Biomedical subjects

S R Powell

Publications and source records attributed to S R Powell.

At least 19 recordsLinked to original sources

PubMed2001

Nicorandil decreases postischemic actin oxidation.

This study examined the hypothesis that preconditioning can decrease postischemic oxidative protein damage. Isolated rat hearts were subjected to 25 min of normothermic global ischemia followed by 45 min of reperfusion. These were compared with hearts pretreated with 20 microM nicorandil or preconditioned with two cycles of ischemia. Changes in the high energy phosphates, ATP and phosphocreatine, were followed using (31)P-NMR spectroscopy. Protein carbonyls were assessed using an immunoblot technique. Postischemic hemodynamic function and high energy phosphates recovered to significantly (p <.05) higher levels in nicorandil-treated and ischemic preconditioned hearts as compared to controls. Postischemic protein carbonyl formation was highest in control reperfused hearts but reduced to intermediate between control and preischemic hearts by ischemic preconditioning and virtually prevented by nicorandil pretreatment, with a prominent band at 43 kDa significantly affected (p <.05). Based on immunoshift and immunoprecipitation studies, this band was identified as a mixture of actin isoforms. These studies support the conclusion that nicorandil diminishes protein oxidative damage in general, and specifically actin oxidation, which in the presence of improved supply of high energy phosphates, leads to enhanced postischemic contractile function.

Actins↗

PubMed2001

Actin is oxidized during myocardial ischemia.

Exposure of isolated rat hearts to 30 min global ischemia followed by 60 min reperfusion resulted in a significant 80% increase (p <.05) in actin content of carbonyl groups, which was associated with significant depression (p <.05) of postischemic contractile function. This result supports the hypothesis that one mechanism of postischemic contractile dysfunction may be oxidation of contractile proteins.

Actins↗

PubMed2001

Post-hypoxic magnesium decreases nuclear oxidative damage in the fetal guinea pig brain.

This study was to determine if administration of MgSO(4) after the hypoxic insult (post-hypoxia) would attenuate neuronal damage in the fetal guinea pig brain. Pregnant guinea pigs (45-60 days gestation) were exposed to hypoxia (7% O2) for 1 h. Following hypoxia, one group recovered for 24 h with no additional treatment (post-hypoxia) and another group received MgSO(4), 300 mg/kg i.p., followed by 100 mg/kg i.p., each hour for three doses (post-hypoxia+Mg) and allowed to recover for 24 h. Fetal brain magnesium content was decreased (P<0.05) 4 h post-hypoxia which was prevented by treatment with MgSO(4). High energy phosphates were significantly lower (P<0.05) in the post-hypoxia group which was partially prevented by post-hypoxic magnesium. Na+,K+-ATPase activity was significantly lower (P<0.05) and nuclear membrane fluorescent compounds were significantly higher (P<0.05) in the post-hypoxia group but were not significantly changed in the post-hypoxia+Mg group compared with the normoxic control group. DNA fragmentation was observed to be lower in the Mg-treated post-hypoxic group. This study demonstrates that maternal MgSO(4) administration following in utero hypoxia prevents associated decreases in fetal brain magnesium and suppresses alterations in both the neuronal and nuclear membranes and genomic fragmentation in the fetal guinea pig brain.

Adenosine Triphosphate↗

PubMed2000

Association of increased ubiquitinated proteins with cardiac apoptosis.

