Reduction of infarct size in a rat model of regional myocardial ischemia and reperfusion by the synthetic peptide DAHK.
OBJECTIVE
The increased mobilization of iron and copper during ischemia is reported to contribute to postischemic injury. DMI-4983 is a small synthetic peptide, Asp-Ala-His-Lys (DAHK), that mimics the high-affinity copper-binding site of the N-terminus of human albumin. This peptide was reported to inhibit copper-induced formation of reactive oxygen species in vitro, reduce interleukin-8 formation in cultured endothelial cells, and improve left ventricular function after global ischemia and reperfusion in the isolated blood-perfused heart of the rat. The aim of this study was to investigate the effects of DMI-4983 on myocardial infarct size caused by regional ischemia and reperfusion in vivo.


METHODS
Rats were subjected to regional myocardial ischemia (25 mins) followed by reperfusion (2 hrs). Randomized groups received either vehicle or DMI-4983 administered as a 5, 10, or 20 mg/kg intravenous bolus along with a 10 mg/kg/hr continuous infusion starting just before reperfusion and continuing throughout the experiment. Infarct size was determined at the end of the experiment.


METHODS
Basic research institute and trauma research laboratory.


METHODS
Anesthetized male Wistar rats.


RESULTS
The area at risk of infarction and hemodynamic variables were similar in all groups. Rats treated with vehicle resulted in an infarct size of 64% +/- 3% of the area at risk of infarction. Intravenous administration of DMI-4983 reduced infarct size to 52% +/- 3%, 50% +/- 2%, and 45% +/- 3% of the area at risk of infarction for 5, 10, and 20 mg/kg, respectively (p < .05 compared with vehicle for each dosage).


CONCLUSIONS
Intravenous DMI-4983 administered before the onset of reperfusion and continuously throughout the reperfusion period caused a significant reduction in tissue necrosis in this in vivo model of regional myocardial ischemia and reperfusion, suggesting that DMI-4983 may represent a novel approach for the treatment of myocardial ischemia and reperfusion injury.
Bar-Or
David
D
Trauma Research Department, Swedish Medical Center, Englewood, CO, USA.
McDonald
Michelle C
MC
Thiemermann
Christoph
C
D000818:Animals; D004195:Disease Models, Animal; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000473:pathology*; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar
D009842:Oligopeptides; C431583:aspartyl-alanyl-histidyl-lysine