High dose propofol enhances red cell antioxidant capacity during CPB in humans

PURPOSE: To compare low vs. high dose propofol and isoflurane on red cell RBC antioxidant capacity in patients during aortocoronary bypass surgery (ACBP). METHODS: Twenty-one patients, for ACBP, were anesthetized with sufentanil 0.5-10 microg x kg(-1) and isoflurane 0-2%; ISO = control; n = 7), or sufentanil 0.3 microg x kg(-1), propofol 1-2.5 mg x kg(-1) bolus then 100 microg x kg(-1) min(-1) before, and 50 microg x kg(-1) x min(-1) during CPB (LO; n = 7), or sufentanil 0.3 microg x kg(-1), propofol 2-2.5 mg x kg(-1) bolus then 200 microg x kg(-1) x min(-1) (HI; n = 7). Venous blood was drawn pre- and post-induction, after 30 min CPB, 5, 10, and 30 min of reperfusion, and 120 min post-CPB to measure red cell antioxidant capacity (malondialdehyde (MDA) production in response to oxidative challenge with t-butyl hydrogen peroxide) and plasma propofol concentration. Pre- induction blood samples were analyzed for antioxidant effects of nitrates on red cells. The tBHP concentration response curves for RBC MDA in ISO, LO and HI were determined. RESULTS: Preoperative nitrate therapy did not effect RBC MDA production. Perioperative RBC MDA production was similar in ISO and LO groups. Sustained intraoperative decrease in RBC MDA was seen with propofol 8.0+/-2.4 - 11.8+/-4.5 microg x ml(-1) in HI (P<0.05-0.0001). MDA production vs. log plasma propofol concentration was linear in HI dose. CONCLUSIONS: During CPB, RBC antioxidant capacity is enhanced and maintained with HI dose propofol. Propofol, at this dose, may prove useful in protecting against cardiopulmonary ischemia-reperfusion injury associated with ACBP.     

Evaluation of antioxidant capacity in lung carcinoma

Background Free radicals lead to oxidative stress and tissue damage. In malignant tissues, decreased levles of antioxidant enzymes and increase of reactive oxygen metabolites have hazardous effects on cell membrane and other vital cellular components. This investigation was carried to determine the levels of superoxide SOD dismutase MDA and malondialdehyde in lung cancerous tissues and to compare with normal lung tissue in order to evaluate the antioxidant status in lung cancer. Methods and Material 21 Male patients who were diagnosed to have lung cancer were studied. Control group contained 11 patients who were operated for nonmalignant lung disease and some lung tissue specimen had been extracted. Lung tissue specimens were assessed at the department of pathology. Superoxide dismutase and Malondialdehyde levels were determined at biochemistry laboratory by the method of Misra and Fridovich as modified by Sykes et al. Results The level of glutathione, an antioxidant tripeptide, was also in a separate control group of patients. Mean SOD level in cancer tissue was determined to be 8.08±4.8 U/mg protein and 13.33±5.83 U/mg protein in normal tissue. Mean MDA level was 2.8±1.66 Umol/gr tissue in cancer lung and 1.025±0.59 Umol/gr tissue in normal lung. In this study it is observed that oxidative stress increases in patients of lung cancer. Conclusions Oxidative damage might have an important role for cancer development; therefore strengthening the antioxidant capacity might probably prevent this malignant transformation.     

Propofol enhances red cell antioxidant capacity in swine and humans

Purpose  To determine the effect of an anaesthetic with antioxidant potential, propofol, on red blood cell (RBC) antioxidant enzyme activities and RBC susceptibility to peroxidative challenge. Methods  Propofol was administered by intravenous bolus (2.5 mg·kg⁻¹) and continuous infusion (36 and 72 ml·hr⁻¹ in nine swine; 216 ml·hr⁻¹ in two swine), to achieve serum concentrations between 5 and 30μg·ml⁻¹ for two hours at each rate. Arterial blood sampling was at 0,10, 30, 60, and 120 min for each rate of infusion, for measurement of plasma propofol concentration, activities of plasma and RBC Superoxide dismutase, glutathione peroxidase, gluthathione reductase, RBC catalase, and RBC malondialdehyde (MDA) formation in response to exvivo oxidative challenge with t-butyl hydrogen peroxide (tBHP; 1.5mM). Antioxidant mechanisms were determined byin vitro study of MDA formation, GSH depletion, and oxidation of haemoglobin to methaemoglobin in human erythrocytes exposed to propofol 0–75 μM. The antioxidant potential of propofol was compared with that of alpha-tocopherol utilising the reaction with 2,4,6-tripyridyl-s-triazine (TPTZ). Results  Propofol had no effect on plasma or RBC antioxidant enzyme activities. It inhibited RBC MDA production over the range of 0–20 μg·ml⁻¹ (y = −18.683x + 85.431 ; R² = 0.8174). Effective propofol concentrations for 25% and 50% reductions in MDA levels were 7–12 and 12–20 μg·ml⁻¹, respectively. Propofol has a similar effect on human erythrocytesin vitro (R₂ = 0.98). Conclusion  Propofol antagonises the effects of forced peroxidation of red cells at anaesthetic and sub-anaesthetic concentrations in swine. Its actions include scavenging of oxygen derived free radicals in a tocopherol-like manner.