Intracellular proteases play an important role in the regulation of apoptosis. A study was performed to determine whether inhibition of the cardiac ATP-dependent ubiquitin 26S protease complex affects cardiomyocyte apoptosis. Isolated rat hearts were perfused for up to 80 min with Krebs-Henseleit buffer +/- the 26S-proteasome inhibitor, MG132 (Z-leu-leu-leucinal). TUNEL-staining of hearts perfused with 25 microM MG132 for 50 min revealed a significant increase (p < 0.05) in the apoptotic index from 1.1% to 15.5% when compared with control hearts perfused with buffer only. Histology of adjacent myocardial sections revealed no signs of necrotic or late apoptotic (nuclear condensation) changes, indicating that the TUNEL-positive nuclei were in the early stages of apoptosis. This early stage of apoptosis was associated with a significant (p < 0.05) reduction in cardiac function. There was a 63% decrease in the rate pressure product in hearts perfused with 25 microM MG132 as compared with a 35% decrease in control hearts over the 80-min perfusion period. Soluble ubiquitin-conjugated proteins, as detected by probing with a specific antibody to ubiquitin, were increased in MG132-treated hearts. In hearts perfused with 50 microM MG132, a greater accumulation of ubiquinated proteins was observed accompanied by a more rapid and greater reduction in hemodynamic function. These observations indicate that prolonged inhibition of the ubiquitin-26S-proteasome results in cardiomyocyte apoptosis accompanied by increased ubiquinated proteins, thus suggesting that accumulation of these abnormal proteins may act as a signal to activate the cell death program.

Animals↗

PubMed2000

The antioxidant properties of zinc.

The ability of zinc to retard oxidative processes has been recognized for many years. In general, the mechanism of antioxidation can be divided into acute and chronic effects. Chronic effects involve exposure of an organism to zinc on a long-term basis, resulting in induction of some other substance that is the ultimate antioxidant, such as the metallothioneins. Chronic zinc deprivation generally results in increased sensitivity to some oxidative stress. The acute effects involve two mechanisms: protection of protein sulfhydryls or reduction of (*)OH formation from H(2)O(2) through the antagonism of redox-active transition metals, such as iron and copper. Protection of protein sulfhydryl groups is thought to involve reduction of sulfhydryl reactivity through one of three mechanisms: (1) direct binding of zinc to the sulfhydryl, (2) steric hindrance as a result of binding to some other protein site in close proximity to the sulfhydryl group or (3) a conformational change from binding to some other site on the protein. Antagonism of redox-active, transition metal-catalyzed, site-specific reactions has led to the theory that zinc may be capable of reducing cellular injury that might have a component of site-specific oxidative damage, such as postischemic tissue damage. Zinc is capable of reducing postischemic injury to a variety of tissues and organs through a mechanism that might involve the antagonism of copper reactivity. Although the evidence for the antioxidant properties of zinc is compelling, the mechanisms are still unclear. Future research that probes these mechanisms could potentially develop new antioxidant functions and uses for zinc.

Animals↗

PubMed2000

Health status and resources of rural homeless women and children. Iowa Homeless Research Team.

The purpose of this research is to describe the health status and health resources for homeless women and children in a Midwestern rural community. A group of 31 rural homeless women in a shelter participated in the study by answering questions on the Rural Homeless Interview developed by the investigators. The findings revealed higher than expected rates of illness, accidents, and adverse life events, with the incidence of substance abuse and mental illness being comparable to data from other homeless populations. The data on children were limited by lack of knowledge on the part of their mothers. Some mothers reported that their children were in foster care, had been adopted, or were being cared for by others. The inability to access health and dental care was reported by half of the participants.

Adolescent↗

PubMed1999

Promotion of copper excretion from the isolated rat heart attenuates postischemic cardiac oxidative injury.

This study examined the role of Cu as a mediator of cardiac postischemic oxidative injury. Isolated rat hearts were subjected to 20 min of normothermic global ischemia, followed by 30 min of reperfusion; after 20 min of preischemic loading with Krebs-Henseleit buffer +/- 20 or 30 microM zinc-bis-histidinate (Zn-His2), 0.5 mM deferoxamine (DEF) or 42 microM neocuproine (NEO). Postischemic developed systolic pressure and rate-pressure product were highest and postischemic end-diastolic pressure was lowest in hearts treated with 20 or 30 microM Zn-His2 and 0.5 mM DEF. Cu efflux was significantly increased by 225 and 290% (end of preischemic loading), and 325 and 375% (immediate postischemic period) of control basal rates in hearts treated with 30 microM Zn-His2 and 0.5 mM DEF, respectively. NEO did not effect any of these parameters. By the end of ischemia, protein carbonyls were lowest in Zn-His2-treated hearts and highest in DEF-treated hearts when compared with control hearts. The results of this study suggest that removal of redox-active Cu before ischemia has beneficial effects, indicating a mediatory role in postischemic cardiac oxidative injury.

