Formation Of Oxygen Free Radicals Research Articles

Inhaled prostacyclin is safe, effective, and affordable in patients with pulmonary hypertension, right-heart dysfunction, and refractory hypoxemia after cardiothoracic surgery

Inhaled prostacyclin is safe, effective, and affordable in patients with pulmonary hypertension, right-heart dysfunction, and refractory hypoxemia after cardiothoracic surgery

Simultaneous Production of Superoxide Radical and Singlet Oxygen by Sulphonated Chloroaluminum Phthalocyanine Incorporated in Human Low‐density Lipoproteins: Implications for Photodynamic Therapy¶

ABSTRACTSulfonated chloroaluminum phthalocyanines have been studied for their use in the photodynamic therapy (PDT) of tumors. Plasma low‐density lipoproteins (LDL) are important carriers of phthalocyanines in the blood, but on exposure to visible light, phthalocyanine‐loaded LDL undergo an oxidation process that propagates to erythrocytes. We attempted to identify the reactive species involved in LDL and erythrocyte oxidation by means of electron paramagnetic resonance (EPR) spectroscopy in the presence of 2,2,6,6‐tetramethyl‐4‐piperidone (TEMP) and the spin trap 5,5′‐dimethyl‐1‐pyrroline‐N‐oxide (DMPO). Irradiation of phthalocyanine‐loaded LDL in the presence of DMPO resulted in the formation of a four‐line EPR spectrum with relative intensity of 1:2:2:1 (aN= aH= 14.8 G), characteristic of DMPO‐hydroxyl radical spin adduct. This signal was sensitive to superoxide dismutase and slightly sensitive to catalase, but a mixture of the two enzymatic activities was the most efficient in promoting a decrease in the intensity of the EPR signal. In the presence of erythrocytes, an increase in the quartet intensity for a hematocrit of 1% and 4% was observed, decreasing for higher erythrocyte concentrations. The irradiation of phthalocyanine‐loaded LDL in the presence of TEMP resulted in the formation of a nitroxide radical, 2,2,6,6‐tetramethyl‐4‐piperidone‐N‐oxyl radical, intensity of which was sensitive to histidine, a singlet oxygen (1O2) quencher. Under both incubation conditions, with DMPO and TEMP, the formation of the respective EPR signals required the sensitizer (phthalocyanine), light and oxygen. Overall, the results are compatible with the simultaneous formation of superoxide anion and 1O2, implying that Type‐I and Type‐II mechanisms of photochemistry are simultaneously operative in phthalocyanine‐loaded LDL. However, for a constant LDL/phthalocyanine ratio, the formation of oxygen free radicals shows a biphasic behavior with the concentration of LDL increasing and reaching a plateau, whereas the formation of 1O2 increases linearly with LDL concentration. Erythrocytes at high (physiological) concentrations induced a decrease in the intensity of both EPR signals. The physiological relevance of these findings in the framework of PDT is briefly discussed.

Ebselen decreases oxygen free radical production and iron concentrations in the hearts of chronically iron-overloaded mice.

Chronic iron overload is a major cause of cardiac failure throughout the world, but its pathogenesis remains to be clarified. It is conjectured that the toxicity of iron is due to its ability to catalyze the formation of oxygen free radicals (OFR), which can damage cellular membranes, proteins, and DNA. The authors report on the cardioprotective effects of the glutathione peroxidase (GPx) mimic ebselen on iron concentrations in the heart and GPx activity, and on the production of the cytotoxic aldehydes hexanal, 4-hydroxyl-2-nonenal (HNE), and malondialdehyde (MDA). Fifteen B6D2F1 mice were randomized to 1 of 3 treatment groups for a total of 20 treatments: 1) control (0.1 mL normal saline i.p. per mouse, per day); 2) iron-only (10 mg iron dextran i.p. per mouse, per day); 3) iron plus ebselen (25 mg/kg p.o. per mouse, per day). In comparison to iron-only treated mice, the authors' findings show that supplementation with ebselen can decrease both cytotoxic aldehyde and iron concentrations in heart tissue. Additionally, mice supplemented with ebselen had an increase in GPx activity level in comparison to iron-only treated mice. To the authors' knowledge, this is the first study to examine the cardioprotective effects of ebselen against OFR damage in a model of chronic iron overload. These findings suggest that ebselen may have significance in the management of disorders of iron overload.