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Résumé Objectif  Déterminer l’effet d’un agent anesthésique possédant un potentiel antioxydant, le propofol, sur l’activité d’un enzyme antioxydant des globules rouges (GR) et sur la susceptibilité des GR à une provocation peroxydative. Méthodes  Le propofol a été administré en bolus intraveineux (2,5 mg·kg⁻¹) et en infusions continues (36 et 72 ml·h⁻¹ chez 9 porcs; 216 ml·h⁻¹ chez 2 porcs) pour obtenir des concentrations sériques entre 5 et 30 μg·ml⁻¹ durant deux heures à chaque vitesse d’infusion. Des prélèvements sanguins par voie artérielle ont été réalisés à 0, 10, 30, 60 et 120 min. pour chaque vitesse d’infusion; on a mesuré la concentration de propofol, l’activité de la superoxyde dismutase du plasma et des GR, de la peroxydase du glutathion, de la réductase du glutathion, de la catalase du GR, ainsi que de la formation dans le GR de la malondialdehyde (MDA) en réponse à une provocation oxydative exvivo avec le peroxyde d’hydrogène t-butylique (tBHP, 1,5 mM). Les mécanismes antioxydants ont été déterminés par l’étudein vitro de la formation de MDA, de la déplétion de GSH ainsi que de l’oxydation de l’hémoglobine en methémoglobine dans des GR humains exposés au propofol 0–75 μM. Le potentiel antioxydant du propofol a été comparé à celui de l’alpha-tocophérol en utilisant la réaction avec le 2,4,6-tripyridyl-s-triazine (TPTZ). Résultats  Le propofol n’a pas eu d’effet sur l’activité de l’enzyme antioxydant du plasma ou des GR. Il a inhibé la production de MDA par les GR pour tout le spectre de 0–20 μg·ml⁻¹ (y = −18.683x + 85.431 ; R² = 0,8174). Les concentrations de propofol efficaces pour obtenir une réduction des taux de MDA de 25 et de 50% étaient respectivement de 7–12 et de 12–20 μg·ml⁻¹. Le propofol a un effet analogue sur les globules rouges humainsin vitro (R₂ = 0,98). Conclusion  Le propofol, à des concentrations anesthésiques et subanesthésiques chez le porc, antagonise les effets d’une peroxydation forcée des globules rouges. Son mode d’action comporte l’épuration des radicaux libres provoqués par l’oxygène comme le fait le tocophérol.

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Supported in part by a research grant from Zeneca Pharma Inc (Canada Ltd.).

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Presented at the 71st Clinical and Scientific Congress of the International Anesthesia Research Society, March 14–18,1997 San Francisco, Ca, USA.     

Determination of erythrocyte antioxidant capacity in haemodialysis patients using electron paramagnetic resonance.

BACKGROUND: The increased oxidative stress of uraemia is caused both by an increased generation of oxygen-free radicals and a decrease of antioxidative forces. There are, however, conflicting data concerning disturbances of the radical-scavenging power of red blood cells (RBCs) in uraemic patients. METHODS: The antioxidant capacities of the RBCs of 10 haemodialysis (HD) patients and 10 controls were examined after treatment with 0.324 mM tert-butylhydroperoxide (t-BOOH) in phosphate-buffered saline at 37 degrees C using electron paramagnetic resonance (EPR) with 5,5-dimethylpyrroline-N-oxide (DMPO) as a spin trap and glutathione (GSH) regeneration as an indicator of hexose monophosphate shunt (HMPS) activity. EPR investigations were also done after pre-incubation with N-ethylmaleimide (NEM) to inhibit the GSH system. Furthermore, we determined the RBC redox state in 15 HD patients and 15 controls. RESULTS: There was no difference between HD patients and controls in the elimination of t-BOOH-generated free radicals in the RBCs. A more than 20-fold increase in radical concentration was observed after GSH trapping with NEM. In this case, we found a delayed decrease of the relative radical concentration in HD patients compared with controls with a significant difference after 7 min (2.2+/-0.26 vs 1.60+/-0.21; P=0.005) and after 10 min (1.82+/-0.41 vs 0.83+/-0.44; P=0.001). GSH regeneration via HMPS did not differ between the RBCs of HD patients (99.5+/-13.5 nmol/min x ml RBC) and those of the controls (94.2+/-16.9 nmol/min x ml RBC). There were no differences in the RBC concentrations of GSH, GSSG, NADP, NADPH, and in the GSH/GSSG and NADP/NADPH ratios between HD patients and controls. CONCLUSIONS: These data suggest a strong antioxidant potential in the GSH system of erythrocytes without any evidence of a disturbance in HD patients. The HMPS pathway also appears not to be impaired in the RBCs of HD patients. However, the slower radical elimination in the RBCs of HD patients after inhibition of GSH-depending radical scavengers as compared with controls indicates a defect in the antioxidant forces outside the GSH system, and could be one reason for the reduced lifespan of RBCs in HD patients.     

