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Polymorphonuclear leukocytes (PMNs) have been implicated in postischemic myocardial injury and associated derangements in contractile function. To examine the direct effects of PMNs on cardiac function, isolated right ventricular papillary muscles of the rabbit were exposed to increasing concentrations of purified rabbit PMNs in the presence of cimetidine. PMNs induced a significant concentration-dependent decrease in contractile function, where 5 x 10(5) PMNs/ml reduced contractile force to 75 +/- 2.1% of control (vs. 95 +/- 5% for time control; P less than 0.005). Similar decreases were also observed for peak positive and negative first derivatives of contractile force. The degree of PMN-induced contractile dysfunction correlated with the activity of the PMNs in an aggregation assay (r = 0.82, P less than 0.01). The loss of contractile function in response to PMNs was attenuated by catalase, which metabolizes H2O2, but not by superoxide dismutase, a scavenger of the superoxide anion. PMNs can convert H2O2 to either the hypochlorite anion or the hydroxyl radical, which are removed by methionine or mannitol, respectively. However, these scavengers did not ameliorate the PMN-induced loss of cardiac function. Exposure of papillary muscles to H2O2 resulted in a concentration-dependent decrease in contractile function where 100 microM reduced contractile force to 78 +/- 4%, an effect prevented by catalase. Thus PMNs reduce the contractile function of isolated papillary muscles probably by the release of H2O2.

Necrotizing enterocolitis (NEC) was produced in anesthetized rabbits by transmural injection of intestinal loops with an acidified solution of casein and calcium gluconate, mimicking the luminal milieu of afflicted neonates. Intravenous infusion of superoxide dismutase (SOD) 15 min after NEC induction prevented intestinal damage. In ex vivo perfused intestinal loops, we determined the sites of eicosanoid release and their contribution to the vascular effects of N-formyl-methionyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF) in damaged and SOD-salvaged intestine. The vascular effluent was the primary site of stimulated eicosanoid release. The vascular responses to fMLP (vasoconstriction) and PAF (vasodilation) were not altered by SOD, although vascular resistance was higher in the SOD group. SOD treatment attenuated 1) transmural fluid shifts in ex vivo perfused intestinal preparations, an index of vascular permeability, 2) fMLP-induced prostaglandin E2, 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and leukotriene B4 (LTB4) release, and 3) PAF-induced release of 6-keto-PGF1 alpha and LTB4. Stimulated thromboxane B2 release was not altered by SOD. Thus NEC can be established by a luminal insult that causes local generation of free radicals and exaggerated release of prostaglandins and leukotrienes.