Ochratoxin A and some of its derivatives modulate radical formation of porcine blood monocytes and granulocytes

Modulating effects of ochratoxin A (OTA) and some of its derivatives on viability and oxidative burst activity of porcine monocytes and granulocytes have been studied. The formation of free oxygen radicals by monocytes was suppressed by OTA and ochratoxin C (OTC) at concentrations between 10 and 1000 ng/ml. Intracellular radical formation of granulocytes was in part already significantly reduced at 1 ng/ml of these mycotoxins. Conversely, the intracellular formation of radicals in monocytes of individual pigs was stimulated by the toxins at 1–100 ng/ml. A biologically active fraction of the crude toxin (RE2) which had been identified as OTC had a stronger effect than all other derivatives of ochratoxin A. Whether these modulating effects of OTA and OTC on phagocyte functions are of significance in the pathogenesis of infectious diseases, needs to be studied in more detail. In this context, the occurrence of OTC in food and feeds should be examined more closely.

Myocardial injury and its prevention in the perioperative setting

Myocardial injury and its prevention in the perioperative setting

Letter to the editor

I read Önen et al’s article entitled “Effects of whole blood, crystalloid, and colloid resuscitation of hemorrhagic shock on renal damage in rats: an ultrastructural study” in the November 2003 issue (pp 1642–1649). The authors have shown that resuscitation of hemorrhagic shock with dextran 40 have beneficial effects on renal histology and relate this beneficial effect to reduced red cell slugging, volume expansion, and hemodilution-induced reduction in blood viscosity. However, intravital microscopic study of the intestinal mesenteric microcirculation has shown that resuscication of hemorrhagic shock with hypertonic saline solution containing dextran (HSD; 7.5% NaCl/6% dextran 70) restores microvascular blood flow better than resuscitation with an equal volume of Ringer’s lactate.1 Laser Doppler flowmetry has been used to show beneficial effects of HSD on restoration of intestinal and renal blood flows after resuscitation of hemorrhagic shock.2 Intravital microscopy has been used to show the prevention of hemorrhagic shock- induced leukocyte-endothelium adherence in liver sinusoids after resuscitation with HSD.3 Low-molecular-weight dextran has beneficial effects similar to those of high-molecular-weight dextran on microcirculation. Radioisotopic study of blood flow to multiple organs has shown that resuscitation of hemorrhagic shock with a pure solution of dextran 40 restores blood flow to these organs better than Ringer’s lactate.4 Additionally, dextran has been shown to have free oxygen radical scavenging capacity.5 Hemorrhagic shock has been shown to induce P-selection expression through free oxygen radical formation that leads to no-reflow phenomenon.6,7 Dextran 40 has been shown to prevent hemorrhagic shock-induced P-selectin expression thus abolish no-reflow phenomenon.8

Peripheral markers of oxidative stress and excitotoxicity in neurodegenerative disorders: tools for diagnosis and therapy?

Oxidative stress has been implicated as a common pathogenetic mechanism in neurodegenerative disorders. Central nervous system is particularly exposed to free radical injury, given its high metal content, which can catalyze the formation of oxygen free radicals, and the relatively low content of antioxidant defenses. Indeed, several studies show markers of oxidative damage - lipid peroxidation, protein oxidation, DNA oxidation and glycoxidation markers - in brain areas affected by neurodegenerative disorders. Oxidative stress damage is intimately linked to glutamate neurotoxicity - known as "excitotoxicity". An excessive concentration of extracellular glutamate over-activates ionotropic glutamate receptors, resulting in intracellular calcium overload and a cascade of events leading to neural cell death. In this study we reviewed pathogenetic mechanisms that link oxidative stress and excitotoxicity in three neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease) and described peripheral markers of these mechanisms, that may be analyzed in patients as possible diagnostic and therapeutic tools.

