salicylates and Ischemia

Cerebral edema is a potentially life-threatening complication shared by diseases of different etiology, such as diabetic ketoacidosis, acute liver failure, high altitude exposure, dialysis disequilibrium syndrome, and salicylate intoxication. Pulmonary edema is also habitually present in these disorders, indicating that the microcirculatory disturbance causing edema is not confined to the brain. Both cerebral and pulmonary subclinical edema may be detected before it becomes clinically evident. Available evidence suggests that tissue hypoxia or intracellular acidosis is a commonality occurring in all of these disorders. Tissue ischemia induces physiological compensatory mechanisms to ensure cell oxygenation and carbon dioxide removal from tissues, including hyperventilation, elevation of red blood cell 2,3-bisphosphoglycerate content, and capillary vasodilatation. Clinical, laboratory, and necropsy findings in these diseases confirm the occurrence of low plasma carbon dioxide partial pressure, increased erythrocyte 2,3-bisphosphoglycerate concentration, and capillary vasodilatation with increased vascular permeability in all of them. Baseline tissue hypoxia or intracellular acidosis induced by the disease may further deteriorate when tissue oxygen requirement is no longer matched to oxygen delivery resulting in massive capillary vasodilatation with increased vascular permeability and plasma fluid leakage into the interstitial compartment leading to edema affecting the brain, lung, and other organs. Causative factors involved in the progression from physiological adaptation to devastating clinical edema are not well known and may include uncontrolled disease, malfunctioning adaptive responses, or unknown factors. The role of carbon monoxide and local nitric oxide production influencing tissue oxygenation is unclear.

Topics: Altitude Sickness; Animals; Brain Edema; Capillaries; Diabetic Ketoacidosis; Humans; Ischemia; Liver Failure, Acute; Renal Dialysis; Salicylates

Topics: Animals; Cells; Chemical and Drug Induced Liver Injury; Drug Resistance; Environmental Pollution; Epithelium; Gases; Hematopoietic System; Irritants; Ischemia; Kidney; Liver; Lung; Maleates; Mercury; Organ Specificity; Rabbits; Rats; Receptors, Drug; Salicylates; Tachyphylaxis; Toxicology; Uranium

Topics: Analgesics; Arthritis, Rheumatoid; Aspirin; Headache; Humans; Ischemia; Kinetics; Neoplasms; Neuralgia; Phenacetin; Phenylbutazone; Salicylates; Time Factors; Wounds and Injuries

Microglial cells, known to play key roles in neuroinflammation, can be immunotoxically eliminated from hippocampal slice cultures by treatment with saporin coupled to the microglial receptor Mac1. Considering microglial cells as a target for anti-inflammatory treatment we studied the effects of microglial depletion on anti-inflammatory treatment of mouse hippocampal slice cultures subjected to ischemia-like neurodegeneration, induced by oxygen-glucose deprivation (OGD). Hippocampal slice cultures, derived from 7-day-old mice and grown for 2 weeks, were divided into 8 groups: (1) control cultures; (2) sham-OGD cultures; (3) OGD cultures; (4) OGD cultures treated with triflusal during OGD; (5) microglia-depleted control cultures; (6) microglia-depleted sham-OGD cultures; (7) microglia-depleted OGD cultures; and (8) microglia-depleted OGD cultures treated with triflusal during OGD. The resulting neurodegeneration was quantified by densitometric measurements of cellular uptake of propidium iodide (PI), with focus on the hippocampal CA1 subfield. Subjection of regular cultures to OGD for 30 min induced a significant increase in PI uptake in the CA1 pyramidal cell layer, compared to control cultures. The presence of 100 microM triflusal during OGD protected against OGD-induced neurodegeneration, and reduced the number of OGD-induced NFkB positive-cells correspondingly. Cultures treated with the Mac1-saporin complex for 7 days displayed an almost total loss of microglial cells. When subjected to OGD after microglial depletion, these cultures displayed a significant increase in OGD-induced PI uptake compared to non-depleted cultures. The presence of triflusal during OGD of these cultures reduced neurodegeneration of the irrespective absence of microglia. In accordance with that, the presence of triflusal during OGD significantly inhibited the increase in the number of reactive microglia and proliferative cells in the CA1 pyramidal and dentate granule cell layers. We conclude that immunotoxic microglia depletion significantly increases the susceptibility of CA1 pyramidal cells to neurodegeneration and that the anti-inflammatory drug triflusal still can exert its neuroprotective role following depletion of microglia.

