Free radicals reperfusion

Turner, J.J.O., Rice-Evans, C., Davies, M.J. and Newman, E.S.R. (1990). Free radicals, myocytes and reperfusion injury. Biochem. Soc. Trans. 18, 1056-1059. 

Figure 4.1 Time-course of free-radical production during aerobic (a) or anoxic (b) reperfusion of the isolated rat heart. Radical production was assessed using e.s.r. and quantified as the formation of a Af-tert-butyl-a-phenylnitrone (PBN) spin adduct. After a 35 min stabilization period of aerobic perfusion, hearts were made globally ischaemic for 15 min. Hearts were then reperfused, either with oxygenated buffer (a) (n = 6), or with anoxic buffer, switching to an oxygenated buffer after 10 min (b) (n = 5). The bars represent the standard errors of the means. Redrawn with permission from Garlick et af. (1987).

Figure 4.3 Effect of a variety of anti-free-radical interventions on reperfuslon-induced ventricular fibrillation In the Isolated perfused rat heart. Regional Ischaemia was induced by occluding a snare around the left anterior descending coronary artery and, after 10 min, hearts were reperfused by releasing the snare. Superoxide dismutase (SOD) (1 x 10° U/l), catalase (CAT) (1 X 10 U/l), mannitol (Mann) (50 mM), l-methlonlne (Methlon) (10 mM), glutathione (Glutath) (10 iiM) or desferrioxamlne (Deafer) (150 iim) were included throughout the experimental time course (n = 15/group). Redrawn with permission from Bernier et af. (1986).

Figure 4.4 Effect of a free-radical scavenger M-(2-mercaptoproplonyl)-glycine (MPG) on the recovery of contractile function following 15 min of regional ischaemia in the dog heart, (a) MPG infused 1 min before reperfusion, (b) MPG infused 1 min after reperfusion. Contractile function was assessed as changes in ventricular wall thickening measured using an ultrasonic pulsed-Doppler epicardial probe. Note The free radical scavenger MPG can reduce myocardial stunning only when present during the first minute of reperfusion. Redrawn with permission from Bolli et af. (1989).

During ischaemia, the activity of cellular antioxidant systems may be reduced (Ferrari et al. 1985 GaUnanes etal. 1992). In addition, a number of cellular pathways that produce free radicals are primed during ischaemia such as the xanthine/xanthine oxidase system (McCord, 1987), catecholamine auto-oxidation (Jackson et al., 1986) and the arachadonic acid pathway (Halliwell and Gutteridge, 1989). Thus, during early reperfusion there is a burst of free radical production (see Fig. 4.1) that may overwhelm the antioxidant systems of the cells. 

Bernier, M., Hearse, D.J. and Manning, A.S. (1986). Reperfusion-induced arrhythmias and oxygen-derived free radicals. Studies with anti-free radical interventions and a free radical-generating system in the isolated perfused rat heart. Circ. Res. 58, 331-340. 

Garlick, P.B., Davies, M.J., Hearse, D.J. and Slater, T.F. (1987). Direct detection of free radicals in the reperfused rat heart using electron spin resonance spectroscopy. Circ. Res. 61, 757-760. 

Goldhaber, J.I., Ji, S., Lamp, S.T. and Weiss, J.N. (1989). Effects of exogenous free radicals on electromechanical function and metabolism in isolated rabbit and guinea pig ventricle. Implications for ischemia and reperfusion injury. J. Clin. Invest. 83, 1800-1809. 

Kim, M.-S. and Akera, T. (1987). O2 free radicals cause of ischemia-reperfusion injury to cardiac Na -K ATPase. Am. J. Physiol. 21, H252-H257. 

Misra, H.P., Weglicki, W.B., Abdulla, R- and McCay, P.B. (1984). Identification of a carbon centered free radical during reperfusion injury in ischemic rat heart. Circulation II, 260 (abstract). 

Pallandi, R.T., Perry, M.A. and Campbell, T.J. (1987). Proar-rhythmic efects of an oxygen-derived free radical generating system on action potentials recorded from guinea pig ventricular myocardium possible cause of reperfusion-induced arrhythmias. Circ. Res. 61, 50-54. 