Combined l-arginine and antioxidative vitamin treatment mollifies ischemia-reperfusion injury of skeletal muscle

Enhanced production of superoxide in l-arginine–depleted environments and concomitant reduction of nitric oxide (NO) concentration are involved in ischemia-reperfusion (I/R) injury. Treatment with l-arginine or antioxidative vitamins alone and in combination was used to mollify I/R injury in skeletal muscle. Untreated rabbits were compared with those treated with l-arginine/antioxidative vitamin cocktail Omnibionta only, or a combination of l-arginine/ antioxidative vitamins during hind limb I/R (2.5 hours/2 hours). NO was continuously measured in vivo. Plasma malondialdehyde (MDA) served as the measure of oxygen free radical formation. Interstitial edema formation, microvessel diameter alterations, microvessel plugging, and blood flow changes were used as indicators of I/R injury. The MDA level in untreated animals 2 hours after reperfusion was significantly higher than in control animals (0.81 μmol/L ± 0.14 μmol/L vs 0.57 μmol/L ± 0.11 μmol/L; P < .05), indicating enhanced production of oxygen free radicals. This sequela paralleled the decreasing concentration of NO, which dropped below the detection limit (1 nmol/L) after reperfusion. Microvascular changes during I/R injury were expressed as a 40% decrease in microvessel diameter and adhesion of neutrophils in 20% of microvessels, which led to a consequent 60% reduction in blood flow, demonstrating “no reflow” (reperfusion failure after restoration of blood flow). The increase in the fraction of muscle interfiber area by 85% indicated prominent edema formation. Treatment with antioxidative vitamins alone had a minimally positive effect on edema formation and microvascular plugging, possibly by suppression of oxygen free radical production, as expressed by the reduction in plasma MDA levels. However, this therapy failed to preserve basal NO production and to protect from microvascular constriction and no reflow. Treatment with l-arginine alone had a stronger protective effect, maintaining basal NO production, further reduction of neutrophil plugging, abolition of microvascular constriction, and no reflow. The combination of antioxidative vitamins and l-arginine was the best treatment against I/R injury, expressed not only by the protection of microvessel constriction, but also by abolition of microvascular plugging, increase in NO production (68 nmol/L ± 5 nmol/L) over the basal level (52 nmol/L ± 7 nmol/L), and higher blood flow, as compared with treatment with l-arginine or antioxidative vitamins alone.

Preconditioning with prolonged oxygen exposure induces ischemic tolerance in the brain via oxygen free radical formation.

To determine if 100% oxygen (O2) inhalation induces ischemic tolerance to focal cerebral ischemia and if the effect is induced via O2 free radical formation. Experiment 1: 36 rats were randomly assigned to four groups (n = 9 each): Group A, control rats inhaled air for 24 hr; Groups B, C and D animals inhaled 100% O2 for six hours, 12 hr and 24 hr respectively. Experiment 2: 32 rats were randomly assigned to four groups (n = 8 each): Groups E and F rats received normal saline (5 mL.kg(-1) intraperitoneally) and then inhaled air (Group E) or 100% O2 (Group F) for 24 hr; Groups G and H animals received 10% dimethylthiourea (500 mg.kg(-1) intraperitoneally) and then inhaled 100% O2 (Group G) or air (Group H) for 24 hr. Twenty-four hours after the treatments, the right middle cerebral artery was occluded in all rats for 120 min. The neurologic deficit scores (NDS) and brain infarct volumes were evaluated at 24 hr after reperfusion. Experiment 1: the infarct volume and NDS of Group D were smaller than in controls (P = 0.004 and 0.042 respectively). The infarct volume was reduced by 47% in Group D. There was no statistical difference among Groups A, B and C. Experiment 2: the infarct volume and NDS in Group F were less than in controls (Group E; P = 0.001 and 0.036 respectively). The infarct volume was reduced by 60% in Group F. There was no difference among Groups E, G and H. Our study demonstrates that preconditioning with 100% O2 for 24 hr can induce ischemic tolerance via formation of O2 free radicals in transient focal cerebral ischemia in rats.

