Aprotinin is associated with a decrease in nitric oxide production during cardiopulmonary bypass

Background. Cardiopulmonary bypass (CPB) is associated with an increase in airway nitric oxide (NO), plasma levels of tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 beta. Cytokine induction of the inducible form of nitric oxide synthase (iNOS) has been implicated in organ injury. In addition, serine protease inhibitors reduce cytokine-induced iNOS expression. Aprotinin, a serine protease inhibitor, has been demonstrated to exhibit significant antiinflammatory effects. We hypothesized that aprotinin administration during CPB would significantly reduce endogenous airway NO production. Methods. Airway NO was measured during CPB in 10 patients receiving aprotinin and in 10 control subjects. In vitro, aprotinin was added to cultures of a murine lung epithelial cell line and was stimulated with cytomix a combination of TNF, interleukin-1, and interferon-gamma. Results. Airway NO concentration was increased after 50 minutes of CPB duration compared with that measured at 5 minutes in control subjects (53 +/- 5 versus 19 +/- 3 parts per billion, P < 0.05) but not in the aprotinin group (21 +/- 6 versus 15 +/- 3 parts per billion). Aprotinin reduced nitrite concentrations in the cell culture supernatant fluids after 24 hours (cytomix, 21.5 +/- 2.1 mu mol/L; cytomix plus aprotinin, 2.7 +/- 0.6 mu mol/L, p < 0.05). Immunohistochemistry showed a reduction in cytokine-induced iNOS expression and Northern blot analysis showed a decrease in iNOS mRNA. Conclusions. These data demonstrate that aprotinin reduces NO production in vivo and reduces cytokine-induced iNOS expression in vitro.