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Biomedical subjects

S R Powell

Publications and source records attributed to S R Powell.

At least 37 records · Page 2Linked to original sources
PubMed1991

Cardiac reperfusion damage prevented by a nitroxide free radical.

Experimental evidence is presented that directly links ischemia/reperfusion injury to the formation of oxygen-derived free radicals. 2,2,6,6-Tetramethylpiperidine-N-oxyl (TEMPO)--a stable nitroxide radical that disproportionates superoxide radicals and oxidizes reduced metal ions required for OH. formation--was tested for its ability to prevent reperfusion damage in the isolated rat heart subjected to regional ischemia. Severe reperfusion arrhythmia--ventricular fibrillation and ventricular tachycardia--were prominent in control hearts, and their duration was significantly reduced by the presence of 0.4 or 1 mM TEMPO. TEMPO also repressed both postischemic release of lactate dehydrogenase and OH. formation. TEMPO slowed the heart rate, but compensatory pacing did not alter the dramatic effect of the nitroxide on reperfusion arrhythmia. TEMPO was partially protective when introduced at the end of ischemia but had no effect when added 1 min into reperfusion. It was concluded that both reperfusion arrhythmia and cell damage were directly related to oxidative damage incurred during the critical first minute of reperfusion. TEMPO strongly protected against reperfusion injury by preventing the formation of OH. and not by decreasing heart rate or by direct suppression of arrhythmia.

Animals↗
PubMed1991

Copper loading of hearts increases postischemic reperfusion injury.

We studied the role of copper as a potential mediator of postischemic reperfusion injury in the isolated, perfused rat heart. Hearts were equilibrated with Krebs-Henseleit buffer for 10 minutes and then loaded with copper by way of perfusion with buffer containing 20 microM copper(II)-bis-histidial for 30 minutes. Control hearts were perfused with Krebs-Henseleit buffer alone during the loading period. Hearts than were washed with buffer for 10 minutes and subjected to 20 minutes of normothermic global ischemia followed by 30 minutes of reperfusion. Atomic absorption spectroscopy revealed a 67% increase in total copper content in loaded hearts by the end of the wash. By the end of the 30-minute period of reperfusion, control hearts demonstrated a 50-60% recovery of myocardial function as determined by peak systolic pressure, contractility, and heart rate. In contrast, copper-loaded hearts exhibited virtually no functional recovery within the 30-minute time period. Using salicylate as a probe, we determined that peak and duration of .OH formation appears to be increased in copper-loaded hearts during reperfusion. Furthermore, efflux of lactic dehydrogenase was significantly increased in copper-loaded hearts. Our results clearly demonstrate that increasing cardiac content of copper results in enhanced postischemic reperfusion injury associated with increased formation of .OH, thus suggesting an important catalytic role for this transition metal.

Analysis of Variance↗
PubMed1991

The effect of chronic administration of doxorubicin on the rat cardiac and hepatic glutathione redox system.

The effect of chronic administration of doxorubicin on the rat heart and liver glutathione redox system was studied. Rats were administered doxorubicin, 1 mg/kg, ip., three times a week, on Monday, Wednesday and Friday. One week was skipped and then the cycle repeated for a total of one, four, seven or ten doses. It was determined that treatment in this manner had no effect on rat heart glutathione, glutathione peroxidase or glucose-6-phosphate dehydrogenase, at any of the time intervals tested. However, hepatic glutathione content was found to be moderately increased after the fourth dose and glucose-6-phosphate dehydrogenase activity was found to be markedly increased after the seventh and tenth doses. Hepatic glutathione peroxidase was not affected. These results suggest that the cardiac glutathione redox system does not respond to chronic administration of doxorubicin. In contrast, the hepatic systems do respond, which may explain the apparent resistance of this organ to doxorubicin toxicity.

Animals↗
PubMed1990

Use of salicylate as a probe for .OH formation in isolated ischemic rat hearts.

Salicylic acid was used as a probe for .OH formed during reperfusion of the ischemic myocardium. .OH adds to the phenolic ring of salicylate to yield dihydroxybenzoic acid species. The two principal dihydroxybenzoic acids formed are the 2,3- and 2,5-derivatives and can be isolated and quantitated using HPLC combined with electrochemical detection. In these experiments, dihydroxybenzoic acids were detectable in the f molar range. Rat hearts were perfused in the Langendorff mode with Krebs-Henseleit buffer containing 100 microM salicylate. Following 20 min of global ischemia a 173% increase in tissue content of 2,5-dihydroxybenzoic acid was detected after 2.5 min of reperfusion. The duration of ischemia did not significantly affect tissue content of 2,5-dihydroxybenzoic acid peaked at 250 to 300% of control within 2.5 min of reperfusion. The inclusion of 100 microM salicylate in the perfusion buffer had no effect on myocardial function during the duration of the experiments. The results indicate that salicylate can be used as a very sensitive probe for .OH in the isolated ischemic heart.

Animals↗
PubMed1990

The effect of 1,3 bis-(2-chloroethyl)-1-nitrosourea on rat brain glutathione status under conditions of normoxia and hyperoxia.