Effects of ozone oxidative preconditioning on nitric oxide generation and cellular redox balance in a rat model of hepatic ischaemia-reperfusion.

Many studies indicate that oxygen free-radical formation after reoxygenation of liver may initiate the cascade of hepatocellular injury. It has been demonstrated that controlled ozone administration may promote an oxidative preconditioning or adaptation to oxidative stress, preventing the damage induced by reactive oxygen species and protecting against liver ischaemia-reperfusion (I/R) injury. In the present study, the effects of ozone oxidative preconditioning (OzoneOP) on nitric oxide (NO) generation and the cellular redox balance have been studied. Six groups of rats were classified as follows: (1). sham-operated; (2). sham-operated+l-NAME (N(omega)-nitro-l-arginine methyl ester); (3). I/R (ischaemia 90 min-reperfusion 90 min); (4). OzoneOP+I/R; (5). OzoneOP+l-NAME+I/R; and (6). l-NAME+I/R. The following parameters were measured: plasma transaminases (aspartate aminotransferase, alanine aminotransferase) as an index of hepatocellular injury; in homogenates of hepatic tissue: nitrate/nitrite as an index of NO production; superoxide dismutase (SOD), catalase (CAT) and glutathione levels as markers of endogenous antioxidant system; and finally malondialdehyde+4-hydroxyalkenals (MDA+4-HDA) and total hydroperoxides (TH) as indicators of oxidative stress. A correspondence between liver damage and the increase of NO, CAT, TH, glutathione and MDA+4-HDA concentrations were observed just as a decrease of SOD activity. OzoneOP prevented and attenuated hepatic damage in I/R and OzoneOP+l-NAME+I/R, respectively, in close relation with the above-mentioned parameters. These results show that OzoneOP protected against liver I/R injury through mechanisms that promote a regulation of endogenous NO concentrations and maintenance of cellular redox balance. Ozone treatment may have important clinical implications, particularly in view of the increasing hepatic transplantation programs.

Impairment of endothelium-dependent dilation response after resuscitation from hemorrhagic shock involved postreceptor mechanisms.

Resuscitation from hemorrhagic shock is associated with impairment of the endothelium-dependent dilation response, whereas the dilation response induced by the endothelium-independent pathway, which is mediated by nitroprusside, a nitric oxide (NO) donor and a direct activator of guanylate cyclase, remains unaltered. Whether the impairment of the endothelium-dependent dilation response is caused by a specific receptor alteration or generally a defect in signal transduction pathway remains undetermined. Anesthetized rats were monitored for hemodynamics, and the terminal ileum was prepared for intravital videomicroscopy. Hemorrhage was 50% of mean arterial pressure for 60 min followed by resuscitation with the shed blood returned plus 2 volumes of normal saline. Intestinal microvascular reactivity to the endothelium-dependent receptor-dependent agonists acetylcholine or substance P (10(-8) or 10(-6) M), as well as the endothelium-dependent receptor-independent calcium ionophore, was determined at baseline and at 2 h postresuscitation from hemorrhagic shock. Measured vascular diameters for premucosal A3 arterioles (pA3 and dA3) were normalized and expressed as percentage of the maximal dilation capacity, as obtained from the response to the endothelium-independent NO donor sodium nitroprusside (10(-4) M). At 2 h postresuscitation, there was a marked constriction of pA3 (-70.1 +/- 20) and dA3 (-61.5 +/- 11.6) from maximal dilation capacity. Baseline premucosal arteriolar response to substance P (10(-8) M) was 30.68 +/- 4.19% and 34.66 +/- 5.82% for pA3 and dA3 arterioles, respectively. This was significantly reduced to 20.97 +/- 2.41% and 17.94 +/- 3.60% at 2 h postresuscitation. However, no significant difference between baseline and postresuscitation arteriolar responses was observed at the higher dose of substance P (10(-6) M). Postresuscitation premucosal arteriolar response to the endothelium-dependent receptor-independent calcium ionophore (10(-9) to 10(-5) M) is characterized by a marked decrease in sensitivity and an enhanced threshold for calcium ionophore-mediated dilation. The logEC50 was -7.62 +/- 0.39 and -7.75 +/- 0.32 for the pA3 and dA3 at baseline, respectively. This was significantly (P < 0.01) reduced to -5.15 +/- 0.14 and -4.39 +/- 0.71 at 2 h postresuscitation. These data suggest that impairment of the endothelium-dependent dilation response after resuscitation from hemorrhagic shock is not mediated by specific receptor alteration. Cellular mechanisms that participate in or are part of oxygen free radical formation after resuscitation from hemorrhagic shock such as Ca2+ and leukocytes, appear to have a pivotal role in the mechanism of cellular dysfunction.

