The isolated perfused hearts of rabbits previously subjected to in vivo left ventricular
myocardial infarction (LVMI) show a 5-10-fold increase in
f-Met-Leu-Phe (FMLP) and
bradykinin (BK)-stimulated
eicosanoid metabolite production relative to noninfarcted hearts. This exaggerated arachidonate metabolism has been shown to occur primarily in the cardiac atria, a site remote from the zone of injury and to be associated with a 10-15-fold increase in atrial
FMLP receptor number in the absence of atrial
inflammation. All of these changes were temporally related to leukocyte infiltration into the
infarct zone. To determine whether invading leukocytes mediate these responses, acute inflammatory cell influx was suppressed either by inducing
leukopenia with
nitrogen mustard or by administration of
BW-755C, a mixed
cyclooxygenase-
lipoxygenase inhibitor. Both pharmacological manipulations resulted in a decrease in inflammatory cells in the
infarct zone and a marked suppression (50-70%) of ex vivo agonist-stimulated
eicosanoid metabolite production from perfused hearts and isolated atria. These manipulations also resulted in reversal of ex vivo FMLP-induced coronary vasoconstriction as well as augmentation of BK-induced coronary vasodilation. Further studies in
nitrogen mustard-treated animals revealed a suppression of the LVMI-stimulated increase in atrial
FMLP receptor number. These data show that suppression of leukocyte invasion after LVMI attenuates enhanced cardiac and atrial
eicosanoid metabolite production, and results in marked changes in coronary vascular reactivity. An additional finding was that basal and stimulated
LTB4 production was markedly increased in infarcted hearts. In vivo suppression of the increase in
LTB4 production by
BW-755C was associated with inhibition of inflammatory cell influx into the
infarct zone. It therefore appears that
LTB4 may be an important proinflammatory mediator of leukocyte invasion after LVMI.