Heart reperfusion

It was earlier thought that activated neutrophils do not play an important role in reoxygenation injury [1]. However, Duilio et al. [16] pointed out that this conclusion was drawn from the experiments with brief episodes of ischemia resulted in myocardial stunning, while neutrophil-mediated damage is expected after prolonged ischemia associated with myocardial infraction. These authors demonstrated that neutrophils were a major source of oxygen radicals in hearts reperfused under in vivo conditions after prolonged ischemia. 

Enables pretreated cardiac cells to become more resistant to the damage caused by hypoxia-reoxygenation and oxidative stress, enables isolated hearts reperfused in its presence (10 pM) after an ischemic event to display a significant recovery in myocardial performance and to produce a marked and significant reduction in cardiac muscle damage and infarct size [142]... 

T. L. Broderick, A. Quinney, C. Barker, G. Lopaschuk, Beneficial effect of carnitine on mechanical recovery of rat hearts reperfused after a transient period of global ischemia is accompanied by a stimulation of glucose oxidation, Circulation 87,972-981 (1993). 

In rabbit myocardial reperfusion MnSOD was dramatically protective up to 5 pg/ml perfusate beyond which it lost its abihty to protect and, at very high doses (50 pg/ml), exacerbated the injury (Nelson et al. 1994). While isolated rabbit hearts reperfused with standard buffer for 45 min showed a prominent release of GSSG, which peaked 5 min after reflow, GSSH release from hearts treated with superoxide dismutase for 15 min, followed by 30 min of standard perfusion, was neghgible (Tritto etal. 1998). 

In the isolated rat heart perfused according to Langendorff s technique, the 8-hydroxyguanine content in the DNA significantly increased after an ischaemia of 30 or 60 min followed by reperfusion with oxygenated Krebs-Henseleit buffer (You et al. 2000). The levels of 8-hydroxyguanine did not increase either in the ischaemic hearts reperfused with a nitrogenated solution or in the ischaemic-reperfused hearts treated with superoxide dismut-ase, mannitol or allopurinol. 

ACE inhibitors inhibit the degradation of bradykinin and potentiate the effects of bradykinin by about 50-100-fold. The prevention of bradykinin degradation by ACE inhibitors is particularly protective for the heart. Increased bradykinin levels prevent postischemic reperfusion arrhythmia, delays manifestations of cardiac ischemia, prevents platelet aggregation, and probably also reduces the degree of arteriosclerosis and the development of cardiac hypertrophy. The role of bradykinin and bradykinin-induced NO release for the improvement of cardiac functions by converting enzyme inhibitors has been demonstrated convincingly with use of a specific bradykinin receptor antagonist and inhibitors of NO-synthase. 

Gavins FN, Leoni G, Getting SJ (2006) Annexin 1 and melanocoitin peptide therapy for protection against ischaemic-reperfusion damage in the heart. Scientific-WorldJournal 6 1008-1023... 

Acute over-activation of NHE1 results in a marked elevation in intracellular sodium concentration with a subsequent increase in intracellular calcium, via the Na +/Ca++ exchanger. This in turn triggers a cascade of injurious events that can culminate in tissue dysfunction and ultimately apoptosis and necrosis. This is commonly seen in organs such as the heart, brain and kidneys as a consequence of ischemia-reperfusion. 

Urata H, Kinoshita A, Misono KS, Bumpus FM. Husain A Identification of a highly specific chy-mase as the major angiotensin Il-forming enzyme in the human heart. J Biol Chem 1990 265 22348. Silver RB, Reid AC, Mackins CJ, Askwith T, Schaefer U, Herzlinger D, Levi R Mast cells a unique source of renin. Proc Natl Acad Sci USA 2004 101 13607. Mackins CJ, Kano S, Sevedi N, Schafer U, Reid AC, Machida T, Silver RB, Levi R Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion. J Clin Invest 2006 116 1063. 

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 4.2 Epicardial ECG recorded from an isolated blood-perfused rat heart at the moment of reperfusion. The heart was made regionally ischaemic by occluding a snare around the left anterior descending coronary artery and, after 10 min, reperfused by releasing the snare. Note the rapid onset of ventricular tachycardia (VT) and its subsequent degeneration into ventricular fibrillation (VF). Reproduced with permission from Lawson (1993).