The effect of inhibition of rat brain glutathione reductase, under conditions of normoxia and hyperoxia, on tissue ratios of reduced:oxidized glutathione was tested. Under conditions of normoxia, inhibition of brain glutathione reductase by approximately 50%, had no effect on reduced or oxidized glutathione in any of the three brain regions analyzed. After exposure of rats to 4 ATA 100% oxygen for one hour, in the presence of the same degree of enzyme inhibition, significant increases in oxidized glutathione in the cortical and subcortical areas of the brain were detected. Coupled with small, but nonsignificant decreases in reduced glutathione, a highly significant decrease in the ratio of reduced:oxidized glutathione was demonstrated in these two brain regions. These results indicate that under the conditions of an increased oxidizing environment, inhibition of brain glutathione reductase enhances the oxidative stress experienced by this organ.

Animals↗
PubMed1989

Quantitating the superior visual field loss associated with ptosis.

The effect of blepharoptosis on the superior visual field was assessed using a series of specially designed contact lenses to simulate ptosis in normal subjects. We found a progressive decrease in the superior visual field at the 90 degree vertical meridian, which was proportional to the degree of simulated ptosis. Our results were in close agreement with both a theoretical model and previous clinical observations. These results are important in evaluating patients contemplating ptosis surgery, as well as in visual field testing for neuro-ophthalmic disorders.

Adult↗
PubMed1989

In-hospital cardiopulmonary resuscitation during asystole. Therapeutic factors associated with 24-hour survival.

The most recent American Heart Association (AHA) guidelines for cardiopulmonary resuscitation (CPR) during asystole include ventricular defibrillation, intubation, and the administration of epinephrine and atropine. This study reports results from a retrospective analysis of clinical, demographic, and treatment data collected during in-hospital CPR efforts in 123 patients in whom the initial rhythm was asystole. Twenty-eight (22.8 percent) of these patients were alive 24 h after CPR initiation. Patients who received norepinephrine drip (N = 43) were more likely to survive than those who did not (39.5 percent vs 14.1 percent; p less than .01), and those who received lidocaine drip were more likely to survive than those who did not (47.6 percent vs 18.2 percent; p less than .01). The best survival rate (57.1 percent) occurred among those who received both norepinephrine and lidocaine (N = 14). Survivors did not differ significantly from nonsurvivors in terms of age, gender, primary diagnosis, location of arrest, or duration of CPR efforts. The results suggest that aggressive resuscitation efforts which include the addition of norepinephrine and lidocaine drips to the AHA-recommended regimen of epinephrine and atropine may substantially increase the number of 24-h survivors. A pharmacologic mechanism involving norepinephrine-induced myocardial irritability and peripheral vasoconstriction, combined with lidocaine-induced suppression of abnormal automaticity, is offered as a possible explanation of the obtained results.

Atropine↗
PubMed1988

Inhibition of doxorubicin-initiated membrane damage by N-acetylcysteine: possible mediation by a thiol-dependent, cytosolic inhibitor of lipid peroxidation.

Peroxidative damages are thought to be a component of doxorubicin-induced cardiac toxicity. Administration of certain thiols, such as N-acetylcysteine, are reported to be protective against the cardiac toxicity and mortality associated with chronic doxorubicin administration. We have investigated the possibility that N-acetylcysteine exerts its protective effect by inhibiting doxorubicin-induced lipid peroxidation in a process mediated by a heat-labile cytosolic factor. Dialyzed rat liver cytosol plus N-acetylcysteine significantly inhibited doxorubicin-induced lipid peroxidation in a microsomal system whereas neither cytosol nor N-acetylcysteine alone does so. Concomitantly, it was observed that N-acetylcysteine is rapidly consumed in a system containing cytosol, microsomes, and doxorubicin. The inhibition of lipid peroxidation by the cytosol and accompanying N-acetylcysteine oxidation is heat labile. Rat heart cytosol showed a similar N-acetylcysteine-dependent inhibition of doxorubicin-induced lipid peroxidation, but heart cytosol was less potent than hepatic cytosol on the basis of protein content. The antioxidant property of heart cytosol as well as its capacity to oxidize N-acetylcysteine was inhibited by prior treatment of the cytosol with iodoacetic acid. This suggested that the factor possessed essential sulfhydryl groups. These results suggest that hepatic and cardiac cytosols contain heat-labile components capable of utilizing N-acetylcysteine as a substrate to suppress the doxorubicin-induced peroxidative damage to microsomes induced by doxorubicin. These components may play a role in the protective effects of N-acetylcysteine against doxorubicin-induced cardiac toxicity and mortality.

Acetylcysteine↗
PubMed1987

Effect of inhibition of glutathione reductase by carmustine on central nervous system oxygen toxicity.

