Increased nitric oxide synthase activity after canine cardiopulmonary bypass is suppressed by S-nitrosoglutathione

Objectives: Hemodynamic instability and generalized organ dysfunction are common after cardiopulmonary bypass in human beings. Previous studies have suggested that alterations of nitric oxide metabolism may be associated with this impaired function. Using a canine model we tested whether nitric oxide synthase activity is increased after cardiopulmonary bypass. We also tested whether administration of a nitric oxide donor can influence nitric oxide synthase activity after cardiopulmonary bypass. Methods: After induction of anesthesia, dogs were randomized to receive cardiopulmonary bypass (n = 12) or to serve as controls (n = 12), They were further randomized to receive a continuous infusion of a nitric oxide donor, S-nitrosoglutathione, or an equivalent volume of placebo. Cardiopulmonary bypass was maintained for 90 minutes, and then 4 hours later dogs were put to death. Cardiac and coronary artery sections were frozen in liquid nitrogen immediately after death for later determination of nitric oxide synthase activity using a citrulline assay. Results: After cardiopulmonary bypass, 4 of 6 placebo-treated but only 2 of 6 S-nitrosoglutathione-treated animals required phenylephrine infusion (3.1 +/- 3.1 mu g/min and 0.2 +/- 0.4 mu g/min, respectively P =.05) to maintain a predetermined blood pressure. Furthermore, after cardiopulmonary bypass, Ca2+-dependent nitric oxide synthase activity in the left ventricle, atrium, and coronary artery did not increase compared with activity in the control animals, but Ca2+-independent nitric oxide synthase activity did increase (P =.005): left ventricle (+28.0% +/- 9.0%), atrium (+45.0% +/- 12.0%) and coronary artery (+17.0% +/- 12.0%), Conclusions: We have found that (1) cardiopulmonary bypass results in increased activity of Ca2+-independent nitric oxide synthase, (2) S-nitrosoglutathione can prevent the increase of Ca2+-independent nitric oxide synthase after cardiopulmonary bypass,and (3) Ca2+-independent nitric oxide synthase may contribute to hemodynamic dysfunction after cardiopulmonary bypass.