Sustained limitation of myocardial reperfusion injury by a monoclonal antibody that alters leukocyte function.
Pentobarbital anesthetized dogs were subjected to 90 minutes of left circumflex coronary artery (LCCA) occlusion followed by 72 hours of reperfusion. Control or anti-Mo1 (904) F(ab')2 fragments of monoclonal antibodies were administered intravenously at a dose of 1 mg/kg beginning 45 minutes after occlusion and at a dose of 0.5 mg/kg at 12, 24, 36, and 48 hours after reperfusion. Myocardial infarct size expressed as a percentage of the area at risk (IN/AR) measured postmortem after 72 hours of reperfusion was significantly reduced by 904 F(ab')2 (21.6 +/- 2.8%, n = 8) compared with control F(ab')2 (37.4 +/- 5.8%, n = 8; p less than 0.025). There were no significant differences between groups in heart rate, mean arterial blood pressure, rate-pressure product, or LCCA blood flow that could account for a reduced infarct size. Regional myocardial blood flow (RMBF) was determined with 15-microns radiolabeled microspheres. Transmural blood flows (ml/min/g) within the region of myocardium at risk were not statistically different between treatment groups. Infarct size in both groups was related to regional myocardial blood flow, and the relation was shifted downward in the group treated with the anti-Mo1 F(ab')2 antibody (analysis of covariance, p = 0.01). Thus, anti-Mo1 F(ab')2 produces a sustained limitation of myocardial infarct size compared with controls under similar hemodynamic conditions and a similar degree of myocardial ischemia as determined by RMBF. These data suggest that inhibition of neutrophil adhesive interactions (as suggested by the inhibitory effect of anti-Mo1 on canine neutrophil aggregation) may be an effective mechanism for protection against myocardial injury secondary to myocardial ischemia and reperfusion.
Simpson
P J
PJ
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109.
Todd
R F
RF
Mickelson
J K
JK
Fantone
J C
JC
Gallagher
K P
KP
Lee
K A
KA
Tamura
Y
Y
Cronin
M
M
Lucchesi
B R
BR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology / Q000627:therapeutic use*; D002449:Cell Aggregation; D003326:Coronary Circulation; D004285:Dogs; D006439:Hemodynamics; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007958:Leukocyte Count; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009504:Neutrophils / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D009195:Peroxidase