Simultaneous production of superoxide radical and singlet oxygen by sulphonated chloroaluminum phthalocyanine incorporated in human low-density lipoproteins: implications for photodynamic therapy.

Sulfonated chloroaluminum phthalocyanines have been studied for their use in the photodynamic therapy (PDT) of tumors. Plasma low-density lipoproteins (LDL) are important carriers of phthalocyanines in the blood, but on exposure to visible light, phthalocyanine-loaded LDL undergo an oxidation process that propagates to erythrocytes. We attempted to identify the reactive species involved in LDL and erythrocyte oxidation by means of electron paramagnetic resonance (EPR) spectroscopy in the presence of 2,2,6,6-tetramethyl-4-piperidone (TEMP) and the spin trap 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO). Irradiation of phthalocyanine-loaded LDL in the presence of DMPO resulted in the formation of a four-line EPR spectrum with relative intensity of 1:2:2:1 (a(N) = a(H) = 14.8 G), characteristic of DMPO-hydroxyl radical spin adduct. This signal was sensitive to superoxide dismutase and slightly sensitive to catalase, but a mixture of the two enzymatic activities was the most efficient in promoting a decrease in the intensity of the EPR signal. In the presence of erythrocytes, an increase in the quartet intensity for a hematocrit of 1% and 4% was observed, decreasing for higher erythrocyte concentrations. The irradiation of phthalocyanine-loaded LDL in the presence of TEMP resulted in the formation of a nitroxide radical, 2,2,6,6-tetramethyl-4-piperidone-N-oxyl radical, intensity of which was sensitive to histidine, a singlet oxygen ((1)O(2)) quencher. Under both incubation conditions, with DMPO and TEMP, the formation of the respective EPR signals required the sensitizer (phthalocyanine), light and oxygen. Overall, the results are compatible with the simultaneous formation of superoxide anion and (1)O(2), implying that Type-I and Type-II mechanisms of photochemistry are simultaneously operative in phthalocyanine-loaded LDL. However, for a constant LDL/phthalocyanine ratio, the formation of oxygen free radicals shows a biphasic behavior with the concentration of LDL increasing and reaching a plateau, whereas the formation of (1)O(2) increases linearly with LDL concentration. Erythrocytes at high (physiological) concentrations induced a decrease in the intensity of both EPR signals. The physiological relevance of these findings in the framework of PDT is briefly discussed.