Exposure of animals to O2 at increased partial pressures above 2.5 atmospheres absolute results in seizures. The endogenous intracellular antioxidant defense mechanisms are thought to play a protective role in mitigating such seizures. Investigations were carried out to determine if inhibiting brain glutathione reductase with carmustine would result in an alteration in time to seizures of rats exposed to high pressure O2. Treatment of air-breathing rats with carmustine (12.5, 25 and 50 mg/kg i.v.) resulted in a dose-dependent decrease (P less than .001) in whole-brain glutathione reductase activity without affecting the activities of the other components of the antioxidant defense mechanisms determined. This treatment also resulted in a dose-dependent decrease (P less than .001) in time to seizure of rats exposed to four atmospheres absolute O2. Conversely, treatment of rats with lomustine (30 mg/kg i.v.), a nitrosourea compound related to carmustine, failed to affect the activity of brain glutathione reductase or any other component of the antioxidant defense mechanism determined, or did it influence the seizure time of rats exposed to four atmospheres absolute O2. These results suggest that glutathione reductase is an integral component of the antioxidant defense mechanisms. Inhibition of this enzyme results in an alteration in sensitivity of the organism to the toxic effects of O2.

Animals↗
PubMed1985

Effect of delta 9-tetrahydrocannabinol on intraocular pressure after removal of autonomic input.

Sympathetic input to the anterior segment of the eyes of cats was unilaterally removed by either superior cervical ganglionectomy or treatment with 6-hydroxydopamine. Parasympathetic input was unilaterally removed by extirpation of the ciliary ganglion. delta 9-tetrahydrocannabinol (delta 9-THC; 20 micrograms/hr) was delivered unilaterally to the denervated eyes and to eyes of surgically intact control cats via osmotic minipumps and connecting extraocular cannulas over a total period of nine days. The results indicated that the degree of reduction of intraocular pressure by delta 9-THC was not affected by removal of input from either branch of the autonomic nervous system. Outflow facility during chronic administration of THC showed a two-to-three fold increase. Ciliary ganglionectomy alone produced a moderate decrease in intraocular pressure that endured for one week. These findings indicate that neither adrenergic nor cholinergic input to the cat eye is apparently required for the mediation of the tension lowering effect of THC. They additionally suggest that cholinergic input may normally play a role in the regulation of steady-state intraocular pressure levels, presumably by modulating aqueous humor formation.

Animals↗
PubMed1984

Intraocular pressure, ocular toxicity and neurotoxicity after administration of delta 9-tetrahydrocannabinol or cannabichromene.

delta-9-Tetrahydrocannabinol (delta 9-THC) or cannabichromene, a structurally diverse naturally occurring cannabinoid, was delivered unilaterally to the corneas of cats either acutely by application of single drops or chronically via osmotic minipumps over a period of nine days. While delta 9-THC only reduced intraocular pressure (IOP) minimally after acute administration, this cannabinoid produced substantial reductions in ocular tension during the entire period of chronic administration. Ocular toxicity during chronic treatment, however, was pronounced; conjunctival chemosis, erythema, and hyperemia were sustained, and corneal opacities approximating the site of drug delivery became evident within three to five days. In contrast, cannabichromene did not significantly alter IOP either acutely or during the nine days of chronic administration, and ocular toxicity was not apparent. After systemic administration of delta 9-THC to rats, a dose-related increase in the appearance of 8-13 Hz polyspike discharges became evident in the electrocorticogram during wakefulness and behavioral depression. These polyspikes subsequently reappeared during rapid eye movement (REM) sleep episodes. Cannabichromene was devoid of this effect. These results indicate that, in contrast with acute administration, chronic delivery of delta 9-THC to cat eyes produces substantial reductions in IOP. The tension lowering effect, however, is accompanied by considerable ocular toxicity and neurotoxicity. As cannabichromene lacked these activities, the terpenoid portion of the cannabinoid structure appears to be important for their mediation.

Action Potentials↗
PubMed1984

Inhibition of cellular antioxidants: a possible mechanism of toxic cell injury.

Cells that utilize molecular oxygen generate highly reactive oxygen-derived free radicals. Endogenous cellular oxidants inactivate oxidant free radicals and protect aerobic cells from oxidant injury. Glutathione, glutathione reductase, and superoxide dismutase are key components of this antioxidant defense. Inhibition of antioxidant components would be expected to result in cell injury. Using exposure to oxygen at high pressure to increase the level of oxidant free radicals, evidence is presented to support the hypothesis that inhibition of cellular antioxidants renders organisms more susceptible to oxygen toxicity. Diethyldithiocarbamate at doses of 250, 500 and 1000 mg/kg inhibited rat brain superoxide dismutase activity and shortened onset time to seizures in a dose-related manner in 4 ATA oxygen. Carmustine at doses of 12.5, 25 and 50 mg/kg inhibits glutathione reductase activity in rat brain in proportion to the dose. Time to onset of seizures of rats pretreated with carmustine prior to exposure to 4 ATA oxygen was shortened, and oxidized glutathione levels were increased in the cortex and subcortex. These data suggest that inhibition of antioxidant components results in organisms becoming more sensitive to oxygen toxicity. Compounds that inhibit cellular antioxidants may produce toxic cell injury by permitting intracellular oxidant free radicals to attack essential cell constituents.

Aerobiosis↗