Animals↗

PubMed1998

Estrogen diminishes postischemic hydroxyl radical production.

Reperfusion of blood flow to an ischemic myocardium is imperative to survival; ironically, it may also manifest several pathophysiological conditions. The most important of these are reperfusion arrhythmias and tissue injury and/or death. The mechanisms involved in reperfusion arrhythmias remain to be fully elucidated; however, increasing evidence indicates that reperfusion-induced arrhythmias are a free radical-mediated phenomenon. Acute administration of conjugated equine estrogen to dogs attenuates ischemia- and reperfusion-induced arrhythmias. The cardioprotective effect of estrogens in postmenopausal women is well documented, and recent studies suggest that estrogens possess strong antioxidant properties, with equine estrogens most potent. In this study we show that administration of conjugated equine estrogen to fully anesthetized dogs abolishes the burst of .OH radicals typically produced on reperfusion of the myocardium. This indicates that estrogen might attenuate reperfusion-induced ventricular arrhythmias by virtue of its antioxidant properties, suggesting a novel cardioprotective effect of the hormone.

Animals↗

PubMed1997

Zinc-bis-histidinate preserves cardiac function in a porcine model of cardioplegic arrest.

BACKGROUND: We examined the ability of zinc-bis-histidinate to preserve postarrest myocardial function when added to a standard crystalloid cardioplegic solution. METHODS: Domestic pigs (35 to 50 kg) on left-sided cardiopulmonary bypass were subjected to 90 minutes of regional ischemia followed by 60 minutes of hypothermic cardioplegic arrest induced by antegrade infusion of 20 mL/kg cold St. Thomas' #2 cardioplegic solution with or without 100 mumol/L of zinc-bis-histidinate and maintained by infusion of 10 mL/kg of the same every 20 minutes. During reperfusion function was assessed at 1 and 3 hours over increasing preloads using the right-sided bypass method. RESULTS: At roller pump flows up to 2,000 mL/min, stroke work index-end-diastolic pressure curves were significantly (p < 0.05) higher and shifted to the left in treated hearts. In a series of pigs, echocardiography was used to determine end-diastolic and end-systolic volumes. At roller pump flows up to 3,500 mL/min, end-systolic pressure-end-systolic volume curves were significantly higher and shifted to the left in treated hearts. Left ventricular ejection fraction, fractional shortening, stroke volume, and cardiac output were significantly (p < 0.05) higher in treated hearts. Electron microscopy revealed that mitochondria in tissue not at risk appeared more swollen in control hearts. CONCLUSIONS: The results of this study support the conclusion that zinc-bis-histidinate is effective as a myocardial preservative when added to a crystalloid cardioplegic solution.

Animals↗

PubMed1997

Alterations in cardiac contractility and gene expression during low-T3 syndrome: prevention with T3.

The low-T3 syndrome is a metabolic response resulting in a decreased serum triiodothyronine (T3) concentration that has uncertain effects on thyroid hormone-responsive gene expression and function. We measured cardiac myocyte gene expression and cardiac contractility in young adult female rats using chronic calorie deprivation as a model of the low-T3 syndrome. Sarcoplasmic reticulum calcium adenosinetriphosphatase (SERCA2) and myosin heavy chain (MHC) isoform mRNA content were measured after 28 days on a 50% calorie-restricted diet (low T3) with or without T3 treatment (6 micrograms.kg body wt-1.day-1). The low-T3 animals had decreased maximal rates of contraction (-13%; P < 0.05) and relaxation (-18%; P < 0.05) compared with the control and the T3-treated groups. There was a 21% (P < 0.05) increase in left ventricular (LV) relaxation time in the low-T3 animals vs. both control and T3-treated groups. The LV content of the SERCA2 mRNA was decreased significantly (37%) in the low-T3 rats and was increased (P < 0.05) with T3 treatment vs. controls. The alpha-MHC mRNA isoform decreased in the low-T3 animals but was unchanged in the T3-treated animals. T3 supplementation normalized both cardiac function and phenotype of calorie-restricted animals, suggesting a role for the low-T3 syndrome in the pathophysiological response to calorie restriction.