Simultaneous Production of Superoxide Radical and Singlet Oxygen by Sulphonated Chloroaluminum Phthalocyanine Incorporated in Human Low-density Lipoproteins: Implications for Photodynamic Therapy¶

Sulfonated chloroaluminum phthalocyanines have been studied for their use in the photodynamic therapy (PDT) of tumors. Plasma low-density lipoproteins (LDL) are important carriers of phthalocyanines in the blood, but on exposure to visible light, phthalocyanine-loaded LDL undergo an oxidation process that propagates to erythrocytes. We attempted to identify the reactive species involved in LDL and erythrocyte oxidation by means of electron paramagnetic resonance (EPR) spectroscopy in the presence of 2,2,6,6-tetramethyl-4-piperidone (TEMP) and the spin trap 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO). Irradiation of phthalocyanine-loaded LDL in the presence of DMPO resulted in the formation of a four-line EPR spectrum with relative intensity of 1:2:2:1 (a(N) = a(H) = 14.8 G), characteristic of DMPO-hydroxyl radical spin adduct. This signal was sensitive to superoxide dismutase and slightly sensitive to catalase, but a mixture of the two enzymatic activities was the most efficient in promoting a decrease in the intensity of the EPR signal. In the presence of erythrocytes, an increase in the quartet intensity for a hematocrit of 1% and 4% was observed, decreasing for higher erythrocyte concentrations. The irradiation of phthalocyanine-loaded LDL in the presence of TEMP resulted in the formation of a nitroxide radical, 2,2,6,6-tetramethyl-4-piperidone-N-oxyl radical, intensity of which was sensitive to histidine, a singlet oxygen ((1)O(2)) quencher. Under both incubation conditions, with DMPO and TEMP, the formation of the respective EPR signals required the sensitizer (phthalocyanine), light and oxygen. Overall, the results are compatible with the simultaneous formation of superoxide anion and (1)O(2), implying that Type-I and Type-II mechanisms of photochemistry are simultaneously operative in phthalocyanine-loaded LDL. However, for a constant LDL/phthalocyanine ratio, the formation of oxygen free radicals shows a biphasic behavior with the concentration of LDL increasing and reaching a plateau, whereas the formation of (1)O(2) increases linearly with LDL concentration. Erythrocytes at high (physiological) concentrations induced a decrease in the intensity of both EPR signals. The physiological relevance of these findings in the framework of PDT is briefly discussed.

In Vitro and In Vivo Studies on Oxygen Free Radical and DNA Adduct Formation in Rat Lung and Liver during Benzo[a]pyrene Metabolism

Reactive oxygen species (ROS), possibly produced during the metabolic conversion of benzo(a)pyrene (B[a]P), could be involved in B[a]P-induced genotoxicity and, eventually, carcinogenicity. Therefore, ROS formation by rat lung and liver microsomes was studied in vitro by electron spin resonance (ESR/EPR) spectrometry. B[a]P-mediated generation of ROS was detected in incubations with rat lung, but not with liver microsomes. Inhibition of cytochrome P450 (CYP450) by the non isoform-specific inhibitor SKF-525A resulted in a complete inhibition of B[a]P-dependent ROS formation, whereas ROS formation was not affected by inhibition of prostaglandin H synthase by indomethacin. Subsequently, bulky DNA adduct formation and 8-oxo-dG levels after a single oral dose of B[a]P were examined in vivo in rat lung and liver, in combination with urinary excretion of 8-oxodG. B[a]P exposure resulted in increased urinary 8-oxo-dG levels. On the contrary, 8-oxo-dG levels decreased in liver and lung after B[a]P exposure. Bulky DNA adducts reached higher levels and were more persistent in rat lung than in liver. These results indicate that ROS are generated during the CYP450 dependent metabolism of B[a]P, particularly in the rat lung, but this does not necessarily result in increased levels of oxidative DNA damage in vivo, possibly by induction of DNA repair mechanisms.