Topics: Analysis of Variance; Animals; Animals, Newborn; Cell Count; Cell Death; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Glucose; Hippocampus; Ischemia; Mice; Mice, Inbred C57BL; Microglia; Nerve Degeneration; Neurons; Neuroprotective Agents; NF-kappa B; Plant Lectins; Propidium; Salicylates; Tissue Culture Techniques

Free-radicals are reported to cause the tissue-damage associated with some toxins and diseases, yet there is no suitable method for routine in-vivo monitoring of these species. This paper introduces an in-vivo microdialysis technique in which the hydroxyl radical reacts with salicylate to generate dihydroxybenzoic acids (DHBA) which are measured by HPLC with electrochemical detection. When pargyline, a monoamine oxidase inhibitor, was infused into rat brain, the levels of DHBA increased markedly. When noradrenaline was administered to animals pre-treated with pargyline, DHBA levels increased markedly compared with the group treated with noradrenaline only. When the heart was subjected to 15-min regional ischaemia by occlusion of the left anterior descending coronary artery, levels of DHBA in heart dialysate were unchanged. Electrical stimulation of the stellate ganglion resulted in marked elevation of levels of DHBA the myocardial dialysate. Infusion of Fe2+ into rat liver resulted in increased formation of DHBA. When the intestine was rendered ischaemic for 10, 20 and 30 min, the highest DHBA level was obtained after 10-min ischaemia and the lowest after 30 min. These results confirm that free-radical production might make a major contribution at certain stages in the progression of the injury.

Topics: Animals; Brain; Chromatography, High Pressure Liquid; Electric Stimulation; Gentisates; Hydrogen Peroxide; Hydroxybenzoates; Hydroxyl Radical; Iron; Ischemia; Jejunum; Liver; Male; Microdialysis; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Myocardium; Norepinephrine; Pargyline; Rats; Rats, Wistar; Reperfusion Injury; Salicylates; Superoxides; Sympathetic Nervous System

The difficulty in direct detection of oxygen-derived free radicals (OFR) in the intact kidney has left uncertain the role of OFR in renal hypoperfusion injury. Salicylate hydroxylation was used as a sensitive method of estimating the extent of production of highly reactive hydroxyl radicals in renal ischaemia-reperfusion injury in the intact rat kidney perfused with recirculating cell-free medium. The reaction products were detected and quantified by HPLC with electrochemical detection. Hydroxyl radicals were detected as 2,5-dihydroxybenzoic acid (2,5-DHBA). Ischaemia for 15 min followed by reperfusion for 15 min caused more than a twofold increase in 2,5-DHBA concentration (to 2279 +/- 225 pg/g tissue weight) compared to controls (933 +/- 103, P < 0.001). Addition of 15 mM dimethylthiourea (DMTU) before induction of ischaemia prevented this increase. Induction of hypoxia for 15 min with continued perfusion (as a model of low-flow ischaemia) had no significant effect on hydroxyl radical formation. We conclude that significant quantities of hydroxyl radicals form in the absence of circulating leucocytes during reperfusion following ischaemia, but not during hypoxia in the perfused rat kidney.

Topics: Animals; Chromatography, High Pressure Liquid; Gentisates; Hydroxybenzoates; Hydroxyl Radical; Hypoxia; Ischemia; Kidney; Male; Rats; Rats, Wistar; Reperfusion; Salicylates

A previous study indicated that hydroxyl radicals are generated in the cat retina during the early reperfusion phase after 90 minutes of ischemia. Salicylate was injected intravenously, and its conversion to 2,3-dihydroxybenzoic acid (2,3-DHBA) served as a marker of hydroxyl radicals. The authors attempted to prevent this free radical generation during reperfusion.. After salicylate administration, both eyes (15 minutes apart) of 15 cats were subjected to 90 minutes retinal ischemia. Following 5 minutes of reperfusion in the control eye, it was enucleated and processed for DHBA quantitation. Then, 7.5 mg of Zn-desferrioxamine (Zn-DFO) was injected intravenously into nine cats and saline into six cats. Five minutes later, reperfusion was induced in the experimental eye for 5 minutes, followed by enucleation. In one eye each of 12 other cats, scotopic electroretinographic (ERG) studies were carried out during 90 minutes of ischemia and 16 to 18 hours of reperfusion. Five minutes before termination of the ischemia, six animals were injected with 7.5 mg Zn-DFO and six with saline.. The normalized levels of 2,3-DHBA were lower in the experimental eyes than in their fellow controls only after Zn-DFO treatment (P = 0.01). In the ERG studies, after 16 to 18 hours of reperfusion, the mean b-wave-ERG amplitudes in the eyes of the saline-treated cats (n = 6) were 8.4% +/- 4.0% of the preischemic stage, and 70.5% +/- 6.7% of the Zn-DFO-treated cats (n = 6, P = 0.004).. Protection of the cat retina against ischemia and reperfusion injury by Zn-DFO was evident, most probably through its inhibitory effect on the generation of hydroxyl radicals during reperfusion.

