), suggesting direct hydroxyl radical scavenging. Thus, these results demonstrate that the SH-containing ACE agents are capable of protecting the endothelial cells against free radical induced lipid peroxidation and cell injury; the mechanism may be due to direct hydroxyl radical scavenging.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Magnesium deficiency-induced cardiomyopathy: protection by vitamin E.

Syrian male hamsters weighing 80-100g were placed on either a magnesium deficient diet (MgD) or an identical diet supplemented with 100 mmols/Kg MgCl. Animals from each group received vitamin E 10, 15, and 25mg three-week slow release pellets, as subcutaneous implants. The animals were sacrificed after 14 days and their hearts isolated for morphological analysis. H&E stained sections were examined by a computer image analysis system for a morphometric determination of the severity of myocardial injury. Vitamin E significantly (p less than 0.01) reduced both the numerical density and the area fraction of MgD lesions. These data indicate possible free radical participation in the mechanism of injury.

Animals↗
PubMed1990

Oxygen radical-mediated injury of myocytes-protection by propranolol.

UIe effects of propranolol and atenolol on free radical mediated injury in myocytes were examined. Freshly isolated adult canine myocytes were incubated with a superoxide generating (from dihydroxyfumarate) and Fe-catalyzed free radical system. Exposure of the myocytes to free radicals for 20 min resulted in more than a 5-fold increase in thiobarbituric acid reactant (peroxide) formation and elevated levels of lactate dehydrogenase (LDH) activity released into the media compared to controls. Ultrastructurally, severe sarcolemmal damage, mitochondrial and myofibril derangements were evident. At 40 min, cellular viability (trypan blue exclusion) in the samples exposed to free radicals decreased to about one-third of controls; concomitantly, major losses in total cellular phospholipids occurred. When the cells were pretreated with 200 microM propranolol before the addition of free radicals, both peroxide formation and increased LDH release were inhibited; in agreement, complete ultrastructural preservation was observed. In addition, the subsequent losses in cellular viability and phospholipids were prevented. For comparison, the more water soluble beta-blocker, atenolol at 200 microM was shown ineffective in providing significant protection against the induced injury. The results suggest that propranolol may provide antiperoxidative protection to myocytes when elevated levels of free radicals are present.

Animals↗
PubMed1990

Chlorinated aliphatic hydrocarbons promote lipid peroxidation in vascular cells.

Chlorinated aliphatic hydrocarbons such as trichloroethylene and trichloroethane cause acute and chronic cardiotoxicities via mechanisms that are still obscure. Some of these toxic effects may result from free-radical-induced membrane damage to the vascular tissues. The pro-oxidant effects of carbon tetrachloride, trichloroethylene, 1,1,1-trichloroethane, 1,2-dichloroethane, and trans-1,2-dichloroethylene were assessed in cultured arterial endothelial and aortic smooth muscle cells. Exposure of the cells to the above chemicals alone did not increase the formation of thiobarbiturate reactive products above background levels. However, in the presence of low levels of iron (3.1-25 microM Fe3+ chelated by ADP), all five agents promoted lipid peroxidation up to 200% of control. The rank order of potency is carbon tetrachloride greater than or equal to trichloroethylene greater than 1,1,1-trichloroethane greater than trans-1,2-dichloroethylene greater than 1,2-dichloroethane. The synergistic interaction between iron and chlorinated hydrocarbons in promoting lipid peroxidation may contribute to the cardiotoxicities of these agents.

Animals↗
PubMed1990

Comparative antioxidant activities of propranolol, nifedipine, verapamil, and diltiazem against sarcolemmal membrane lipid peroxidation.

The antiperoxidative activities of nifedipine, verapamil, and diltiazem were compared with that of propranolol by using an in vitro model of sarcolemmal membrane lipid peroxidation. Highly purified sarcolemmal membranes, isolated from canine ventricular myocytes, were peroxidized by a superoxide anion-producing and iron-catalyzed free radical-generating system (dihydroxy-fumarate plus FeCl3 and ADP). Lipid peroxidation after 20 minutes of incubation was monitored by malondialdehyde formation. Similar to propranolol, all three calcium blockers exhibited concentration-dependent (10-400 microM) inhibitory effects against sarcolemmal lipid peroxidation. The order of potency of these agents was nifedipine greater than propranolol greater than verapamil greater than diltiazem. Nifedipine, the most effective calcium blocker, was greater than twofold more potent than propranolol and achieved a significant effect at 10 microM. This study suggests that calcium blockers may provide antiperoxidative protection to cardiac membranes.

Animals↗