Circulation, Vol 81, 226-237, Copyright © 1990 by American Heart Association
PJ Simpson, RF Todd 3d, JK Mickelson, JC Fantone, KP Gallagher, KA Lee, Y Tamura, M Cronin and BR Lucchesi
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.
ARTICLES
Sustained limitation of myocardial reperfusion injury by a monoclonal antibody that alters leukocyte function
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109.
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