Woodward, B. and Zakaria, M.N.M. (1985). Effea of some free radical scavengers on reperfusion induced arrhythmias in the isolated rat heart. J. Mol. Cell. Cardiol. 17, 485—493. 

Zweier, J.L., Flaherty, J.T. and Weisfeldt, M.L. (1987). Direct measurement of free radical generation following reperfusion of ischemic myocardium. Proc. Natl Acad. Sci. USA 84, 1404-1497. 

The most extensive evidence that supports a role for free radicals in pathological conditions of the brain is provided by studies on experimental models of cerebral ischaemia/reperfusion. Although a burst of free-radical production occurs during the reperfusion phase after temporary cerebral ischaemia, the contribution of this radical burst to brain cell death can not be directly quantified. Perhaps the best way to quantify the contribution of free radicals to brain damage after ischaemia/ reperfusion is to assess damage after treatment with free-radical scavengers or antioxidants. Numerous studies have been reported where free-radical scavengers/ antioxidants have been used to try to ameliorate brain... 

Oliver, C.N., Starke-Reed, P.E., Stadtman, E.R., Liu, G.J., Carney, J.M. and Floyd, R.A. (1990). Oxidative damage to brain proteins, loss of glutamine synthetase activity, and production of free radicals during ischemia/reperfusion-induced injury to gerbil brain. Proc. Natl Acad. Sd. USA 87, 5144-5147. 

Sakomoto, A., Ohnishi, S.T., Ohnishi, T. and Ogawa, R. (1991). Relationship between free radical production and lipid peroxidation during ischemia-reperfusion injury in the rat brain. Brain Res. 554, 186-192. 

Koyama, L, Bulkley, G.B., Williams, G.H. and Im, H.J. (1985). The role of oxygen free radicals in mediating the reperfusion injury of cold-preserved ischaemic kidneys. Transplantation 40, 590-595. 

Ratych, KE. and Bulkley, G.B. (1986). Free-radical-mediated postischaemic reperfusion injury in the kidney. J. Free Rad. Biol. Med. 2, 311-319. 

The theory underlying the pathophysiology of ischaemia-reperfusion injury, and the role of free radicals in this process has been discussed in detail above. The human colon contains relatively little XO (Parks and Granger, 1986) and so the arguments supporting a role for this enzyme in the pathogenesis of small bowel... 

There is some support for a role for free radicals in the pathogenesis of ischaemic colitis from animal studies. Murthy and Qi (1992) used a spin trap to demonstrate increased production of free radicals up to 60 min after reperfusion, whereas Douglas etal. (1989) demonstrated increases in malondialdehyde and conjugated dienes (presumptive measures of lipid peroxidation) in a rat model of ischaemic colitis. There is no data relating to human ischaemic colitis. 

Adkinson, D., Hollwarth, M.E., Benoit, J.N., Parks, D.A., McCord, J.M. and Granger, D.N. (1986). Role of free radicals in ischaemia-reperfusion injury to the liver. Acta Physiol. Scand. 548 (Suppl.), 101-107. 

Filez, L.E.A., Kerremans, R., Gebocs, K., Stalmans, W. and Penninckx, F. (1990). Oxygen free radicals are the most important oxygen species involved in the development of reperfusion lesions. Gastroenterolt 98, A169. 

Marubayashi, S., Dohi, K., Sumimoto, K., Oku, J., Ochi, K. and Kawasaki, T. (1989). Changes in activity of free radical scavengers and in levels of endogenous antioxidants during hepatic ischaemia and subsequent reperfusion. Transplant. Proc. 21, 1317-1318. 

Stein, H.J., Oosthuizen, M.M., Hinder, R.A. and Lamprechts, H. (1991). Oxygen free radicals and glutathione in hepatic ischaemia/reperfusion injury. J. Surg. Res. 50, 398-402. 

Von Ritter, C., Oostuizen, M.M.J., Lambrechechts, H., Hunter, S., Svensson, E G. and Hinder, R.A. (1986). Free radical scavengers decrease reperfusion damage of the gastric mucosa in baboons. Gastroenterology 90, A1682. 

Oredsson, S., Plate, G. and Quarfordt, P. (1991). AUopurinol - a free radical scavenger - reduces reperfusion injury in skeletal muscle. Eur. J. Vas. Surg. 5, 47-52. 

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