Large-dose propofol during cardiopulmonary bypass decreases biochemical markers of myocardial injury in coronary surgery patients: a comparison with isoflurane

We investigated if increasing propofol's dosage to augment its antioxidant capacity during cardiopulmonary bypass (CPB) could confer cardiac protection. Fifty-four coronary artery bypass graft surgery patients were randomly assigned to small-dose propofol (Group P; n = 18), large-dose propofol (Group HiP; n = 18), or isoflurane Group (Group I; n = 18). After the induction, anesthesia was maintained with an inspired concentration of isoflurane 1%-3.5% (Group I) or a continuous infusion of propofol 60 microg x kg(-1) x min(-1) (Group P) throughout the surgery. In Group HiP, this dose of propofol was increased to 120 microg x kg(-1) x min(-1) for 10 min before the onset of CPB until 15 min after aortic unclamping and then decreased to 60 microg x kg(-1) x min(-1) until the end of surgery. The duration of aortic cross-clamping was 83 +/- 24, 88 +/- 22, and 81 +/- 20 min in Group P, Group HiP, and Group I, respectively (P > 0.1). Plasma malondialdehyde, a marker of oxidative stress, was significantly lower at 8 h after CPB, and Troponin I was lower at 24 h after CPB in Group HiP compared with Group P and Group I (P < 0.05). There was a significant reduction in inotropic requirements for separation from CPB in Group HiP compared with Group I. Postoperative systemic vascular resistance was significantly reduced in Group HiP as compared with Group I. Mean cardiac index was significantly higher at 24 h after CPB in Group HiP compared with Group P and Group I (P < 0.05) (Group I, 2.2 +/- 0.1; Group P, 2.3 +/- 0.2; and Group HiP, 2.8 +/- 0.3 L x min(-1) x m(-2), respectively). The duration of intensive care unit stay was significantly shorter in Group Hi-P compared with Group I. We conclude that administration of a large dose of propofol during CPB attenuates postoperative myocardial cellular damage as compared with isoflurane or small-dose propofol anesthesia.     

Propofol attenuates lung endothelial injury induced by ischemia-reperfusion and oxidative stress

Lung dysfunction after cardiopulmonary bypass and lung transplantation results from oxidant-mediated cellular damage. Previously, we observed the shedding of angiotensin-converting enzyme (ACE) from the endothelial cell surface to be a more sensitive and earlier marker of oxidative lung endothelial injury than lung wet-to-dry weight ratio. The aim of this study was to evaluate the potential of the anesthetic propofol, which has antioxidant properties, to prevent oxidative lung injury by measuring ACE shedding. ACE release from isolated perfused rat lungs increased significantly after ischemia-reperfusion (I/R). Propofol significantly decreased I/R-induced ACE release by 23.4% (P < 0.05). Perfusion with 0.75 mM H(2)O(2) also caused ACE release from the lung microvasculature, which was similarly attenuated by propofol. The protective effect of propofol on H(2)O(2)-induced ACE shedding was confirmed in vitro using Chinese Hamster Ovary cells overexpressing human ACE. Thus, propofol can attenuate oxidative injury of the pulmonary endothelium as detected by ACE shedding in I/R and H(2)O(2) models of acute lung injury.     