Animals↗

PubMed1996

Increased oxidative stress and decreased antioxidant defenses in mucosa of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation whose cellular components are capable of oxidative respiratory bursts that may result in tissue injury. Mucosal biopsies were analyzed for protein carbonyl content (POPs), DNA oxidation products [8-hydroxy-2'-deoxyguanosine (8-OHdG)], reactive oxygen intermediates (ROIs), trace metals (copper, zinc, and iron) and superoxide dismutase (Cu-Zn SOD). In Crohn's disease biopsies, there was an increase in ROIs, POPs, 8-OHdG, and iron, while decreased copper and Cu-Zn SOD activity were found in inflamed tissues compared to controls. For ulcerative colitis, there was an increase in ROIs, POPs, and iron in inflamed tissue compared to controls, while decreased zinc and copper were observed. An imbalance in the formation of reactive oxygen species and antioxidant micronutrients may be important in the pathogenesis and/or perpetuation of the tissue injury in IBD and may provide a rationale for therapeutic modulation with antioxidants.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1995

Inhibition of doxorubicin-induced membrane damage by thiol compounds: toxicologic implications of a glutathione-dependent microsomal factor.

The hypothesis was tested that glutathione exerts its protective actions against doxorubicin-induced oxidative stress through an enzyme-dependent mechanism. Glutathione at biological concentrations decreased doxorubicin-dependent rat hepatic microsomal lipid peroxidation, whereas N-acetylcysteine had no effect. Glutathione was utilized during this inhibition at a rate dependent on the concentration of both doxorubicin and the sulfhydryl. Increasing glutathione concentrations resulted in significant increases in utilization. N-acetylcysteine was also oxidized in the microsomal system; however, the rate of oxidation was not enhanced by doxorubicin. If bovine cardiac microsomes were substituted for the hepatic microsomes, no lipid peroxidation was detected in the presence of doxorubicin, yet significant utilization of glutathione was detected. Microsomes isolated from tocopherol-deficient rats utilized less glutathione in the presence of doxorubicin, and there was no inhibition of doxorubicin-dependent lipid peroxidation. These findings support the conclusion that glutathione inhibits hepatic microsomal lipid peroxidation initiated by the redox-cycling of doxorubicin. Inhibition of doxorubicin-dependent lipid peroxidation appears to be enzyme-mediated and to require tocopherol. A similar mechanism for protection against doxorubicin appears to be present in heart microsomal membranes.

Animals↗

PubMed1995

Zinc supplementation enhances the effectiveness of St. Thomas' Hospital No. 2 cardioplegic solution in an in vitro model of hypothermic cardiac arrest.

The present study was done to assess the effectiveness of a zinc-supplemented cardioplegic solution in an in vitro model of hypothermic arrest. Isolated hearts were perfused in the nonworking mode. All hearts were subjected to 2 hours of hypothermic arrest, at 10 degrees C, followed by 60 minutes of recovery. In protocol 1, arrest was initiated with infusion of cardioplegic solution with or without 30 mumol/l zinc for 5 minutes, which was then reinfused for 5 minutes every 15 minutes during arrest. In protocol 2, arrest was initiated with infusion of cardioplegic solution with or without 40 mumol/L zinc for 10 minutes. Cardioplegic solution (without zinc) was then reinfused for 5 minutes before the hearts were rewarmed. In protocol 1 hearts, peak postischemic left ventricular developed systolic pressure was 106 +/- 5 mm Hg and 80 +/- 3 mm Hg in zinc-treated versus control hearts, respectively (p < 0.05 by repeated-measures analysis of variance). In protocol 2 hearts, recovery of postischemic left ventricular developed systolic pressure peaked at 74 +/- 4 mm Hg and 46 +/- 8 mm Hg in zinc-treated and control hearts, respectively (p 0.05, repeated-measures analysis of variance). Similar effects were observed for the left ventricular rate of relaxation (p < 0.05, repeated-measures analysis of variance). Except for some minor effects, lactate dehydrogenase release was not affected by zinc supplementation. The present study demonstrates that zinc supplementation further enhances the normally observed preservation of postarrest cardiac function and suggests possible clinical utility for this metal as an additive to standard crystalloid cardioplegic solutions.

