Attenuation of trace element-mediated injury during ischemia and reperfusion by an N-terminus analogue of human albumin (H4DUS60131).
The N-terminus region of human albumin binds strongly to trace metals (Co, Cu, Ni). Ischemia, acidosis and reperfusion can cause a marked increase in plasma free Cu and its normal regulation by plasma proteins may be overwhelmed and predispose to oxidative injury by Cu-catalyzed oxyradical production. H4DUS60131 is an analogue of the N-terminus of human albumin, it binds copper tightly and in vitro, is a potent inhibitor of Cu-catalyzed radical formation. We have tested the ability of H4DUS60131 to reduce injury during ischemia and reperfusion in isolated blood-perfused rat hearts (n = 6/group) subjected to 20-min aerobic perfusion, followed by a 2-min infusion of saline or saline plus H4DUS60131. Following infusion, hearts were subjected to 30-min global ischemia plus 40-min reperfusion. The 2-min infusion was repeated in both groups at the start of reperfusion. In the vehicle controls, left ventricular developed pressure recovered to only 15.3 +/- 3.2%, whereas the H4DUS60131 group recovered to 50.5 +/- 9.3% (p < 0.005). The H4DUS60131 group normalised their left ventricular end diastolic pressure more quickly and completely than the controls (44.1 +/- 11.5 vs. 91.5 +/- 5.5 mm Hg). In conclusion, H4DUS60131 greatly improves the recovery of the rat heart from ischemia and reperfusion and may represent a novel approach to the limitation of myocardial injury.
Sutherland
F J
FJ
Cardiovascular Research, The Rayne Institute, St. Thomas' Hospital, London, UK.
Bar-Or
D
D
Curtis
C G
CG
Hearse
D J
DJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D010477:Perfusion / Q000295:instrumentation / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D014131:Trace Elements / Q000009:adverse effects* / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D012709:Serum Albumin; D014131:Trace Elements