Effects of propofol and halothane on long-term potentiation in the rat hippocampus after transient cerebral ischaemia

BACKGROUND: Propofol is reported to have protective effects on cerebral ischaemia-induced neuronal death. The aim of this study was to explore whether propofol and halothane can protect hippocampal neuronal function from ischaemic injury during general anaesthesia in rats. METHODS: Rats were divided into 2-vessel occlusion (incomplete cerebral ischaemia) and 4-vessel occlusion (complete cerebral ischaemia) groups consisting of three subgroups each (sham-operated, propofol and halothane groups). One hour after starting propofol 1 mg kg(-1) min(-1) with 30% O2 and N2 or halothane 0.8% in 30% O2 and N2 rats with or without bilateral vertebral artery occlusion had bilateral common carotid arteries occluded by vessel clips for 10 min. Anaesthesia was maintained for another 1 h. Seven days after ischaemia-reperfusion, hippocampal long-term potentiation in the perforant path-dentate gyrus synapse was determined as an index of cerebral outcome. RESULTS: In the propofol groups, the formation of long-term potentiation was significantly impaired in the 2-vessel and 4-vessel occlusion groups compared to the respective sham-operated groups (P < 0.01 and P < 0.05, respectively). Impaired formation of long-term potentiation in propofol groups was comparable to that in halothane groups. The formation of long-team potentiation in the propofol and halothane 2-vessel group was not significantly different from that in the awake 2-vessel group. CONCLUSIONS: Propofol and halothane administered during ischaemia do not possess protective effects against hippocampal neuronal dysfunction induced by cerebral ischaemia-reperfusion as evaluated by our transient ischaemic rat models.     

Propofol as a sole agent for paediatric day care diagnostic ophthalmic procedures: comparison with halothane anaesthesia

BACKGROUND: Our aim was to study the feasibility of total intravenous anaesthesia with propofol in spontaneously breathing children undergoing ophthalmic procedures. METHODS: Fifty-five children (aged 6 months to 5 years) were randomly allocated to receive either propofol bolus (until loss of eyelash reflex) followed by infusion [group P (n=29)] or halothane 3-4% for induction, followed by 1-2% in 70% nitrous oxide and oxygen via face mask [group H (n=28)]. Dose for induction and maintenance, intraoperative adverse events, time to recovery (on an Observer's Assessment of Alertness/Sedation Scale, 5 at each level) and duration of procedure were recorded. All children in both groups, were anaesthetized successfully. RESULTS: 4.0 +/- 0.7 mg x kg(-1) and 5.1 +/- 1.0 mg x kg(-1) of propofol were required for loss of eyelash reflex and tolerance of the ophthalmic speculum, respectively. An infusion rate of 8.3 +/- 1.7 mg x kg(-1) x h(-1) was needed for maintenance of anaesthesia; 3.4 +/- 0.5%, 3.6 +/- 0.4% and 1.4 +/- 0.4% halothane was needed for induction, tolerance of the eye speculum and maintenance of anaesthesia, respectively. Induction and recovery were significantly faster with halothane compared with propofol [induction - 38.3 +/- 6.6 s (group H)/60.9 +/- 15.2 s (group P) (P < 0.001); recovery 12.8 +/- 4.6 min (group H)/27.0 +/- 23.3 min (group P) (P < 0.001)]. Apnoea, coughing and breath-holding were seen only in group H. Group P had significantly higher incidence of involuntary movements (minor degree) (n=6) (P < 0.01). CONCLUSIONS: Propofol is a feasible option for paediatric diagnostic ophthalmic procedures with the advantage over halothane of providing complete access to the eye.     

Impaired antioxidant defence in guinea pig heart tissues treated with halothane

Purpose

To investigate the effects of halothane and halothane plus vitamin E treatment on myocardial free radical metabolism in guinea pigs.

Methods

Four groups of seven animals were studied; control, halothane, halothane plus vitamin E and vitamin E groups. In the halothane group, halothane 1.5% in oxygen was given for 90 min over three days. In the halothane plus vitamin E group, 300 rng · kg^?1 · day^?1 vitamin Eim was started three days before the first halothane treatment and continued for three days. Following sacrifice, the hearts were assayed for superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) and malondialdehyde (MDA) level was determined. Electron spin resonance (ESR) analysis and electron microscopy (EM) were also performed.

Results

In the halothane group, SOD activities and MDA concentrations were increased compared with control and GSH-Px and CAT activities were decreased. In the halothane plus vitamin E group, there were no differences in enzyme activity compared with halothane alone but the MDA level was decreased. In the vitamin E group, enzyme activities were increased compared with control. Mainly the CF₃CHCl radical was identified by ESR analysis in heart tissues exposed to halothane and the concentration of this radical was reduced by vitamin E. Electron microscopy showed cytoplasmic vacuolisation and dilation in sarcoplasmic reticulum in the heart tissues exposed to halothane: both were prevented by vitamin E.

Conclusion

Although halothane causes impairment in enzymatic antioxidant defence potential, due to lowered GSH-Px and CAT activity, and accelerates peroxidative reactions in the tissues affected, no subcellular damage occurred. Vitamin E may protect tissues against free radical attack by scavenging toxic free radicals formed in heart tissue during halothane anaesthesia.     