Topics: Animals; Cats; Deferoxamine; Electroretinography; Fundus Oculi; Hydroxybenzoates; Hydroxyl Radical; Injections, Intravenous; Ischemia; Organometallic Compounds; Reperfusion Injury; Retinal Vessels; Salicylates; Salicylic Acid

The formation of hydroxyl radical in the post-ischemic reperfused heart was measured with high performance liquid chromatography and ultraviolet detection using salicylic acid. Hydroxyl radicals react with salicylic acid yielding 2,3- and 2,5-dihydroxybenzoic acid, which can be separated by the liquid chromatography. Isolated rat hearts were perfused with 1 mM salicylic acid and were subjected to 30 mins of global ischemia followed by aerobic or anaerobic reperfusion at 37 degrees C. The effluent from the hearts was collected at various intervals, extracted with ether, and injected into the high performance liquid chromatography unit. 2,5-dihydroxybenzoic acid was present only after aerobic reperfusion and was not detected before ischemia. The liquid chromatography peak of 2,3-dihydroxybenzoic acid was too small for quantitation. The concentration of 2,5-dihydroxybenzoic acid was the highest within 300 s of reperfusion. 2,5-dihydroxybenzoic acid was not detected in the ischemic hearts during anaerobic reperfusion. In ischemic hearts perfused with mannitol, the amount of 2,5-dihydroxybenzoic acid after reperfusion was reduced. These data suggest that hydroxyl radicals are produced in the post-ischemic reperfused heart and that the present method is useful and reliable for the measurement of hydroxyl radicals in the heart.

Topics: Animals; Chromatography, High Pressure Liquid; Gentisates; Hydroxides; Hydroxybenzoates; Hydroxyl Radical; Hydroxylation; In Vitro Techniques; Ischemia; Male; Myocardial Reperfusion; Oxygen; Rats; Rats, Inbred Strains; Salicylates; Salicylic Acid

Topics: Angiography; Diagnosis, Differential; Foot; Hand; Humans; Ischemia; Raynaud Disease; Recurrence; Reserpine; Salicylates; Salicylic Acid; Scleroderma, Systemic; Snake Venoms; Subclavian Steal Syndrome; Sympathectomy; Thoracic Outlet Syndrome; Thromboangiitis Obliterans

A group of 15 patients, suffering of chronic ischaemia of the lower limbs, were treated with triflusal, a new antiaggregant and antithrombotic agent, at the dose of 300 mg/day, during the first 90 days after artery by-pass grafting. Clinical exploration of patients included: physical inspection, pulses palpation, intermittent claudication (in metres), arteriography before surgery, and postoperative evolution of oscillometric and Doppler indexes. Determinations of platelet aggregation, induced by ADP, epinephrine and collagen, as well as of prothrombin time, platelet adhesiveness, and of thromboelastography parameters in PRP ane PPP were also carried out. Biochemical and hematological data were determined; gastric tolerance and other side effects were written down. Results show a clear improvement of all patients due to surgery, but with triflusal, it has been possible to maintain a prophylactic effect without thrombosis of the graft or of the distal vessel of patients, during the postoperative period. Actually, lower limbs temperature and pulses were maintained, with a good capillary content and with an improved walking distance. No changes in prothrombin time an platelet adhesiveness, have been observed. Five patients showed a clear hypoaggregant tendency, and thromboelastography in PRP indicates a statistically significant increase of R and K parameters as well as a decrease of am. It must be noticed the absence of gastric, hepatic, renal or metabolic side effects and no haemorrhagic lesions were observed. In conclusion, the treatment of these patients with triflusal prevents the otherwise frequent appearance of postoperative thrombosis in this kind of arterial surgery.

Topics: Adult; Aged; Blood Vessel Prosthesis; Drug Evaluation; Endarterectomy; Female; Fibrinolytic Agents; Humans; Ischemia; Leg; Male; Middle Aged; Postoperative Complications; Salicylates; Thrombosis

Topics: Angiography; Arteriosclerosis Obliterans; Atherosclerosis; Barbiturates; Diagnosis, Differential; Drug Therapy; Humans; Ischemia; Leg; Salicylates; Thiamine; Thrombophlebitis; Vascular Diseases; Vascular Surgical Procedures; Vasodilator Agents; Vitamin B 12; Vitamin B Complex