mia followed by reperfusion (I/R) in the presence of polymorphonuclear leukocytes (PMNs) results in marked cardiac contractile dysfunction. A cell-permeable PKC-peptide inhibitor was used to test the hypothesis that PKC-inhibition could attenuate PMN-induced cardiac contractile dysfunction by suppression of superoxide production from PMNs and increase nitric oxide (NO) release from vascular endothelium. The effects of the PKC-peptide inhibitor were examined in isolated ischemic (20 min) and reperfused (45 min) rat hearts reperfused with PMNs. The PKC-inhibitor (2.5 or 5 M, n ϭ 6) significantly attenuated PMN-induced cardiac dysfunction compared with I/R hearts (n ϭ 6) receiving PMNs alone in left ventricular developed pressure (LVDP) and the maximal rate of LVDP (ϩdP/ dt max) cardiac function indexes (P Ͻ 0.01), and these cardioprotective effects were blocked by the NO synthase inhibitor, N G -nitro-L-arginine methyl ester (50 M). Furthermore, the PKC-inhibitor significantly increased endothelial NO release 47 Ϯ 2% (2.5 M, P Ͻ 0.05) and 54 Ϯ 5% (5 M, P Ͻ 0.01) over basal values from the rat aorta and significantly inhibited superoxide release from phorbol-12-myristate-13-acetate-stimulated rat PMNs by 33 Ϯ 12% (2.5 M) and 40 Ϯ 8% (5 M) (P Ͻ 0.01). The PKC-inhibitor significantly attenuated PMN infiltration into the myocardium by 46 -48 Ϯ 4% (P Ͻ 0.01) at 2.5 and 5 M, respectively. In conclusion, these results suggest that the PKC-peptide inhibitor attenuates PMN-induced post-I/R cardiac contractile dysfunction by increasing endothelial NO release and by inhibiting superoxide release from PMNs thereby attenuating PMN infiltration into I/R myocardium. neutrophils; superoxide radicals; left ventricular developed pressure; endothelial dysfunction THE RESTORATION OF BLOOD FLOW is the primary objective for treatment of cardiac tissue experiencing prolonged ischemia (i.e., Ͼ20 min). However, reperfusion of blood flow induces endothelium and myocyte injury, resulting in cardiac contractile dysfunction (4, 23, 24). The sequential events associated with reperfusion injury are initiated by endothelial dysfunction, which is characterized by a reduction of the basal endothelial cell release of nitric oxide (NO) within the first 2.5-5 min postreperfusion (36). The decrease in endothelium-derived NO is associated with adhesion molecule upregulation on endothelial and polymorphonuclear leukocyte (PMN) cell membranes (26,39). This event promotes PMN-endothelium interaction, which occurs by 10 to 20 min postreperfusion, and subsequent PMN infiltration into the myocardium is observed by 30 min postreperfusion (20,21,35,39). The time course of events are similar in ex vivo and in vivo myocardial ischemia-reperfusion (I/R) models within the first 30 min of reperfusion with respect to endothelial dysfunction and PMN-endothelium interactions (26, 35-37). However, the in vivo model requires a longer reperfusion period (i.e., 270 min) to accumulate PMNs in the reperfused myocardium and induce myocardial injury (i.e., infarct size) (26, 3...

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