Cyclosporine effects on the antioxidant capacity of rat renal tissues

OBJECTIVE: Cyclosporine (CsA) has been shown to improve long-term survival after organ transplantation. However, CsA therapy is associated with a variety of side effects, among which nephropathy is the major one. Recent studies have suggested increased oxidative stress as a cause of drug nephrotoxicity. Therefore, this study was designed to evaluate the effects of CsA administration on the antioxidant capacity of kidney tissue. METHODS: Adult male Sprague-Dawley rats were randomly assigned into 2 groups: one group received CsA (25 mg/kg/d, IP for 2 weeks) and a control group (no CsA administration). After 2 weeks, the kidneys of the rats from both groups were removed under anesthesia. A 50 mg fresh kidney tissue sample was homogenized in ice-cold phosphate buffer. Total antioxidant capacity (Ferric Reducing Ability of Plasma [FRAP]) in the homogenates was assayed based on the Benzie spectrophotometric method. RESULTS: FRAP in the kidney tissues had been significantly decreased by 2 weeks of CsA administration when compared with control rats (P<.05). CONCLUSIONS: These data suggested that CsA administration may decrease the antioxidant capacity of renal tissues. More studies on the evaluation of the protective effects of antioxidant therapy against CsA nephrotoxicity are underway.     

Propofol decreases reperfusion-induced arrhythmias in a model of "border zone" between normal and ischemic-reperfused guinea pig myocardium

We examined the effect of propofol on the main mechanisms involved in ischemia/reperfusion-induced arrhythmias (i.e., spontaneous arrhythmias, conduction blocks, and dispersion of repolarization) in vitro. In a double-chamber bath, guinea pig right ventricular muscle strips were subjected to 30 min of simulated ischemia followed by 30 min of reperfusion (altered zone; AZ) and to standard conditions (normal zone; NZ). Action potential (AP) parameters were recorded in the NZ and AZ. We studied the effects of Intralipid(R) and of propofol at 10(-6), 10(-5), and 2 x 10(-5) M on the occurrence of spontaneous sustained arrhythmias, conduction blocks, and the dispersion of repolarization. In NZ, Intralipid and propofol did not significantly modify the AP parameters. Propofol, but not Intralipid, lessened the ischemia-induced decrease in AP duration (APD) at 90% of repolarization (APD(90)) and attenuated the APD dispersion around the "border zone." Propofol did not modify the occurrence of ischemia-induced arrhythmias. Propofol 10(-6) M, but not Intralipid or propofol at 10(-5) and 2 x 10(-5) M, decreased the occurrence of ischemia-induced conduction blocks. Propofol decreased the occurrence of reperfusion-induced spontaneous sustained arrhythmias. We conclude that, in vitro, propofol attenuated the ischemia-induced APD(90) dispersion around the "border zone" and decreased the occurrence of spontaneous arrhythmias related to myocardial reperfusion injury. IMPLICATIONS: In isolated guinea pig ventricular myocardium propofol, but not Intralipid(R), attenuated the ischemia-induced shortening of action potential and, thus, the dispersion of repolarization and decreased the occurrence of spontaneous ventricular arrhythmia related to reperfusion injury. This result may be important for propofol-based anesthesia in patients at high risk for intraoperative ischemia.     

The dose-range effects of propofol on the contractility of fatigued diaphragm in dogs.

Diaphragmatic fatigue may contribute to the development of respiratory failure. We studied the dose-range effects of propofol on the contractility of fatigued diaphragm in dogs. Animals were divided into three groups of eight each. In each group, diaphragmatic fatigue was induced by intermittent supramaximal bilateral electrophrenic stimulation at a frequency of 20-Hz stimulation for 30 min. Immediately after the end of a fatigue-producing period, Group 1 received no study drug; Group 2 was infused with small-dose propofol (0.1 mg/kg initial dose plus 1.5 mg x kg(-1) x h(-1) maintenance dose); Group 3 was infused with large-dose propofol (0.1 mg/kg initial dose plus 6.0 mg x kg(-1) x h(-1) maintenance dose). We assessed diaphragmatic contractility by transdiaphragmatic pressure (Pdi). After the fatigue-producing period, in each group, Pdi at low-frequency (20-Hz) stimulation decreased from baseline values (P < 0.05), whereas there was no change in Pdi at high-frequency (100-Hz) stimulation. In Groups 2 and 3, with an infusion of propofol, Pdi at 20-Hz stimulation decreased from fatigued values (P < 0.05). Compared with Group 1, Pdi at 20-Hz stimulation decreased from fatigued values (P < 0.05) during propofol administration in Groups 2 and 3. The decrease in Pdi was more in Group 3 than in Group 2 (P < 0.05). We conclude that propofol decreases the contractility of fatigued canine diaphragm in a dose-related fashion. IMPLICATIONS: Propofol is a widely used IV anesthetic for the induction and maintenance of general anesthesia and sedation. It decreases, in a dose-related fashion, the contractility of fatigued diaphragm in dogs.     