Conditioned blood reperfusion markedly enhances neurologic recovery after prolonged cerebral ischemia

Objectives To determine whether controlled reperfusion using conditioned leukodepleted blood can substantially limit cerebral reperfusion injury following prolonged ischemia. Methods Eighteen pigs (25-35 kg) underwent 90 minutes of hypothermic circulatory arrest (19°C) to produce brain ischemia. At the start of rewarming, 10 pigs received uncontrolled reperfusion with unmodified (normal) blood. The other 8 pigs underwent 10 minutes of controlled reperfusion by selectively perfusing both common carotid arteries with blood passed through a CoBRA filter. This filter conditions the blood by removing white blood cells, platelets, and attenuating complement. Two other pigs underwent cooling and rewarming only (controls) without ischemia. Neurologic assessment was done using neurologic deficit scoring (0 = normal, 500 = brain death), and jugular venous samples were obtained for biochemical analysis postreperfusion. Results There were no statistical differences in hemodynamics between groups. At 6 hours postanesthesia, all animals receiving normal blood were substantially neurologically impaired. At 24 hours, they all had abnormal positioning and all but 1 were unable to sit or stand (neurologic score 124 ± 19). In contrast, nonischemic controls and pigs receiving conditioned blood reperfusion showed only minor neurologic deficits at 6 hours, and at 24 hours all were considered normal (neurologic scores 0 and 6 ± 5; P < .005 vs uncontrolled reperfusion). Compared with pigs receiving normal blood reperfusion, oxygen free radical formation (conjugated dienes 1.70 ± 0.03 vs 1.60 ± 0.02 Abs 240 nm; P < .05 vs uncontrolled reperfusion), and endothelin-1 release (2.12 ± 0.09 vs 1.84 ± 0.06 pg/mL; P < .05 vs uncontrolled reperfusion) were also significantly lower in animals receiving conditioned blood. Conclusions Following prolonged cerebral ischemia, reperfusion injury is avoided by delivering conditioned blood, which is devoid of white cells, platelets, and membrane attack complex. These results suggest that this modality is clinically useful in situations where the brain is subjected to prolonged ischemia.

Calcium antagonists and atherosclerosis protection in hypertension.

Calcium antagonists are effective in hypertensive patients of all ethnic groups, irrespective of age, dietary salt intake, salt-sensitivity status or plasma renin activity profile. Some prospective studies show that the calcium antagonists, nifedipine GITS and nitrendipine, reduce cardiovascular morbidity and mortality at least to the same extent as the diuretics. Other prospective studies are in progress to evaluate the effect of calcium antagonists on cardiovascular morbidity and mortality, and the progression of atherosclerosis in hypertensive patients. Calcium antagonists, especially the highly lipophilic amlodipine, lacidipine and nisoldipine, are shown to possess antioxidant properties. These drugs reduce the oxidation of LDL and its influx into the arterial wall, and reduce atherosclerotic lesions in animals. Platelet production of malondialdehyde, a marker of oxygen free radical formation, is suppressed by amlodipine, lacidipine or nifedipine in hypertensive patients. New evidence from long-term clinical trials of calcium antagonists indicates that these drugs can reduce the rate of progression of atherosclerosis in hypertensive and coronary heart disease patients. In the Regression Growth Evaluation Statin Study (REGRESS), co-administration of calcium antagonist, amlodipine or nifedipine with pravasatin caused a significant reduction in the appearance of new angiographic lesions. In the Verapamil in Hypertension and Atherosclerosis Study (VHAS), verapamil was more effective than chlorthalidone in promoting regression of thicker carotid lesions in parallel with a reduction in the incidence of cardiovascular events. In the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), amlodipine slowed the progression of early coronary atherosclerosis in patients with coronary artery disease. In a subprotocol of the Intervention as a Goal in the Hypertension Treatment (INSIGHT) study, nifedipine GITS significantly decreased intima-media thickness as compared to co-amilozide (hydrochlorothiazide + amiloride). Preliminary results of the European Lacidipine Study on Atherosclerosis (ELSA) show that lacidipine reduced the intima-media thickness progression rate as compared to atenolol. Thus, selective calcium antagonists are potential antiatherosclerotic agents.