Animals↗

PubMed1994

Adventitious redox-active metals in Krebs-Henseleit buffer can contribute to Langendorff heart experimental results.

Adventitious redox-active metals in Krebs-Henseleit buffer exhibit a significant enhancement of damage to isolated rat hearts. Using atomic absorption spectroscopy, it was determined that Krebs-Henseleit buffer contains substantial amounts of contaminating iron and copper. Significant copper contamination was found in ACS Reagent grade sodium chloride and sodium bicarbonate; iron contamination in sodium chloride, potassium chloride, sodium bicarbonate, and calcium chloride. Chelating resin treatment of individual reagents was found to decrease copper content of Krebs-Henseleit buffer from 0.32 to 0.17 microM. Using salicylate as a probe for .OH formation, it was determined that considerable amounts of this radical are formed when 0.25 mM ascorbate is added to the buffer indicating significant metal-catalysed autoxidation. Isolated rat hearts, perfused with non-chelexed Krebs-Henseleit buffer plus 0.25 mM ascorbate for 60 min, sustained moderate injury with developed systolic pressure, +dP/dtmax and -dP/dtmax decreased by 30 to 35% by the end of experiment. Hearts perfused with chelating resin-treated Krebs-Henseleit buffer sustained no significant injury within the same time frame. Furthermore, it was observed that hearts perfused with non-chelexed Krebs-Henseleit buffer accumulate significant amounts of copper depending on the amount of contamination and length of perfusion. Significant effects on post-ischemic end diastolic pressure were observed in hearts perfused with a Krebs-Henseleit buffer subsequently found to be contaminated with high levels of copper. These results clearly demonstrate that adventitious redox-active transition metals may be a confounding factor in experimental results. Further, it is recommended that all perfusion media be routinely examined for adventitious metals and treated if deemed necessary.

Animals↗

PubMed1994

Zinc improves postischemic recovery of isolated rat hearts through inhibition of oxidative stress.

We studied the cardiac protective qualities of zinc in the postischemic isolated rat heart. Hearts, perfused with Krebs-Henseleit buffer with or without zinc-bis-histidinate, were subjected to 20 min of "no-flow" normothermic global ischemia. Pre- and postischemic treatment with 0, 10, 20, or 30 microM zinc resulted in concentration-dependent enhancement of postischemic function as evidenced by decreased end-diastolic pressure (37 +/- 3, 25 +/- 5, 17 +/- 5, and 8 +/- 2 mmHg, respectively) and increased recovery of developed systolic pressure (41 +/- 6, 59 +/- 17, 76 +/- 18, and 87 +/- 16 mmHg, respectively) and maximum rate of rise in pressure (+dP/dtmax; 823 +/- 141, 1,413 +/- 396, 1,700 +/- 450, and 2,157 +/- 407 mmHg/s, respectively) as well as decreased lactate dehydrogenase efflux from the hearts (peak: 1,002%, 840%, 580%, and 440%, respectively). Only preischemic treatment resulted in an intermediate protective effect, whereas treatment starting at reperfusion worsened postischemic damage. In hearts perfused with zinc throughout the experiment, prolongation of the preischemic treatment interval further enhanced postischemic recovery. With the use of salicylate as a trap for .OH, it was determined that zinc virtually eliminated the early postischemic "burst" of this species normally observed in this preparation. Atomic absorption studies demonstrated that hearts treated with 30 microM zinc contained 27% less copper than control hearts by the end of the reperfusion period. In control hearts, electron microscopy revealed swollen mitochondria with marked loss of inner matrix density, whereas morphology of postischemic zinc-treated hearts was essentially normal. These studies indicate that zinc possesses cardiac cytoprotective qualities and support the concept that this metal can decrease .OH formation by affecting copper reactivity.

Animals↗

PubMed1993

Detection of alkoxyl and carbon-centered free radicals in coronary sinus blood from patients undergoing elective cardioplegia.