Propofol is a 'safe' anaesthetic agent in malignant hyperthermia susceptible patients.

In this study we investigated in vitro and in vivo effects of propofol in malignant hyperthermia susceptible (MHS) patients in order to assess the safety of propofol infusion as a non-triggering anaesthetic technique for diagnostic and therapeutic procedures. In vitro, human MHS muscle samples were exposed to propofol and changes in (a) baseline tension and (b) contracture tension on exposure to halothane and caffeine were measured. In vivo, (a) anaesthesia was induced in ten muscle biopsy positive MHS patients with propofol 2.5 mg/kg and (b) anaesthesia was produced in five muscle biopsy positive MHS patients with infusions of propofol up to 10 mg/kg/hr. In vitro, human MHS muscle did not develop contractures with propofol alone. Propofol had no significant effect on contracture development in response to halothane and caffeine. In vivo, no evidence of an MH response was detected following induction or maintenance of anaesthesia with propofol. Our results and literature review are in agreement that propofol is a 'safe' induction and maintenance agent in MHS patients. Propofol can be used for muscle biopsy anaesthesia because it does not alter the sensitivity of diagnostic muscle biopsy testing.     

Propofol neuroprotection in cerebral ischemia and its effects on low-molecular-weight antioxidants and skilled motor tasks

BACKGROUND: Propofol is neuroprotective when administered immediately after stroke. The therapeutic window, duration of administration, and antioxidant mechanisms of propofol in neuroprotection are not known. The effects of propofol after stroke were examined in the conscious animal. The authors have previously shown that light propofol anesthesia (25 mg x kg(-1) x h(-1)) for a period of 4 h, even if delayed 1 h after the onset of ischemia, decreases infarct volume 3 days after the stroke. METHODS: Cerebral ischemia was induced in awake Wistar rats by a local intracerebral injection of the potent vasoconstrictor, endothelin (6 pmol in 3 microl) into the striatum. Propofol treatment after ischemia was delayed up to 4 h, and the infusion period shortened from 4 h to 1 h. Infarct volume was assessed 3 or 21 days after the stroke. Neurologic outcome was evaluated on days 14-21 after ischemia. Tissue ascorbate and glutathione concentrations were evaluated at 4 h and 3 days after ischemia. RESULTS: Infarct volumes were reduced 3 days after ischemia when propofol treatment (25 mg x kg(-1) x h(-1)) was delayed for 2 h (0.5+/-0.3 mm3) but not 4 h (2.0+/-0.9 mm3), compared with intralipid controls (2.4 +/- 0.7 mm3). The propofol infusion period of 3 h but not 1 h reduced infarct volume. Propofol treatment did not reduce infarct volume 21 days after the stroke, although motor function improvements (Montoya staircase test) were observed 14-21 days after the stroke. Propofol neuroprotection was independent of tissue ascorbate and glutathione concentrations. CONCLUSIONS: Concurrent or delayed administration of propofol is neuroprotective 3 days after ischemia. Although there were no differences in infarct volume 21 days after ischemia, propofol-treated animals had functional improvements at this time.     

Anesthetic Propofol Enhances Plasma [gamma]-Tocopherol Levels in Patients Undergoing Cardiac Surgery

Background: Propofol (2,6-diisopropylphenol) is an anesthetic drug with antioxidant and antiinflammatory properties, documented both in vitro and in experimental models of ischemia-reperfusion injury and septic shock. These properties have been related to the similarity of its chemical structure to that of endogenous tocopherols, which are phenol-containing radical scavengers. This study evaluated the effects of propofol on [alpha]- and [gamma]-tocopherol ([alpha]- and [gamma]-T) levels and on selected markers of oxidant-antioxidant and inflammatory status in patients undergoing cardiac surgery.

Methods: Patients were randomly assigned for anesthesia with either propofol (propofol group, n = 22) or sevoflurane (control group, n = 21). Plasma levels of [alpha]- and [gamma]-T, individual antioxidant capacity, malondialdehyde, and interleukin 10 were measured before, during, and after anesthesia. In addition, levels of the proinflammatory prostaglandin E2 as a marker of cyclooxygenase-2 activity and those of interleukin 10 were measured in whole blood cultured with bacterial lipopolysaccharide.