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).

Figure 4.8 Reduction of Na/K ATPase activity in isoiated guinea-pig hearts subjected to ischaemia/reperfusion and its prevention by various agents control non-ischaemic hearts (Nl) guinea-pig hearts subjected to global ischaemia for 2 h and subsequently reperfused for 1 h (IR). In other preparations, superoxide dismutase (SOD) 100 U/ml, catalase (CAT) 150 U/ml, dimethylsulphoxide (DMS) 50 mu, histidine (HIS) 10 mu, vitamin E (TOC)...

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. 

Ferrari, R, Caigoni, A., Curello, S., Boffa, G.M. and Ceconi, C. (1989). Effects of iloprost (ZK 36374) on glutathione status during ischaemia and reperfusion of isolated rabbit hearts. Br. J. Pharmacol. 98, 678-684. 

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. 

Haddock, P.S., Hearse, D.J. and Woodward, B. (1989). Effect of anti-oxidants and verapamil on noradrenaline release and contracture in the ischaemic/reperfused rat heart. Br. J. Pharmacol. 78, 745 (abstract). 

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). 

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. 

Compound LY231617 was given at a dose of 10 mg/kg i.v. over a period of 5-7 min beginning 1 h after MCAO. Reperfusion occurred at 2 h after MCAO and at that time the rats received 5.0 mg/kg i.v. for 24 h. Mean arteriai blood pressure (MABP), heart rate, arteriai blood pH, PO2 and pCOi were measured. Body temperature was regulated at 36-37°C for the entire 24 h period. 

In recent studies on perfused rats hearts (Veitch et al., 1992), it was found that differences in the sensitivity of complexes 1-lV to ischaemic damage were dependent upon the duration of ischaemia and the presence of oxygen. The demonstration that complex 1 is a major defective site dependent upon isolation of mitochondria from homogenates of the tissue by in vitro methods seemed important to us. We therefore decided to attempt to make noninvasive measurements of mitochondrial function soon after reperfusion in transplanted rabbit kidneys by surface fluorescence (for mitochondrial NADH levels) and near infra-red spectroscopy (NIRS) for the redox state of cytaas. 

Taegtmeyer, H., Roberts, A.F.C. and Raine, A.E.G. (1985). Energy metabolism in reperfused heart muscle Metabolic correlates to return of funaion. J. Am. Coll. Cardiol. 6, 864-870. 

Ferrari, R., Curello, S., Ceconi, C., Cargoni, A., Condorelli, E. and Albertini, A. (1986). Intracellular effects of myocardial ischaemia and reperfusion role of calcium and oxygen. Eur. Heart J. 7 (Suppl. A), 3-12. 

Hepatic reperfusion injury is not a phenomenon connected solely to liver transplantation but also to situations of prolonged hypoperfusion of the host s own liver. Examples of this occurrence are hypovolemic shock and acute cardiovascular injur) (heart attack). As a result of such cessation and then reintroduction of blood flow, the liver is damaged such that centrilobular necrosis occurs and elevated levels of liver enzymes in the serum can be detected. Particularly because of the involvement of other organs, the interpretation of the role of free radicals in ischaemic hepatitis from this clinical data is very difficult. The involvement of free radicals in the overall phenomenon of hypovolemic shock has been discussed recently by Redl et al. (1993). More specifically. Poll (1993) has reported preliminary data on markers of free-radical production during ischaemic hepatitis. These markers mostly concerned indices of lipid peroxidation in the serum and also in the erythrocytes of affected subjects, and a correlation was seen with the extent of liver injury. The mechanisms of free-radical damage in this model will be difficult to determine in the clinical setting, but the similarity to the situation with transplanted liver surest that the above discussion of the role of XO activation, Kupffer cell activation and induction of an acute inflammatory response would be also relevant here. It will be important to establish whether oxidative stress is important in the pathogenesis of ischaemic hepatitis and in the problems of liver transplantation discussed above, since it would surest that antioxidant therapy could be of real benefit. 

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