Confirmation of the involvement of free radicals in postischemic injury in human heart has been elusive. The present study was performed to determine the presence of free radicals in coronary sinus blood from patients undergoing elective open heart surgery and cardioplegia. Six patients who were scheduled for nonurgent elective open heart surgery were used in this study. Coronary sinus blood samples were withdrawn at 1, 3, 5, 10, 15, 20, and 25 min in post-cross-clamp and immediately mixed with isosmotic alpha-phenyl-tert-butylnitrone (PBN) and then centrifuged to obtain plasma. Plasma samples were extracted with toluene and analyzed using electron spin resonance (ESR) spectroscopy. We observed ESR spectra consistent with the formation of alkoxyl and carbon-centered radical adducts of PBN (aN = 13.6 G, a beta H = 1.9 G, and aN = 14.1 G, a beta H = 4.2 G) in six of six patients. We obtained complete free radical production time courses during reperfusion from five patients, and all demonstrated a biphasic profile with an initial burst from 5 to 10 min followed by a second maxima at 25 min. Total PBN-adduct production during reperfusion increased in patients subjected to longer aortic cross-clamp times (global ischemia). These data demonstrate that postcardioplegia free radical production is detectable in coronary sinus blood using an ex vivo spin-trapping technique and that the extent of formation may be related to the severity of ischemia.

Aged↗

PubMed1992

Mediatory role of copper in reactive oxygen intermediate-induced cardiac injury.

In this report the mediatory role of copper in cardiac injury produced by reactive oxygen intermediates was examined. Isolated rat hearts were perfused with Krebs-Henseleit buffer containing 0.25 mM ascorbate plus varying concentrations of copper-bis-histidial for up to 60 min. Using salicylate as a probe, OH generation by this system was demonstrated. Copper or ascorbate alone had minimal effect on cardiac function as determined by heart rate, coronary flow, left ventricular systolic pressure development, end diastolic pressure and +/- dP/dtmax. Copper, from 0.5 microM to 20 microM, and ascorbate, 0.25 mM, resulted in concentration-dependent decreases in all of the experimental variables. Treatment with 5 or 20 microM copper resulted in complete loss of cardiac function within 40 and 30 min, respectively. By 30 min, 5 microM copper had resulted in increased end diastolic pressure to greater than 40 mmHg. By 60 min, perfusion with 1 microM copper resulted in almost 100% loss of function and end diastolic pressure greater than 25 mmHg. Copper, 0.5 microM, also decreased cardiac function, but to a lesser degree. Catalase, 100 units/ml, was effective in preventing the copper-ascorbate induced cardiac damage while superoxide dismutase, 25 units/ml, was ineffective. Observations by light and electron microscopy demonstrated patchy regions with vacuolization corresponding to swollen mitochondria. These results clearly demonstrate that copper-catalyzed redox reactions can induce cardiac injury via a mechanism which appears to be related to the production of OH.

Animals↗

PubMed1992

Recent advances in the role of reactive oxygen intermediates in ischemic injury. I. Evidence demonstrating presence of reactive oxygen intermediates; II. Role of metals in site-specific formation of radicals.

This article has attempted to bring the reader up to date on advances in selected facets of the area of reactive oxygen intermediate-induced ischemic injury. Specifically, we have discussed the more recent reports that provide evidence for the presence of these species in reperfused ischemic tissue. In addition, we have attempted to introduce the reader to the relatively new concept of "site-specific" formation of radicals and how the use of "push-pull" techniques, such as chelation by high-affinity chelators or displacement by non-redox-active metals such as zinc, may decrease postischemic reperfusion injury. Finally, we have identified a class of compounds that affect the oxidation state of redox-active metals, and have demonstrated how these compounds may also represent a new therapeutic modality. In conclusion, both academic and nonacademic surgeons should have profited from reading this article. For the academic surgeon, who may do research, several new cytoprotectants requiring further study in both in vitro and in vivo models have been identified. For the nonacademic surgeon in clinical practice the realization that there are several promising areas of research that may yield new therapies to mitigate postischemic reperfusion injury should have been gained.

Animals↗