Cyclocreatine inhibits neutrophil accumulation in the myocardium of a canine model of coronary artery occlusion and reperfusion.
This study tests the hypothesis that the administration of cyclocreatine before ischemia inhibits the release of neutrophil chemotactic factors from myocardial tissues and subsequently reduces neutrophil accumulation into ischemic areas. Adult mongrel dogs underwent left anterior descending coronary artery occlusion for 1 h, followed by a 2-h reperfusion. Cyclocreatine-treated dogs (n = 6) were injected intravenously with cyclocreatine solution (600 mg/kg) 1 h before the experiment and during ligation of the coronary artery. Control dogs (n = 6) were injected with saline. Neutrophil chemotactic activity was measured in plasma samples using standard modified Boyden chambers. In controls dogs, significantly elevated levels of chemotactic activity were recovered in blood samples taken during reperfusion (i.e., 2.8-3.5-fold; P < .0001) as compared to base-line activity recovered before occlusion. Preliminary biochemical characterizations revealed that the recovered chemotactic factors (via checkerboard analysis) are proteins of high molecular weight (greater than 100 kDa). Biopsy samples of control hearts showed an accumulation of a large number of neutrophils in the ischemic portions. Cyclocreatine-treated dogs, on the contrary, showed low levels of chemotactic activity during reperfusion, which correlated with the absence of neutrophils in ischemic areas. These results indicate the capability of cyclocreatine to inhibit the release of neutrophil chemotactic factors from ischemic myocardium, which subsequently prevented neutrophil accumulation.
Department of Surgery, Hartford Hospital, Connecticut.
S A
SA
Elgebaly
M E
ME
Allam
S
S
Houser
F
F
Hashmi
F
F
Forouhar
D
D
Miano
D000595:Amino Acid Sequence; D000818:Animals; D002630:Chemotactic Factors / Q000097:blood / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003327:Coronary Disease / Q000473:pathology* / Q000503:physiopathology; D003404:Creatinine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D017202:Myocardial Ischemia / Q000209:etiology / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology* / Q000503:physiopathology; D009205:Myocarditis / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects*; D011817:Rabbits
D002630:Chemotactic Factors; C012260:cyclocreatine; D003404:Creatinine