Results: [gamma]-T levels increased significantly during surgery in propofol group (P < 0.0001 vs. control group). By contrast, [alpha]-T similarly decreased in both groups. Malondialdehyde and interleukin 10 increased markedly and individual antioxidant capacity decreased, without differences between groups. Prostaglandin E2 levels measured 24 h after anesthesia induction were significantly lower in the propofol than in the control group. In vitro studies highlighted the different capacity of [gamma]- and [alpha]-T to impair prostaglandin E2 synthesis by human monocytes challenged with bacterial lipopolysaccharide.     

Propofol attenuates oxidant-induced acute lung injury in an isolated perfused rabbit-lung model

Purpose Reactive oxygen species have been strongly implicated in the pathogenesis of acute lung injury (ALI). Some animal studies suggest that free radical scavengers inhibit the onset of oxidant-induced ALI. Propofol (2,6-diisopropylphenol) is chemically similar to phenol-based free radical scavengers such as the endogenous antioxidant vitamin E. Both in vivo and in vitro studies have suggested that propofol has antioxidant potential. We hypothesized that propofol may attenuate ALI by acting as a free-radical scavenger. Methods We investigated the effects of propofol on oxidant-induced ALI induced by purine and xanthine oxidase (XO), in isolated perfused rabbit lung, in two series of experiments. In series 1, we examined the relationship between the severity of ALI and the presence of hydrogen peroxide (H₂O₂). In series 2, we evaluated the effects of propofol on attenuating ALI and the dose dependence of these effects. The lungs were perfused for 90 min, and we evaluated the effects on the severity of ALI by monitoring the pulmonary capillary filtration coefficient (Kfc), pulmonary arterial pressure (Ppa), and the pulmonary capillary hydrostatic pressure (Ppc). Results In series 1, treatment with catalase (an H₂O₂ scavenger) prior to the addition of purine and XO resulted in complete prevention of ALI, suggesting that H₂O₂ may be involved closely in the pathogenesis of ALI. In series 2, pretreatment with propofol at concentrations in excess of 0.5 mM significantly inhibited the increases in the Kfc values, and that in excess of 0.75 mM significantly inhibited the increase in the Ppa values. Conclusion Propofol attenuates oxidant-induced ALI in an isolated perfused rabbit lung model, probably due to its antioxidant action.     

Oxidative stress status during exposure to propofol, sevoflurane and desflurane

We evaluated the circulating and lung oxidative status during general anesthesia established with propofol, sevoflurane, or desflurane in mechanically ventilated swine. Blood samples and bronchoalveolar lavage fluid (BAL) specimens were respectively performed via an internal jugular vein catheter and a nonbronchoscopic BAL for baseline oxidative activity measurements: malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPX). A 4-h general anesthesia was then performed in the three groups of 10 swine: the Propofol group received 8 mg x kg(-1) x h(-1) of IV propofol as the sole anesthetic; the Desflurane group received 1.0 minimum alveolar concentration of desflurane; and the Sevoflurane group received 1.0 minimum alveolar concentration of sevoflurane. We observed significantly larger levels of MDA in plasma and BAL during desflurane exposure than with the other anesthetics. We also observed smaller concentrations of circulating GPX and alveolar GPX. We found a significant decrease for MDA measurements in the plasma and the pulmonary lavage during propofol anesthesia. We also found larger values of GPX measurements in the serum and the pulmonary lavage. No significant changes were observed when animals were exposed to sevoflurane. No significant changes were found for circulating concentrations of SOD during exposure to all anesthetics. In this mechanically ventilated swine model, desflurane seemed to induce a local and systemic oxidative stress, whereas propofol and sevoflurane were more likely to have antioxidant properties. IMPLICATIONS: Superoxide is an unavoidable byproduct of oxygen metabolism that occurs in various inflammatory reactions. Inhalation of volatile anesthetics under mechanical ventilation induces an inflammatory response. We evaluated the bronchoalveolar and systemic oxidative stress in swine during exposure to propofol and newer volatile anesthetics. Desflurane induces more lipid peroxidation than do the other anesthetics.     

Propofol protection of sodium-hydrogen exchange activity sustains glutamate uptake during oxidative stress.

