To investigate the precise hemodynamic effects of purified human plasma kallikrein, small doses (0.3 U/kg) of this proteolytic enzyme were infused over 10 s in five pigs. Hemodynamic performance was evaluated by means of a Swan-Ganz catheter, and parameters of the plasma kallikrein-kinin, coagulation, and fibrinolytic systems were determined by means of chromogenic peptide substrate assays. The infusions of plasma kallikrein were followed by rapid decreases in mean arterial pressure (to 43 +/- 2% of baseline values) and increases in cardiac output (to 145 +/- 6% of baseline values), accounting for marked decreases in systemic vascular resistance, to 28 +/- 1% of initial values. Heart rate, mean pulmonary arterial, central venous, and pulmonary capillary wedge pressures did not change after the injection. Pulmonary vascular resistance decreased to 69 +/- 3% of baseline values. The hemodynamic changes gradually normalized during the following 10 min. Functional levels of prekallikrein, kallikrein, kallikrein inhibition, prothrombin, antithrombin III, plasmin, and antiplasmin were not affected by the injection or the resulting hemodynamic changes; the hematocrit and the number of circulating leukocytes or platelets were also unaffected.
In order to investigate the importance of potential mediators of pathophysiologic derangements in endotoxemia, we have examined the effects of the combined administration of antagonists against histamine, serotonin and endorphins in a porcine model of endotoxemia. The treatment regimen significantly reduced the increase in pulmonary artery pressure, pulmonary vascular resistance and systemic arterial pressure seen in the early stages of endotoxemia. Also, cardiac output was better maintained. However, the hemodynamic performance after an observation period of 5 h was not statistically different from untreated animals. The treatment regimen did not hinder the activation of the kallikrein-kinin and fibrinolytic systems of plasma, which was evident in both treated and untreated animals, and could not counteract the increase in hematocrit or leukopenia seen in this model. This study shows that the combined blocking of histamine, serotonin and endorphines is not enough to abrogate the detrimental effects of endotoxin in a porcine model.
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