The changing faces of glutathione, a cellular protagonist

Glutathione (GSH) has been described for a long time just as a defensive reagent against the action of toxic xenobiotics (drugs, pollutants, carcinogens). As a prototype antioxidant, it has been involved in cell protection from the noxious effect of excess oxidant stress, both directly and as a cofactor of glutathione peroxidases. In addition, it has long been known that GSH is capable of forming disulfide bonds with cysteine residues of proteins, and the relevance of this mechanism (“S-glutathionylation”) in regulation of protein function is currently receiving confirmation in a series of research lines. Rather paradoxically, however, recent studies have also highlighted the ability of GSH—and notably of its catabolites—to promote oxidative processes, by participating in metal ion-mediated reactions eventually leading to formation of reactive oxygen species and free radicals. A crucial role in these phenomena is played by membrane bound γ-glutamyltransferase activity. The significance of GSH as a major factor in regulation of cell life, proliferation, and death, should be regarded as the integrated result of all these roles it can play.

Association between atherosclerosis and female lung cancer—a Danish cohort study

Patients suffering from atherosclerotic diseases are prone to repeated episodes of ischemia/reperfusion that has been demonstrated to induce oxidative stress by formation of oxygen free radicals. It might therefore be expected that such endogenously exposure to free radicals increases the individual cancer risk in patients with atherosclerotic diseases. We therefore studied the sex-specific risk of lung cancer and other cancers in atherosclerotic patients in a prospective study conducted in the Copenhagen area. The study cohort was linked to the Danish Hospital Discharge Register and we identified 2261 1-year survivors of atherosclerotic diseases through 1977 and 1993, while 26 150 of the study subjects had no record of an atherosclerotic diagnosis. After linkage to the Danish Cancer Registry associations between atherosclerosis and cancer were analysed for each sex separately by means of Cox proportional hazard regression models. Atherosclerotic women had a significant RR of lung cancer of 3.26 (95%CI: 1.95–5.46) compared to non-atherosclerotic women after adjustment for age, calendar period, study population, smoking habits, school education and alcohol consumption. No significant risk of male lung cancer, RR=1.12 (95%CI: 0.77–1.64), or other smoking-related cancers in either sex was observed after multivariate adjustment. Atherosclerosis did not predict non-smoking-related cancers in general in either men, RR=0.91 (95%CI 0.69–1.20), or women, RR=0.93 (95%CI: 0.64–1.35). We hypothesize that oxidative stress due to episodes of ischemia/reperfusion increases the risk of lung cancer in atherosclerotic females because of a gender specific susceptibility to oxidative DNA damage.

Pathophysiology and Management of Abdominal Compartment Syndrome

Abdominal compartment syndrome is a potentially lethal condition caused by any event that produces intra-abdominal hypertension; the most common cause is blunt abdominal trauma. Increasing intra-abdominal pressure causes progressive hypoperfusion and ischemia of the intestines and other peritoneal and retroperitoneal structures. Pathophysiological effects include release of cytokines, formation of oxygen free radicals, and decreased cellular production of adenosine triphosphate. These processes may lead to translocation of bacteria from the gut and intestinal edema, predisposing patients to multiorgan dysfunction syndrome. The consequences of abdominal compartment syndrome are profound and affect many vital body systems. Hemodynamic, respiratory, renal, and neurological abnormalities are hallmarks of abdominal compartment syndrome. Medical management consists of urgent decompressive laparotomy. Nursing care involves vigilant monitoring for early detection, including serial measurements of intra-abdominal pressure.

Can the ischemia-reperfusion syndrome in transplanted kidneys procured from non–heart-beating donors be influenced by adding selenium into the reperfusion solution? an experimental study

The ischemic-reperfusion syndrome significantly influences the function of a kidney transplanted from a non–heart-beating donor (NHBD). The animal model of a NHBD was used to monitor the influence of exogenous addition of selenium into the reperfusion solution (HTK, Custodiol) with respect to the formation of free oxygen radicals at 0 to 120 minutes after the NHBD transplantation. This maneuvers produced a statistically significant decrease in malondialdehyde concentration, an indicator of free oxygen radicals in the venous blood of the transplanted kidney. The augmentation of the antioxidative capacity of the preservation solution might be a possible route to improve the function of kidneys transplanted from NHBDs.