We investigated the role of intracellular pH in protection by propofol of glutamate uptake during oxidative stress. Exposure of primary astrocyte cultures to tert-butylhydroperoxide (t-BOOH, 300 microM) decreased the initial rate of Na-dependent glutamate uptake. Either propofol or alpha-tocopherol, administered 30 min after t-BOOH, attenuated this transport inhibition. These lipophilic antioxidants protected glutamate uptake whether the medium contained 25 mM bicarbonate or was nominally bicarbonate-free. t-BOOH also inhibited Na/H exchanger isoform 1 (NHE1) activation by intracellular protons and propofol prevented this inhibition. Blockade of NHE1 by the potent antagonist, 5-(N-ethyl-N-isopropyl) amiloride (1 microM), abolished the protective effects of small concentrations of propofol (1 microM) and alpha-tocopherol (40 microM) on glutamate uptake during oxidative stress in bicarbonate-free medium. 5-(N-ethyl-N-isopropyl) amiloride had no effect on antioxidant rescue of glutamate transport in medium containing 25 mM bicarbonate. These results indicate that regulation of intracellular pH may contribute to neuroprotection by propofol and other lipophilic antioxidants. Propofol concentrations that are associated with anesthesia and neuroprotection may prevent intracellular acidification during oxidative stress by preserving the NHE1 response to cytosolic protons. However, if intracellular acidification occurs nonetheless, then propofol protection of glutamate uptake activity becomes less effective and the extracellular glutamate concentration may increase to neurotoxic levels. IMPLICATIONS: Anesthetic concentrations of propofol maintain the capacity of brain cells to extrude protons during oxidative stress. However, if intracellular acidification occurs nonetheless, then propofol's protection of glutamate clearance mechanisms from oxidative damage becomes attenuated, and extracellular glutamate concentration may increase to neurotoxic levels.     

Propofol-induced alterations in myocardial beta-adrenoceptor binding and responsiveness.

Propofol (iv) depresses cardiovascular function in both humans and animals. However, the mechanism underlying this action has not been well described. The present study was designed to test the hypothesis that this effect of propofol results in part from an antagonism of adrenergic control of the heart. Experiments examined effects of propofol on: 1) [3H]CGP12177 (a beta-adrenoceptor antagonist) binding in rat myocardial membranes; and 2) the inotropic and chronotropic actions of isoproterenol in rat left atrial muscle and right atria, respectively. Propofol (25-200 microM) increased the apparent dissociation constant for [3H]CGP12177 without affecting binding site density. Similarly, 200 microM propofol increased the 50% effective concentration values for the dose-dependent positive chronotropic and inotropic actions of isoproterenol in right and left atria, and depressed the maximum increase in spontaneous rate elicited by this beta-adrenoceptor agonist. Other experiments demonstrated that propofol does not alter muscarinic receptor binding as monitored using [3H]quinuclidi-nylbenzilate. In conclusion, these results indicate that propofol can decrease cardiac beta-adrenoceptor responsiveness; however, the concentrations of propofol required suggest that this action contributes to the cardiovascular depression produced by this anesthetic only during large-dose bolus injection. IMPLICATIONS: Experiments in membranes and cardiac preparations isolated from rat heart demonstrate that relatively high concentrations of propofol (25-200 microM) are required to antagonize beta-adrenoceptor binding and tissue responsiveness.     

Propofol attenuates intestinal mucosa injury induced by intestinal ischemia-reperfusion in the rat

PURPOSE: We investigated whether propofol at a sedative dose can prevent intestinal mucosa ischemia/reperfusion (I/R) injury, and if propofol can attenuate oxidative stress and increases in nitric oxide (NO) and endothelin-1 (ET-1) release that may occur during intestinal I/R injury. METHODS: Rats were randomly allocated into one of five groups (n=10 each): (i) sham control; (ii) injury (one hour superior mesenteric artery occlusion followed by three hours reperfusion); (iii) propofol pre-treatment, with propofol given 30 min before inducing intestinal ischemia; (iv) simultaneous propofol treatment, with propofol given 30 min before intestinal reperfusion was started; (v) propofol post-treatment, with propofol given 30 min after intestinal reperfusion was initiated. In the treatment groups, propofol 50 mg x kg(-1) was administrated intraperitoneally. Animals in the control and untreated injury groups received equal volumes of intralipid (the vehicle solution of propofol) intraperitoneally. Intestinal mucosa histology was analyzed by Chiu's scoring assessment. Levels of lactic acid (LD), NO, ET-1, lipid peroxidation product malondialdehyde (MDA) and superoxide dismutase (SOD) activity in intestinal mucosa were determined. RESULTS: Histological results showed severe damage in the intestinal mucosa of the injury group accompanied by increases in MDA, NO and ET-1 and a decrease in SOD activity. Propofol treatments, especially pre-treatment, significantly reduced Chiu's scores and levels of MDA, NO, ET-1 and LD, while restoring SOD activity. CONCLUSION: These findings indicate that propofol attenuates intestinal I/R-induced mucosal injury in an animal model. The response may be attributable to propofol's antioxidant properties, and the effects of inhibiting over-production of NO and in decreasing ET-1 levels.